Full Transcript - 2019 Investing in Cures Summit - March 2, 2019

Welcome and Opening Remarks

Male:                          

All right. It's too early. It's too early. We do have a jam packed day today so we are going to get started. We have a very special opening this morning, as the field is changing and evolving so must the tactics and importantly the strategies. It's something that we say all the time our mission at the Foundation Fighting Blindness isn't just to understand [00:00:30] the basic science, it isn't just understand innovations, but it's really to identify treatments and cures for patients. In order to do that we have to be able to have influence and to play our part in accelerating things all the way through.

This morning one of our newest initiatives is going to be presented to you that’s the RD Fund and that is really the opportunity that we have as a foundation to play and on a significant role at the later stages of [inaudible 00:00:57] accelerating getting them into [00:01:00] patient’s hands. The gentleman I'm going to bring up at the moment is a terrific addition to the team. His name is Dr. Rusty Kelley, he’s been with the team for about six months now. I don't think his worn socks one of those days in the six months that he’s been here. But it's just a testament to who he is. His title is the vice President of Investments & Alliances with the foundation. Essentially, he's responsible for all of the external opportunities that strategically align with our mission. He's got a PhD and an MBA. He's a very intelligent and articulate gentleman. I’m excited for him to share with you a little bit about what the RD Fund is and what we're doing with the RD Fund so Dr. Rusty Kelley.

[Applause]

Dr. Rusty Kelley:         

Good morning. Should we go from our show pony Jason Menza to your show mule Rusty Kelley. Welcome I guess as the folks pour in you’re in basketball country so we have to ask does anybody in this room care about the Carolina and Duke rivalry. Carolina, Duke All right [inaudible 00:02:26]. I just wanted to [00:02:30] tell you a little bit about the RD Fund, the RD Fund was ratified last October as the investment vehicle of this continuum that FFB is created from a granting and early basic sciences to the translational activities. The RD Fund is intended to capture some of those activities, some of those technologies that are coming through the [00:03:00] FFB funnel. We are open to outside investments as well, but one of the original intents was to really harvest some of the activities that there were emanating from the foundation.

Born out of the foundation, we share the mission of developing preventions and treatments and cures for RDs. We are solely focused on inherited retinal diseases and dry MD, we are therapeutically [00:03:30] focused. We're not involved with diagnostics or devices, etc. We are geographically agnostic and in fact, two of our investments are overseas and these companies are present in the audience today. We've raised $70 million thus far. We've committed about 25 of that. Half of that's been called and we were still raising funds. We're hoping to get to 100 million [00:04:00] plus by the end of this fiscal year.

Our objective is not to leave these investments. We will co-lead of course, but we want to leverage our funding to attract big larger capital, whether that's bigger VC funds or strategics. It's all about leveraging the FFB resources. We consider ourselves as a strategic investor. [00:04:30] some would call it smart money and that's that we are leveraging all of the FFB resources and that's most importantly our people. We have a fantastic scientific advisory board. We have great internal, scientist and leaders across the ophthalmology space. We have great FFB board and the RD Fund has an independent board. We are a nonprofit [00:05:00] structure where the FFB is the sole member. We're nonprofit and this is an evergreen like fund at the moment where any return on the investment comes back to the foundation to further its mission.

Our allocation size, it varies. The three legacy investments that we've made and [inaudible 00:05:29] sparing vision [00:05:30] for larger investments but moving forward our bite size or allocation, is in the range of $2 to $5 million. That's the initial investment, of course, there's a reserve strategy to invest and follow on rounds. We're open to a variety of financial transactions, whether that's taking an equity stake in the company or a code development strategy where we share cost and it's on a project basis. Any return is negotiated [00:06:00] towards the end of the process of commercialization.

I think, leveraging the great work of the foundation is really key to our strategy. The foundation has created a natural history studies, has its own registry for [00:06:30] phenotyping and genotyping patients. It has a clinical consortium. Of course, the great people we have Ben Yerxa as the CEO of the foundation as well as the RD Fund. We have a terrific and very diverse RD Fund board from those who've been CEOs of an ophthalmology companies to ophthalmologists that are on our SAB. [00:07:00] We have founder and a manager of a large private equity firm. It's very comprehensive and excellent board.

Let's see, what am I missing here? I think the space that we're in is growing the venture philanthropy tactics out there [00:07:30] with the JDRF,ACS leukemia, lymphoma society. FFB has really kind of stepped into this space in a big way. Some I'm going to stop there and ask the audience if there are any questions.

Male:                          

Hi Rusty.

Rusty Kelley:               

Hi.

Male:                          

My name is Benedict [Inaudible 00:08:20] I’m just wondering if this is a great [Faint voice 00:08:22] how do you stop there? Are you getting help from external threshold [00:08:30] fund advisor or you’ve got to make it on your own. Like I appreciate might be following on investments. How would you decide to invest in.

Dr. Rusty Kelley:         

It's a great question. I will repeat the question, the question was how do we pick the investments? How are they sourced and selected? The companies are coming to us, as I said earlier, they're coming to us [00:09:00] through our FFB pipeline. But the ecosystem that we're in with all the major venture capitalist that play at this stage particularly those that are investing in ophthalmology companies, those deals were coming to us via those investors. It’s a great ecosystem that we’re in. The foundation itself is producing a lot of activity [00:09:30] and, of course, with our international companies and VCs there's lots of activity there as well. Did I answer your question?

Male:                          

Do you -- are you planning to get any third party, what I called VC help with [Inaudible 00:09:54] internal process.

Dr. Rusty Kelley:         

Well, as a co-investor with VCs we are obviously getting their help as lead investors. Ben, you have any comments there.

Ben:                            

We’re basically doing ourselves, we’re essentially doing ourselves. We’ve got a lot of [inaudible 00:10:12] based on our position in the community. [inaudible 00:10:15] background in all these different areas really allows us to function like [inaudible 00:10:26] investment company. It's pretty similar, it's a little bit [00:10:30] different it’s a [Inaudible 00:10:31] but that’s kind of how we’re structured.

Male:                          

Thank you.

Dr. Rusty Kelley:         

Great. Well, guess we'll move on. There's a question, yes, sir.

Male:                          

[00:11:00] Rusty I was just going to ask is there a minimum investment level for the RD Fund?

Dr. Rusty Kelley:         

I think the minimum investment level is probably in the $250,000 range. But are we moving forward and we've kind of classified our bite sizes, two to $5 million, and that's the initial investment. Of course, these are therapeutics that we're developing, which require hundreds of million dollars [00:11:30] to get to the patients. We have to have a reserve strategy and think about each of these deals as the circumstances, but think about their exit strategies that optimal exit strategy for each of these companies. There’s question over here.

Female:                      

If somebody had let's say [00:12:00] two to five million, how would they decide if they're giving that money to the foundation directly or to the RD Fund?

Dr. Rusty Kelley:         

That's great question.

Male:                          

It's a good question. The RD Fund set up as essentially a 100% donation to vehicle tax deductible, just like you make a donation to the foundation, you can direct it to the foundation for research or you can [00:12:30] direct it to the RD Fund for investment. We have the companies that you’ll hear about today. It's okay with us either way, you want to direct those, essentially. The stuff in the RD Fund is going to be a little bit later stage and some of the more foundational work that we're doing at the academic level is absolutely critical make sure we have a pipeline of companies to invest in later. We really want to build on both sides in the house, [00:13:00] you want to think about that, right? But of course it's up to the donor to decide how they want to drag those funds. Does that make sense? Other questions?

Dr. Rusty Kelley:         

Great, thank you very much.

[Applause]

Male:                          

Just enjoy your breakfast. We'll take about 15 minutes before we get the main program underway, so enjoy.

Inherited Retinal Disease Science Landscape

Brian:                         

If I could have the first slide please. Well, good morning everyone. It's a delight to be here today to tell you a little bit about the clinical landscape, what we have currently going on in clinical trials. I'd also like to tell you a little bit about some of the new emerging technology that's coming along. Then finally tell you just a couple of things that the foundation is investing in to accelerate the transition of research into clinical trials. [00:00:30] Can I have the first slide please?

The first slide is a blank slide. It's black and I just want to set the scene that in 1971 this is some total knowledge of inherited retinal diseases. Okay, we don't know the cause. We don't know the mechanism of disease. We don't know the genes. We have no treatments. We have no therapies, and the message as you heard last night [00:01:00] from the two blind brothers was pretty blend. Go home, learn Braille, you are going to go blind. I think in that setting now as we move forward, it's a really exciting time. Next slide.

In 1971 which was just three years after the National Institutes of Health had actually been established, a group of affected families decided that it was time for change [00:01:30] and that there needed to be an injection of money and drive into this area to bring research that would lead to clinical trials. A team of people led by Gordon and Llura Gund and Ben and Beverly Berman decided to establish the first dedicated center for research and clinical study of the inherited retinal diseases. That was the Berman-Gund Laboratory at Mass Eye and Ear headed by Eliot Berson. [00:02:00] It's a wonderful thing to think that since then this together we've raised $750 million. That is been invested to accelerate early preclinical research to get it to a stage where companies or industry would be interested in picking up the more expensive part of getting these into clinical trials and approved drugs. Next slide.

This slide is summarizing [00:02:30] the sort of explosion in knowledge that has occurred since the formation of that group of people who turned into the Foundation Fighting Blindness. It took until about 1990 until the first discovery identified the first gene that we knew to cause retinitis pigmentosa. For a brief moment everyone thought, ah we've done it, we've got the gene, we're going ahead. Then as the science [00:03:00] kicked in, there was this rapid linear increase in the discovery of additional genes, until now 2019, we're looking at 270 genes. We have a very large family of diseases that are captured by an inherited retinal diseases.

Retinitis pigmentosa is not one gene disease, it's a many gene disease. There are many different ways of [00:03:30] addressing this to treat it. We know that we really still haven't got there because we know that we're still, if we do genetic diagnosis, we can only diagnose disease on average in about 65% of people. Some diseases like choroideremia, we have a much higher success rate in diagnosing, others of course like Autosomal recessive, much less. We've come a long way in our understanding, we still have a long way to go.

Now I'd like to tell you about what is out there [00:04:00], what is actually approved on the market, and there are some things out there already. The first thing to be approved was the retinal prosthesis which was developed by a company called Second Sight. It's called the Argus II prosthesis and basically it's a little electronic chip that goes in your eye when you've lost a light sensitivity. It detects light and signals that light back to your brain and gives you a cent perception of light. It enables mobility [00:04:30], it gives you a crude resolution so you can see shapes and you can move around without bumping into things, but you're not going to be reading the New York Times with this device. But it's a step forward and it's a very positive thing. In fact, the foundation was involved in seeding money into the early research that led to the proof of concept that led to that product.

The second one product that you all know about, I'm sure it's on the market now in the U.S. [00:05:00] is Luxturna developed by Spark Therapeutics. It's a gene therapy for diseases caused by the RPE65 gene being mutated. Again, the foundation is very proud that the money that was raised through the foundation, $10 million was actually invested into the early preclinical research across a number of groups working in this area and brought it to a stage where Spark Therapeutics were willing to pick it up and carry it through the later clinical trials. [00:05:30] Of course we all know that it was approved in December 2017 and is now available.

In Europe, there are a couple of other devices which are not available yet in the U.S. There are two additional prosthetic devices. One called the IRIS II the other called Alpha IMS. These are said to have perhaps slightly higher resolution than Second Sight who were first on the market. They are currently seeking to get into the [00:06:00] U.S. market also. Finally, in the U.K. there is a gene therapy that did not go through the normal route of multiple clinical trials because the number of people affected by this disease, which is caused by a mutation in the AIPL-1 gene is very small. There is a specials license that allows people who are identified and named to be approved on an individual basis to be treated. Actually there are two gene therapies out there already, so [00:06:30] a total of five products. Well that's great, we've got a long way to go obviously.

Let me talk you through now some of the things that are in the clinical trials. In particular, I think you've heard that there's so much activity at the moment in gene therapy. In fact, in the gene therapy we have 13 different genes currently in clinical trial and between them they represent 23 different clinical trials going on. For instance, LCA there are two genes that we're looking at [00:07:00], the AIPL-1 and the RPE65 gene. Now I know RPE65 is approved. This is an alternative gene therapy for RPE65. It's a competitor on the market. For choroideremia, sorry, is the REP1 gene therapy and of course the foundation has been instrumental in investing in that gene therapy.

There are several studies for choroideremia. One of them now is in phase three. Most of these are in phase one looking at [00:07:30] safety and tolerability, but that's an exciting step forward. Leber’s hereditary optic neuropathy, we had the ND4 gene therapy. There's a gene therapy for Stargardt disease, ABCA4. There are two for achromatopsia, CNGA3 and CNGB3. There are three for autosomal recessive RP is MERTK, PDE6 Beta, and ROBP1. And then there is X-Linked RP, RPGR, foundation again [00:08:00] seeding that work, X-Linked Retinoschisis RS1, foundation again seeding that work. Finally MYO7A for Usher syndrome 1B, again, another of those projects the foundation has been supporting.

For those who are looking at this chart, you're going to be seeing some of those lines have a lot of companies involved. AIPL-1 has MeiraGTx a sole company. But look at REP1 for choroideremia, there are three different companies [00:08:30] there. You know what I think this is really exciting, it says that companies want to be in our space. They're actually competing on the same products to get into this space. Obviously we've generated a lot of interest and we're drawing a lot of industry into this. By the way, these are the ones in clinical trials, but there are actually more than 75 different gene therapies in the preclinical research stage. Next slide please, thank you.

Gene therapy [00:09:00] like that gene augmentation is great if the photoreceptors are alive and you just need to pick them into gear again. But what happens if you've lost light sensitivity, you've lost your photoreceptors and they can no longer respond, so you can't treat them with gene augmentation therapy. Then there's another genetic technique called Optogenetic Gene Therapy and this is where you take a light sensitive protein from the bacteria of all things. Now bacteria don't see but they use light to [00:09:30] navigate around in their environment. You take that and you've put it in a gene therapy vector and you introduce it into the retinal cells. It can restore light sensitivity to the remaining cells in the retina. The cells that normally don't sense light are now being turned into light sensitive cells.

You can think of this like the biological form of the prosthetic and it's probably going to give us a higher level of visual acuity. There are two clinical trials [00:10:00] at the moment, one for a gene called Channelrhodopsin-2, ChR2, and another one for a gene called Crimson. These are both being developed for late stage RP, so these are people who've lost that light sensitivity.

Another technology that I'm sure you've all heard about is CRISPR/Cas9, the gene editing [00:10:30] technology. There are many ways that you can use this amazing CRISPR/Cas9 technology. But one of the most common ways is what we call a cut and paste. The CRISPR is essentially a pair of molecular scissors and there are ways in which you can guide it to find the mutated gene in the retina. Snip out the mutation and replace it with the correct piece of DNA, so you're editing it and putting it back. It's like in a computer where you just go in and edit [00:11:00] your spelling mistake.

Now these technologies tend to be specific to mutations. It's no longer addressing my gene is wrong, it's my gene and a very specific mutation is wrong, but very exciting technology. The company called Editus is close to the clinical trials now. We expect it anytime for SEP-290, which is a course for Leber's congenital amaurosis and a very particular mutation called Cys998X.

Another version of CRISPR technology [00:11:30] is using this technology to do base editing. For those of you who go back to the era of typewriters, it's like whiting out and typing over. For those who use computers, it's backspacing and typing a correction. But you can actually do this at a molecular level using these molecular tools based on the CRISPR/Cas9 technology. While these are not quite in the clinic yet, there's obviously one coming, there is a large of related programs coming [00:12:00] through which the foundation again is funding to encourage them to get into the clinic.

Another technology that again I'm sure you're going to be hearing about as the panels talk today is targeting RNA and things called nonsense mutations. Now RNA is basically the copy of a gene that is used when you're trying to make a protein in a cell. There’s one type of mutation called a nonsense mutation [00:12:30], it's nicely named actually because what it does is it disrupts the RNA. When it's making the protein it bumps into nonsense and stops and leaves you with a dysfunctional protein.

There are now technologies of small molecules and you'll hear I'm sure from Elox [PH] today who are developing these small molecules that can basically camouflage that mutation. When the cell is trying to make the protein that nonsense mutation is hidden and the machinery [00:13:00] runs on over that mutation and continues to make a good functional protein. Now the beauty of this technology is that these sort of nonsense mutations occur in all of the different genes that are implicated in the inherited retinal diseases and they represent about 10% of all mutations. The promise of this technology when it comes to clinic is it could be a PAN disease therapy that is going to impact 10% of patients [00:13:30] which is very exciting. Again, the foundation is forging collaborations and investments in this area. Could we have next slide please?

So now let's shift gears a little bit and talk about self-therapy. Gene therapy technologies are fine when the cells are there, the cells are viable. But what happens when you lose the cells, you lose the photoreceptors, you lose those RPE cells [00:14:00] that support the photoreceptors. The other approach that you can think about is self-therapy based essentially in stem cells. There are a number of different types of stem cells that you can use, so let me walk you through a couple of them.

You can get stem cells out of eye organ donors. You take a donor retina and you can find stem cells in there and you can grow them up in the laboratory. You can induce them to develop [00:14:30] into the type of cell that you want, whether it's a RPE cell or a photoreceptor. Then you can take those cells and inject it back into the retina and hope that they integrate properly and they restore visual function. There are two companies who are in clinical trials at the moment. One called jCyte, one called Dendreon who are developing this sort of retinal precursor stem cells, we call it, for retinitis pigmentosa.

Now there's another type of stem cell that you can get. This [00:15:00] is where instead of taking organ donor eyes, you can actually take embryos and these are human embryonic stem cell. They are being developed in the same manner, you grow them up in the lab, you differentiate them the way you want to and then put them back into the eye. There are a number of companies doing that. I've highlighted just three here for you. Astellas is working on developing this so they can treat Stargardt disease. Then companies like Regenerative Patch Technologies [00:15:30] and other groups are developing for AMD. In fact AMD is where everyone's focusing a lot of their attention because it's actually one of the easier diseases to treat, but once it's proven that technology is directly translatable into these ones.

Then finally there's a different type of stem cell that you can create just by collecting blood or scraping a bit of skin off of your hand, and that is induced pluripotent stem cell. What you do is you take a mature [00:16:00] cell like a skin cell and you encourage it to remember when it was once a baby, an embryo. When it gets to that stage, you can then grow it up in a Petri dish and you can induce it to turn into a retinal cell, which you then introduce back into the eye. There's a group the RIKEN in Japan who are doing that again initially targeting age related macular degeneration.

Now of course the foundation has got a very large investment in this area. Both jCyte [00:16:30] and Dendreon have been supported by the foundation during their early preclinical research, getting there, helping to accelerate their discoveries to get into the clinic. jCyte you may know a while ago reported very positive results in their safety study. They did a 12-month study with 28 patients and it seemed like this therapy is safe. You can actually transfer cells like these, you don't have rejection problems, and what’s more and was very [00:17:00] exciting that they showed that there were trends of improvement in visual acuity. In fact the FDA has encouraged them to up the number of cells they put into the eye to see if they can do even better as they move forward into their more advanced phase two, phase three studies. There are over 20 cell therapy trials ongoing at the moment in the clinic related to the retina mainly focused on RPE cells and AMD. Next slide please.

Now another way [00:17:30] of another therapeutic approach, a small molecule drugs, an easiest way to think about these are they are the drugs are most used to your Aspirin, your Motrin, your Statins. These are small molecules which interact along biochemical pathways and a multitude of different ways. While I don't have time to go into the way all of these work, I wanted you to get the sense that this is also very active area of research that the foundation is also supporting. At the moment there are more than eight of these new [00:18:00] small molecule drugs in the pipeline. Just to give you a sense of where they're being targeted, there's a version of vitamin A which is being used to try and treat retinitis pigmentosa and Leber’s congenital amaurosis due to specific mutations actually in the RPE65 gene and the LRAT gene. That is actually a phase two study, so this is getting down the line now in clinical trials.

There's another type of vitamin A that are little bit different [00:18:30], which is also in phase two trials, which is being developed to treat Stargardt disease and age related macular degeneration. Then there are some other ones here, I won't describe their mechanisms, but there's another four small molecules which are being targeted Stargardt disease, two more of those are in phase two. Stargardt is really doing well here. The five drugs being developed for Stargardt all in fairly advanced clinical trials. Then [00:19:00] there's retinitis pigmentosa. This is an attempt to find small molecules to work no matter what the genetic cause of RP. These are NACA or NAC which are related.

I'm sure you're going to be hearing from the [inaudible 00:19:14] today about the NACA work. Again, NACA and NAC as they’re called are projects, which again, receiving investment for foundation accelerating them through clinical trials and in fact with NACA, helping them in the first early phase [00:19:30] clinical trial of safety. You're also going to be hearing today about a promising pipeline of other PAN disease approaches. One of the companies is going to be Nine Therapeutics [PH] has a small molecule. Another one will be Maraka Medicines [PH] who have a small product also. Thank you.

So now what I'd like to do is change away from that very quick overview of what’s in the clinic, what's coming, what technologies are out there to talk about a couple of [00:20:00] other ways that the foundation is trying to make sure that research gets into the clinic. The first one is a very important issue if you're trying to run a clinical trial, which is you've got to find patients. Now if you're doing diabetes or cancer, it's not too hard to find patients, you probably passing them in the street every day. But when you're dealing with rare diseases like we are, it's much harder to find the patients. They're scattered around and they are in many different locations, seeing many different [00:20:30] doctors. If you're trying to design a clinical trial, it's actually a challenge to find the people you need to run the clinical trial.

One of the things that the foundation has done is it set up a registry, which is called My Retina Tracker. I hope you're all members, if not, there's information in the back of the brochure today that will tell you how to go online and join. Well, what a registry does is it tries to answer and supply solutions to the questions that industry asks. What is the best [00:21:00] disease to test my technology on? I don't want to waste my time testing it on the wrong disease. How many people, when I found that target are actually affected? Where on earth are they? Who's looking after them? How do I get in touch with them? I just don't want to sit on the phone for weeks and weeks phoning clinicians who are very busy asking do you have X? Please go and look and chasing it up.

Also, the registry tries to capture what impact does that disease have on a patient's life? [00:21:30] What's the patient really wants a treatment? Is it really better visual acuity or actually are there other characteristics like social interactions, which are much more important? That's what we tried to capture. What is meaningful for patients? This registry has been growing very rapidly. We grow at about 350 new members a month continuously. I hope that after this meeting we're going to see a real bump in membership from today's meeting.

We have 22,000 members, 11,000 of which who shared a reasonable amount of information [00:22:00] about their disease. By the way, this is international, we have about a 1000 people overseas who are in this registry also. Now because of the genetic data is so important, we also at the moment are running a genetic testing study in this registry where we offer free genetic testing and free genetic counseling for people who are in there who don't know their genetic diagnosis. At the moment, we've tested over 3200 people in a very comprehensive gene panel test, and it's resulted [00:22:30] in 30% of the people in this registry knowing their genetic disease. Here is a wonderful resource for industry, one phone call to one person to find out where those people are, who their clinicians are, and in fact we have ways of helping them contact you if they are interested in you for one of their studies. Last slide please.

The other thing that I'd like to talk about to end is the clinical consortium. We've talked about how you find rare patients and that's [00:23:00] great, that saved you a lot of time and money. But clinical trials are very expensive and so when you set up a trial, you've got to think about what you need. First of all, you need multiple independence clinical sites to run your trial for you. There's a cost there and getting them all up to speed. Secondly, you need to have clinicians who really understand this disease. This is not a disease that most retinal specialists or ophthalmologist or optometrist see. You really need to have people who are devoted [00:23:30] to this group of diseases, studied them and understand them, understand the issues and the clinical measures that are appropriate.

You need those sites to have standardized medical instrumentation so that you can get a set of cohesive data, which is convincing to the FDA. You need them to operate those -- that equipment with standardized protocols. They've got to understand what is the right measure to know we've actually changed the course of this disease and that we're not just giving drug that is not really doing anything. [00:24:00] They need to be an understanding of disease progression and variability.

Finally not every clinician can participate in a clinical trial. It takes a special expertise to be aware of the rigor, the documentation that is round about controlled study that is going to be convincing to the FDA. Finally you need to have a uniform interpretation of the data that these sites are generating. If you've got it from that list, that's a very expensive list. Whenever you [00:24:30] start a clinical trial, if you've got to go and set up each of these components as a company, you're facing a big upfront expense before you even get to the actual trial itself. The foundation has invested in creating a consortium which is currently 20 clinical centers of excellence, which meet all these criteria for the inherited retinal diseases. They are now there clinical trial ready and we fund them also to do research, natural history studies.

At the moment we're looking at the ASH2a [00:25:00] gene. There's a study on the rate of progression of Usher 2A, and what is a good measure of when you slow or stop that progression? In the past, many of the groups that are in this have also done natural history study and end point, as we call it, analysis on Autosomal dominant RP and also Stargardt disease. That's already ordered a lot of information that's going to be useful for clinical trials.

If I could have the final slide [00:25:30] I hope that I've shown you how the foundation is investing a lot of money to support a lot of different shots on goal. We've been very successful, we're getting into clinical trials, there's a long way to go. But I think it's great, it's really an exciting time to be in this field. What really excited me was when Ben Yerxa when he arrived at the foundation challenged me to just put together a list of some of the companies in our space, Brian and see what it looks like.

This is what it looks like for anyone who can see [00:26:00] it's a crowded space and I actually have to admit I ran out of space. We have more than 50 biotechs now who are committed to doing this. If you ever hear another talk, I'll tell you why the eye is such an attractive thing to be working in at the moment, but that's another talk. But anyway, I think that this is a really exciting time, there's a lot of industry commitment, there's a lot of activity within the foundation. It's all due to people like you, the donors who are driving this forward for us and also sharing [00:26:30] what's important in treatments and therapies and cures that we need to tackle these diseases. Thank you.

[Applause]

Male:                          

That was fantastic. Thank you very much Brian. One housekeeping note, I wanted to make sure that was a fantastic baseline of understanding and current depiction of what's happening in the landscape. [00:27:00] Everyone who's here today in the weeks ahead we will send out a link that will have access basically to all of the audio recordings of all the presentations today and we're going to transcribe all the presentations as well. If you didn't have the opportunity to digest everything that Brian just went through, there'll be another opportunity you have in private to review that information. I wanted to also take the opportunity to, again, thank our generous sponsors at MeiraGTx and Elox so thank you very much for supporting us today, letting us put on this program.

[Applause]

Male:                          

We're now going to shift to the bulk of the program today. The way that we designed the program is to essentially follow the life cycle of a potential therapeutic. I use this analogy often that it's like a relay race. Essentially, a program begins at one stage, it's preclinical [00:28:00], it's in academic institutions typically. If a particular program does well, it then graduates to what we would call the translational stage and then eventually moves into the clinic. If it does well, it eventually that little biotech that brought it into the clinic may go public. If they do well then they are participants in what we call the ecosystem. The way that the program is lined up today kind of mirrors that path.

We're going to start right now [00:28:30] with a panel on the science updates, which is more of that first stage. Then as the day goes on, we're going to move into the translational stage. It's just when those programs move from preclinical to the clinical stage. We then have a portfolio updates and emerging biotechs and emerging companies, which are those that have those programs that are now kind of getting ready to come into the market. Then finally we have the public company forum this afternoon [00:29:00] which are those companies that ultimately have these programs, hopefully, in the marketplace. Then the final panel this afternoon will be the ecosystem, which is how all of the different components work together to thrive in the landscape together.

With that, we're now going to begin at the very beginning of the program’s life and that is science and preclinical stage and to help, we've got Dr. Steve Rose. Dr. Rose has been with the foundation [00:29:30] since 2004. He is well known by I think everyone in this room. He's a legend and he manages really all of the relationships in the scientific arena. Please help me welcome Dr. Steve Rose.

Inherited Retinal Disease Science Updates Panel

Interviewer:                

Thank you, Jason. Chief science officer at the foundation, 14 years, Brian showed you 1971 as a blank. What I can say is when I started back in 2004, we certainly knew more, but there was really a week when we talked to you was about Hope. Now as Brian has shown you there is so much going on in the clinic, it's absolutely such an exciting time.

Our panelists now, as Jason said, we're starting at the beginning, which is the discovery science. We have four different topics we're gonna be talking about. We have doctor Joe Carol from Wisconsin who's going to be actually talking about noninvasive imaging, which is really important in clinical trials and understanding retinal degenerations.

We have Leah Byrne who's going to talk about optic genetics and you heard about that from Brian already. Eric's going to talk about gene and genetic therapies. Trevor Miguel [inaudible 00:01:19] is going to talk about cellular therapy. With that, I'd like to bring Dr. Leah Byrne from University of Pittsburgh Medical Center up to talk about optogenetics.

Dr. Leah Byrne:      

Good morning everyone. First of all, I'd just like to say thank you so much to the FFP, to Steve for bringing me here this morning. I had a wonderful dinner last night and I am very excited to be part of the panel this morning and to talk a little bit about optogenetics for vision restoration. Let's see, try this. Great.

It's been really well established at this point that gene therapy is a highly promising approach to treating inherited retinal degeneration. In cases in which photo receptors, is it a light sensitive cells in the retina or kind of past the point at which they can be rescued, or those photo receptor cells are missing.

Gene replacement strategies or strategies even like genome editing are no longer really applicable. In cases like those optogenetics, there is actually a very promising approach to restoring light sensitivity to the retina.

Optogenetics is unapproached where we have identified these lights sensitive proteins called [inaudible 00:02:45] from things like algae, and bacteria, and also from animal cells. Optogenetics is the ectopic expression of those light sensitive proteins in other cells in the retina that are not normally light sentence sensitive.

In other words, it's a way of making artificial photo receptors in the remaining cells in the retina and so that can restore a bit of visual processing the retina and also restore a signaling to the brain.

Now I think I've gone too far. We'll see. One of the main questions in the field of optogenetics is actually which type of cell it's remaining in the retina to target for optogenetic strategies. People have thought about using almost every cell type in the retina to target for these optogenetic strategies.

There are two main cell types that have sort of emerged as the leading candidates sprout to genetic therapies, and those are on bipolar cells or retinal ganglion cells. A lot of the work in the field has really focused on these two cell types.

On bipolar cells are cells that are just right next to the photo receptors are a little bit further upstream in the visual processing pathway, and they're really good targets for early stage retinal disease. These are, as I mentioned, located upstream and we have tools to selectively activate these on bipolar cells. Again, it's a way for us to maintain a little bit of retinal processing.

However, in retinal degenerations, after photo receptors are missing on bipolar cells often go through a little bit of  remodeling. They change their morphology a little bit and change the types of proteins that the cells are expressing. In contrast to bipolar cells which we remodel a little bit, retinal ganglion cells are a little bit more robust to that retinal reorganization. They're maintained a little bit better in late stage retinal degenerations.

These are cells that are located right on the surface of the retina and so they're very easy to target with the viruses that we use to deliver optogenetic genes. They also have very large cell bodies which enables us to deliver a lot of these optogenetic proteins, which may increase light sensitivity. Those are two different kinds of cells that are main targets for optogenetic therapies, and one cell maybe better for a certain type or certain stage of retinal degeneration than the other.

There are many other factors that go into determining the success of optogenetic strategies. Those include factors like the method that we use to deliver the optogenetic tools to the retina as well as the type of ops and protein, the type of optogenetic tools that were actually expressing in the retina.

The method that's most commonly used to deliver optogenetic tools to the retina is to use a virus, that it carries the gene and coding the ops and protein, and the virus that's the most commonly used as a virus called Adeno Associated Virus or AAV. AAVs you've probably heard about them before. They've been proven to be very safe and efficient through the very successful clinical trials for gene therapy, like for LCA2.

Naturally occurring serotypes of AAV viruses, they didn't evolve for millions of years to be gene therapy tools. They're actually not optimally efficient for targeting these particular cell types that we want to deliver our optogenetic tools too. There's a lot of work in the field, around reengineering these viral vectors to be better able to target bipolar cells and RGC cells for example.

I'd just like to mention that this is work that the FFP is actually funding in my lab, engineering new viral vectors to more efficiently deliver optogenetic tools in the retina. I just wanted to say that we are incredibly grateful for that support and really excited about this project that we have going on in the lab, which is to create a very complete toolbox of vectors-- AAV vectors that will really allow us to target every cell, type in the retina and really fine tune these optogenetic strategies.

Also viruses they don't naturally infected just one particular cell type. They tend to be more promiscuous and in fact many cell types all at the same time. You have to partner an AAV with a genetic element that's encapsulated inside the vector called a promoter that drives expression of the optogenetic protein in a specific cell type.

In the images you see here in the middle of this slide, you can see the effect of choosing a good promoter. There's an image on the left showing a lot of expression of a reporter protein, this green fluorescent protein, in an animal eye in the retina. On the right, you see how the use of a promoter, in this case, it's a promoter of for on bipolar cells from the Pan lab, which has an unpronounceable name, but it doesn't matter. It's a promoter that works extremely well for targeting a gene expressions who on bipolar cells, in mice and in pig retina, the dog retina and primary retina. This is a pig retina that you see right here.

The last element that really determines the success of a optogenetic therapy is of course the choice of the opsin proteins itself. Over the past few years, the toolbox of opsin proteins that's available to us has really expanded a lot. There are quite a few different optogenetic tools that we can choose from. There are channelrhodopsin, these are one component systems that had been identified from algae and bacteria for example. These are directly coupled to an ion channel.

What's really interesting I guess about these is that they are very fast, so they're directly coupled to an ion channel. They have a very fast temporal resolution. However, nationally a lot of the channelrhodopsin that were originally identified are maximally activated by blue light and they require a lot of light to be activated. The amount of light that they need is potentially dangerous to the retina.

There's been a lot of work in the field surrounding identifying other opsin molecules that can be activated by more red shifted light or more sensitive to light. Those are proteins like [inaudible 00:09:37], which I mentioned on this slide, or [inaudible 00:09:39]  which you heard mentioned, which is now moving into clinical trials.

There are also other kinds of opsin proteins that are multicomponent systems, and those are a G protein-coupled receptors that when activated can activate this signaling cascade pathway that really amplifies the signal. These are much more sensitive systems, but they are a little bit more sluggish. The temporal resolution isn't quite as good. There's research going on in the area of identifying other animal opsins G protein-coupled receptors that are faster and so they have a better temporal resolution.

So really putting a lot of effort into creating and engineering optogenetic tools that have the best of both worlds.

I think that the most challenging aspect in the arena of optogenetics is actually going to be clinical translation of all of the work that we've been doing into humans. I think this is something that we're going to be talking about a lot today. We are very, very excited and it is amazing the optogenetic therapies are now moving into clinical trials.

As you heard already today, there's a couple of clinical trials going on for optogenetics, including a clinical trial from RetroSense, which is now owned by [inaudible 00:11:10]  Allegan and [inaudible 00:11:11] Gen site, which is using a protein called Crimson [inaudible 00:11:14].

That's fantastic and the field has really culminated in these clinical trials. Most of the preclinical work that has gone on leading to these clinical trials has been performed in rodent models of retinal degeneration. There are a lot of differences in the way that optogenetic therapies or just gene therapies in general work in mice compared to large animals or humans.

On this slide, this is just an illustration of how just the viral vectors that we're developing perform differently in small animals compared to large animals. On this panel, on this slide, the first three panels are just showing the expression of a reporter gene GFP, from a virus called [inaudible 00:12:04] seven and eight, which we have developed in the mouse eye, and it's been developed to have a very efficient gene delivery in the retina.

In the first panel on the left, you see that there was a lot of GFP expression all the way across in this fundus image in a mouse eye. [inaudible 00:12:20] works really well in mouse eyes and can lead to very efficient gene expression. When you take that same [inaudible 00:12:26] and inject either in a dog eye, that's the second panel or any primate eye, which is the third panel, you see that the [inaudible 00:12:34] performs well but it doesn't express quite as pan retinally as it does in the mouse. There's two arrows there pointing to areas of the retina where [inaudible 00:12:45] is not infecting quite as well.

So just illustrates that things that are developed in the mouse, all that work is incredibly important and a foundational but translation into large animals can be challenging. One of the things my lab has been working on is developing, as I said, viral vectors, that will be better able to deliver optogenetic tools to large animal retinas. I just illustrate, I just had a picture of one of those factors that we've been developing, in the context of the primary eye and it's called NHP 26.

This vector has a couple of very promising aspects. For one, we were able to-- With this vector we can get gene expression with lower titers, so safer titers, fewer viral particles in the eye. We also get more uniform expression around the phobia at these lower titers. This is just one vector and this is actually optimized for photo receptors. There's a lot of work that still needs to be done to create a complete toolbox of AV viruses that work well in the context of large animal eyes that are more like humans.

There are a couple other aspects to that I'll just mention very briefly in clinical translation, such as the immune response, which is very different between mice and humans. Also just the fact that promoters may work differently in the context of retinal degeneration.

So just to summarize it's clear that since 2006 when we first started working on optogenetic therapies, the field has really exploded. We've made an incredible amount of progress culminating in these clinical trials. There's a lot of work to be done, but we have not, I think even seen the feeling of what can be accomplished with optogenetics.

[applause]

Interviewer:

Thank you. The next is Dr. Joseph Carol from the Medical College of Wisconsin, and he's going to talk about noninvasive imaging in the retina.

Dr. Joseph Carol:    

Thank you Steve. It's a pleasure to be here-- How do I turn this slide on? There we go. Now I have four slides. None of the pictures matter. They're just for me to remember what I want to say to you guys today, no pressure here. I'm the outcast here because I don't develop therapies, and so I feel like a bit of a fish out of water, but we work on noninvasive imaging of the retina.

I was struck by Brian's slide when he showed that in 1971 there was nothing known about inherited retinal degenerations. One of the themes though is that a lot of what we've learned about inherited retinal degenerations has come not just from animal models but from histology from donor eyes. That's a really crude way to study disease.

We've spent a lot of our effort on developing noninvasive tools to image the living human retina at single cell resolution so that we can study retinal degenerations either through natural history studies, or in response to therapeutic intervention to assess how those interventions effect the retina at a cellular level.

Basically what we used to do a with a microscope was to-- We could in some settings slice up the retina and count the number of photoreceptors, for example. We could count the and see that in a patient with retinitis Pigmentosa, we can get count that there's fewer rods than there are in a normal eye, or that there's fewer cones in a normal eye. That might vary depending on the stage of disease.

What we have today is a technology called adaptive optics, adaptive meaning you can change optics, but you would think of like lenses and mirrors that take pictures. These are cameras that can change depending on what their imaging in order to give us a very high resolution picture, in this case of the living human retina. We can make those same counts of photoreceptors in patients with inherited retinal degenerations.

Now as I mentioned adaptive optics is our technology of choice. One of the important things for those of you who've had pictures taken in the ophthalmologist's office, you've had picture after picture after picture taken, and it's sometimes quite confusing to know why do we have to have so many pictures of the retina. That is with each of these cameras, they deliver sometimes a different type of light, sometimes using completely different technology for imaging the retina. The way that retinal photography works is it's basically assessing the way that light interacts with your retina.

The real light that comes back to the camera could contain quite different information depending on what type of camera we use. In the case of adaptive optics, it's telling us something about the health of the photo receptor, but in other technology is something called optical coherence tomography that can tell us about the thickness of the retina.

Fundus autofluorescence can tell us about buildup of different materials within the rotten. So it's really is an important concept that none of these imaging modalities stand by themselves. That it's really important that we use all of these imaging tools together to provide a very clear picture of what's happening in one retina versus another retina, or in a given retina over different time points.

Now I want to talk to main points here. How do we use imaging, and why is it relevant to therapeutic development of therapies. First is something we call therapeutic potential. What I'm showing on this slide is pictures from two retinas, from two patients who have Achromatopsia. One of the patients has, and in the images there's little tiny bubbles and those bubbles are the cone photoreceptors that we count.

One of the patients has a few dozen photoreceptors remaining in their very central phobia. The phobia is a center of your vision as you know. The other one has thousands. Neither one of these have any cone function. Clinically they look very similar. They have flat electroretinogram. That's a very common tool. Many of you have probably had an ERG, that measures the function of the cones or rods. In this case it's flat for both of them.

Very poor visual acuity, Nystagmus, photophobia. Clinically these are identical patients, and even their genetics are the same. The numbers of what we would call remnant cells, or be them nonfunctional, is quite different between these two retinas. One might ask that given the perfect therapy that could restore function to all of the cones in one retina, and all the cones and the other retina, would you expect the same therapeutic response, and the answer might be no.

This remains to be seen how we might use imaging to assess the therapeutic potential of a given patient. Now besides choosing the right patient  for a treatment we might think about using imaging to assess the outcome of a particular intervention. In this case, I'm showing a graph, it's not very important. This is from a paper from Jackie Duncan back in 2011 where they looked at using this adaptive optics imaging to count photoreceptors in patients who are receiving a treatment an experimental treatment versus patients who were receiving a sham injection.

What they showed was that in patients who received the sham injection, that has no treatment, that their cones continued to degenerate. In the patients who had received the treatment, the cones remained stable. This wasn't an attempt to grow new cones, and that would be one type of therapy. This was a case just to take the ones that were there and help them hang on. Clinically the vision didn't change in either group. There wouldn't have been any information clinically to say that there was a biological effect of this intervention.

So it shows how more sensitive imaging might be useful to tell us whether there's biological effects of a treatment when in fact there's no robust clinical change, which obviously is what we care in the long run. But it's very important early stage trials to assess whether there are biological effects. Lastly, I think I have a very noisy slide,  again, doesn't really matter.

One of the things that we work on with the support that I got from the foundation fighting blindness years ago was not just to work on taking pictures, because a picture it's just a picture. I train my students to analyze those pictures and they count the cells. We locked them in a room and they look at all these images and count the cells, toil away hour after hour.

Simply counting the number of cells might not be of a particularly valuable measurement for an image depending on what we're trying to detect. Sometimes the cells just rearrange themselves and that's an important change that we want to detect. The take home point for me here is that how you quantify an image, whether it's an adaptive optics image or an OCT image, can really change your picture of what's happening in that retina at that time point.

I think imaging has a very important a synergistic role for those of you developing therapies as we move forward together. I thank you for your time and we'll move on.

Interviewer:                

Thank you Joe. Even though Joe says he feels out of place in this session, that's not the case because what you've heard is how imaging is really leading the way for us understanding retinal degenerations and in fact, how a treatment will affect. You saw Joe talked about the slide from Jackie Dunkin where the cones stayed alive, but there was no change in actual vision.

That's the work that Joe and others in the field are looking at to understand how an it particular intervention not only can save the cells, but moving forward how you can interrogate those cells to understand if in fact they are still functional after the treatment. With that next up is Dr. Trevor Mcgill from the Oregon Health and Sciences University, and he's going to talk about cell based therapy for treating inherited retinal degenerations.

Dr. Trevor McGill:    

Thank you Steve and thank you for the organizers for inviting me to be here. I'm excited to be here. I love these sorts of things they give me a really renewed sort of motivation to going back to the lab and doing this work.

You guys have heard a lot about what is cell based therapy, and a lot of times you hear stem cell therapy. I think in a lot of cases what people sort of misconstrue what stem cell therapy really is for the purpose of treating retinal diseases. A main focus of my talk today is to try to clarify a little bit of that.

When I talk about what does a cell based therapy, it's really talking about a therapeutic cell, and I'll get to what stem cells are and how that relates to therapeutic cells. Really the purpose here is to be able to take a therapeutic cell to either prevent the progression of disease, or to be able to restore the cells in the retina such that you can either restore eyesight, or you can prevent the loss of eyesight.

Much like Joe had mentioned, none of these pictures or anything on the slides are of any importance, I'm going to sort of reiterate all of these. There we go.

In the case of cell based therapy you're sort of stuck with two approaches. There's a large sliding scale on these approaches, and the issue is transplanting cells that might be therapeutic at either an early stage of disease or elite stage of disease. Each of those have really the approach changes dependent upon the stage of disease but also the cell types that you use.

For example, moving from a normal healthy retina into one in which you might have early onsets of disease and you can identify disease early on, really that gives you an indication of that there might be some progression of cell atrophy, and the retina is going to deteriorate. That's a no opportunity that we tend to call neuro protection.

This is a situation in which maybe we can put a therapeutic cell into the retina to prevent the progression of disease and prevent the loss of eyesight. The converse to that is a situation in which we have loss of the retinal cells, so loss of photo receptors, or RPE cells us we call them, and maybe that's an opportunity in which we can replace those cells with therapeutic cells.

What is the source of therapeutic cells? Now you guys have heard lots of lots of discussions about what stem cells are. Brian gave a pretty good summary earlier this morning about two of the main sources that we use for stem cells. They're typically embryonic derived stem cells. You get a fertilized egg that begins to grow and then you can harvest cells that then can be used to differentiate into any kind of therapeutic cell you want.

Or there's adult sources of cells in which skin or blood can be used to reprogram those cells to become your therapeutic cells of interest. Now in this figure there's really nothing of interest here, but the point is that we have multiple sources of where we can harvest cells and grow frankly millions upon millions if not billions of these. The point that you really need to take into consideration is differentiating those cells into your therapeutic cell.

There's so much overlap in terms of what stage of disease, where the disease affects the retina, whether it's macular peripheral, whether it becomes a cell type that's more effective than the other, really defines exactly what you're going to do in terms of generating your therapeutic cell. Whether you're going to make photo receptors and try to replace photoreceptors, or if you're going to try to replace retinal pigment epithelial cells.

What I'm trying to express here is that cell based therapy is a massive field with a lot of different angles in terms of which cells you're trying to use, which ones you might use at different stages. A couple of examples and Brian went through this earlier was you know, retinal pigment epithelium cells are ones in which have been used mostly in dry AMD, but also in Stargardt's disease.

There's other groups working on neural progenitor cells, and retinal progenitor cells, and photo receptor progenitors. There's a multitude of different types of cells that can be used potentially for either of the neuro replacement therapies, or the neuroprotection therapies. And really an interesting component of this is that these are not mutually exclusive. In some cases you might need to be able to replace all of them.

In advanced disease you might want to replace the retinal pigment epithelium cells, but you might also, or frankly half to replace photo receptors so that people can regain some of their vision. A lot of this sort of field is sitting at this point right now is trying to determine exactly what's the best approach for the disease state and frankly for, which type of disease. Can I get the next slide please. Thank you.

What's the status? Brian went through this a little bit and there's no, currently no FDA approved cell based therapy for treating any retinal disease. It's not for a lack of trying because boy was there 20 some odd cell based therapy clinical trials ongoing right now. There's a lot of emphasis and a lot of movement towards generating cell based therapies.

There's a lot of hope that that will be able to get one of these trials approved and in the near future. With that there's also a whole bunch of unanswered questions, and some of these are things that the FFB sponsors and in fact, in my lab, one of them is the immunological consequences of transplanting cells. As you can imagine, if you're using a cell type that's exogenous to the body or from a different source than yourself, the immune system might recognize those cells as being foreign and then might not accept that graft of cells.

You have to be cognizant of whether or not the immune system's going to play an important role. There's also considerations that we've been learning over the past several years is just simply how do you transplant cells into the eye to make sure they go into the place in which you really want them to be making little incisions in the retina. Whether those cells escape from the retina or how do I encapsulate them in there?

Those are sort of new things that we didn't realize we needed to learn that we've been learning over the past several years. There's a ton of unanswered questions as to what's the proper dose, how many cells do you need to put in, how many photo receptors do you need to transplant in order to rescue vision. It's kind of unclear still at this point. The best source of cells if there is the best source of cells.

That's where some of these clinical trials are really useful as people are comparing all of these kinds of things indirectly mind you, but they're really comparing doses and the source of cells, etcetera. One of the bigger challenges that that's also being addressed in rodent models and then on nonhuman primate models is how do you track cells after you've transplanted them into the retina?

What if they migrate? What if they move around from the place where you first put them? How can you see them? This is where technologies like what Joe's working on are going to be really useful because maybe you can actually visualize those transplanted cells, see if they're still living, see where they're living in, and maybe be able to determine if they're having a beneficial effect.

As I mentioned, several of these types of preclinical studies are the things that the FFB has been supporting, not just currently even my lab, but I think most of the scientists labs here have been supported on these types of studies regardless of whether it's cell therapy or gene therapy.

I wanted to really give you this important message, and this is one that's kind of near and dear to my heart for a lot of reasons. The term stem cells doesn't necessarily mean it's always a good thing, and it's important that I think people in the retinal field are really, really particular about this is why I make the description between therapeutic cells and stem cells.

In the past four or five, six years, there's been independent clinics that have sprung up talking about the use of stem cells to cure AMD, and stem cells to cure whichever retinal disease you may have. It's unfortunate because these are actually really dangerous approaches.

What's happened is that people are using what we call the so called adipose derived stem cells. So it's sort of a liposuction if you will, and then isolation of cells that then are turned an injected back into a patient's eye, into the vitreous of the eye, which is probably not where they should go anyways.

Unfortunately there's been really dire consequences. These are not FDA approved clinical trials, it's not an FDA approved therapy. Patients are often required to pay for this service and to sign a nondisclosure agreement. Ultimately several patients have had to have long and complicated sort of post treatment, if you will call it that cared bye retinal surgeons.

In some cases people have lost their eyes, not just lost more eyesight, not just disease progressing, but had lost their eyes because of this really unsafe and dangerous approach. Gladly to report that the FDA is investigating these things.

I wanted to get across the message that the work that the FFB has been doing for years in supporting my lab and others is really to develop a safe and well vetted and thoroughly characterized therapy for retinal disease. The reason why I wanted to bring this up is that even-- I'm in Portland, Oregon, but just across the river in Vancouver, Washington there's a newspaper that comes out, it's called the Colombian.

There was a full page ad in that that said stem cell therapy for AMD, we can cure AMD. This is one of those clinics. So it's happened in Florida, it's throughout the country. My plea to you guys as if you know patients with these diseases and the patients in the room please avoid those at all costs because it is not a safe therapy. I think that that's all I have to say.

[applause]

Interviewer:               

Thank you Trevor. also for highlighting the use if you will of these adipose derived 'stem cells' and the problems with that. Our last speaker, Dr Eric Pierce from Mass. Eye and Ear, Harvard, we'll be talking about gene and genetic therapies.

Dr. Eric Pierce:        

Thank you Steve. Thanks for the opportunity to be here to speak with you. I'm just realizing, I think I've been associated with FFP for 16 or 17 years now. As you can imagine, FFP is changing and evolving over time and it's really exciting to see the energy in the foundation in the field and still be part of that now. I can try to talk about gene and genetic therapies, peep things people spend their careers working on in 10 minutes. I could have the next slide please.

I'm just going to hit the highlights as you can imagine. Brian already given introduction to this so it makes my job a little bit easier. I'm going to try to expand on the introduction Brian gave and also set up some of the topics related to new types of gene and genetic therapies which you'll hear about more throughout the day.

As you know gene and genetic therapies very promising forms of treatments for inherited retinal degenerations. At the moment they take kind of three major forms that I'm trying to show on this first slide. There are gene augmentation therapies, which you've heard about. That's taking the gene that's use for therapy packaging it up into a viral vector like AAV and doing a subretinal injection of that. There's a picture on the slide of that kind of injection being done underneath the retina where the gene therapy vectors are currently delivered.

That can be done for genes that are a certain size, about 4,000 DNA letters, without AAV vector or maybe 8,000 letters would lend to virus. That covers most of the inherited retinal disease genes by 80% of disease genes are able to fit in AAV, without at least  20% that are not including some of the more common forms of disease. We need additional approaches to genetic therapies, treatments that address the underlying genetic cause of disease.

One of the newer ones in our field is antisense oligonucleotides. She'll talk a little bit more about shortly. Those are at the moment injected intravitrealy so it's an easier injection. On that picture of the eye there's a blue serene showing an injection of the antisense oligonucleotide into the vitreous.

Other form of therapy which I'll touch on shortly is the genome or base editing, which you've heard about  these are CRISPR-Cas9 based therapeutics. Everybody's very excited about using them for many treatments. As Brian said, they're kind of molecular scissors, so maybe we can do some more fine tuning of genes. We think those are best targeted for large genes or genes that need to be removed because they have a dominant or toxic effect.

I'm going to try to go through each of these three categories in a little more detail. Genetic mutation therapies that you've heard about it very exciting. They're kind of the low hanging fruit in our field right now because of the proof that they can work via the work that Jane Bennett and others started leading to the approval of the [inaudible 00:37:10] drug. With that success under our belt, we're trying to replicate this for many other forms of disease.

What are gene therapies? If you think about our retinas, they have lots of cells and then that are needed for vision. Each of those cells are kind of like machines built up of many parts. The parts in ourselves are proteins. Proteins are encoded by the instructions to make them are included in our genes, right? If you have a retinal cell that has a missing part, just like a car engine, it might work for a little while, but eventually it's going to work less well and then it's going to break down and stop work.

Our retinal cells are the same. The goal of gene therapy is to add new instructions for the missing gene to have retinal cell. The missing part can be made and restore the function of the light sensing machine. There are hundreds of genes that are needed to make hundreds of protein parts per vision and that's why there are hundreds of retinal degeneration disease genes.

The goals of gene therapy is to add the instructions for making the missing part back to retinal cells. That as you heard from Brian's talk being done, my account was a little less than 13 but let's go with 13 different genes are being studied for gene augmentation therapies using AAV Vectors, [inaudible 00:38:29] virus vectors. There's a lot of work going on in the lab to try to improve on those. Leah mentioned some of that work. Can we make better delivery systems?

Can we do better at getting the instructions we need to particular cells or do that, for example, via intravitreal injection instead of subretinal injection. So it's safer and easier. We're also trying to figure out [inaudible 00:38:51] virus really work for inherited retinal diseases. As you heard Brian say, there's a lot of work on testing the use of this approach from many other genetic forms of disease going on in the lab. Brian's number that's 75 more genes on the way for clinical trials. So that's very exciting, and I said sign up the low hanging fruit.

That doesn't address all the genes, right? There are 20% of retinal disease genes that are just too big for gene therapy vectors right now, we need other approaches to treat them. This is where one part is antisense oligonucleotides which you are going to hear more about from a procure later on. There are clinical trials of antisense oligonucleotides directive percept to 90 associated with disease in progress and one for [inaudible 00:39:39] students used to do to start soon.

As you heard last evening the foundation has supported a lot of that work. What do these things do? This is sort of a new type of genetic therapy. I'm going to come back to the what our genes are. Genes are the instructions that are needed for making the protein parts that run the machines of our light sensing cells. Genes are complicated instructions and there's a picture of a gene here, which is a linear molecule made up of seven blocks. Four of the blocks are colored, three of them are white.

Like complicated instructions we want to take the colored blocks, put them together into a protein and allow that part to be used in retinal cells. The white blocks tell us to some degree how to use the colored blocks. Here we have a blue, red, green. yellow block separated by three white blocks. We want to take those instructions, the white blocks cut them out, make a protein that just has blue, red, green, yellow blocks. Pretty straight forward, just like you'd make up part for a machine.

What if one of those blocks say the green block here had a misspilling it? The instructions were just wrong. Instead of making it intact, protein, you couldn't make the protein at all, so you can't make the part. That part's missing. The machine breaks down. Well, you could either replace that whole instruction set in the cell [inaudible 00:41:02] therapy I said, or if you can't do that because the gene is to big and you need another approach.

The approach here is to do what's called exon skipping. What if you could get a drug that would say that misspelled green block don't use it. Let's make our protein part just a red, sorry, blue, red, yellow blocks and leave the green one out. Now sometimes that won't work because you need that green part, but proteins just like many other parts and machines are modular and often they're repetitive, same pieces used over and again.

Sometimes you can actually leave that green part out and the resulting blue red, yellow protein can still work. That's the goal of exon skipping. Antisense oligos are very good at that. You can develop a green block specific drug that prevents that from being used, injected into vitreous and make the protein that's shorter, missing a part, but still works to some degree. That's what's based on early reports working for [inaudible 00:41:57] sub two 90 associated disease, and will soon be tested for [inaudible 00:42:01] disease  and many others.

You can expand on this approach. Next slide. There you go. I'm going to skip that one for time. You can expand on that approach and use genome or base editing to do some of the same things here. These are molec, as Brian said, molecular scissors, and there's a picture here showing a double helix DNA strand with a surgeon holding a forceps taking one of the bases out of that strand and exchanging it for another one.

You're taking the misspelled piece out and putting a new one in. Here are the differences. We're not adding the instructions to a cell to make a new protein. We're actually fixing the misspelling that prevents the use of those instructions inside someone's own retinal cells using genome and base editing tools. This is very exciting. I think it has a lot of promise for multiple forms of inherited retinal disease.

In the lab this is being studied actively for [inaudible 00:43:00] associated disease with the same kind of approach, exon skipping that I mentioned, but also with changing the spelling of specific basis one at a time, which would be incredibly exciting. That's being used for rhodopsin associated disease as well, and there's a really important use here, which is you can imagine if you can fix misspellings in a gene, you can also make misspellings in a gene on purpose.

You can make models of disease by taking normal animals or normal cells using genome editing to introduce a mutation that you know causes disease and study it, and that's incredibly powerful and there's some beautiful work going on modeling some of the important causes of inherited retinal disease both in cells and rodents and primates. As Brian mentioned, there's clinical translation of this, which is incredibly exciting [inaudible 00:43:49] Allegan are bringing forward genome editing for [inaudible 00:43:53]sub two 90 associated [inaudible 00:43:54] to clinical trials. That's going to be starting at Mass Eye and Ear and six other centers around the world hopefully later this year.

That may be the first use of CRISPR based genome editing in Vivo ever. Here's where again, the [inaudible 00:44:13] fueled by years of investment from [inaudible 00:44:13]  is leading the way not just for eye research but also for genetic and gene therapies to research overall. I hope you get some sense that these are multiple techniques can be used for very exciting approaches to fix the underlying genetic cause of retinal diseases, and we're looking forward to many more clinical trials and eventual approval so that these kinds of drugs going forward. Thank you.

Interviewer:               

Thank you, Eric. We now have some time for questions and we have mic runners, so if you have a question, please raise your hand. Right over here is a question. Dan, they're coming. Please say who it's to.

Question:                  

The question is regarding the advanced imaging. I think one of our major components of our strategy has been to shorten the time to the end points for FDA trial approval. I don’t know if you could say-- I'm thinking that the advanced imaging certainly has the potential to help shorten the time to the end point. I wonder if you can comment on that.

Answer:                    

Yeah, I think you're exactly right that that's one of the potential applications of the imaging tools. Structural outcomes and functional outcomes aren't necessarily equally valued by the FDA. There's a lot of dialogue that one has to provide to them to get them to accept a new outcome measure, a new end point. Obviously we care about function, those are going to be-- I think remains the primary outcomes for a lot of the trials.

In that early stages, trying to determine quickly whether there is, what is the effect at cellular level, certainly imaging can play a roll at it. The main advantage is quite objective, and so in that sense relying on how someone feels that they have a [inaudible 00:46:20] task can be really effective and that's what's happening in the retina. I think that is potential allocation and [inaudible 00:46:28].

Interviewer:               

Another question. Oh, here we go.

Question:                  

Thank you for all these information [inaudible 00:46:39]. Just a quick questions for Dr. Pierce. With CRISPR gene editing, does that mean cells have to still be viable or [inaudible 00:46:49] I guess [inaudible 00:46:54] or regenerated?

Dr. Pierce:                

Thanks [inaudible 00:47:00]. Its likely genetic therapy or CRISPR-Cas9 or genome editing [inaudible 00:47:06]  approach does need to work in someones own retinal cells [inaudible 00:47:11] cells that are sick, not functioning so well, functioning [inaudible 00:47:16] by fixing and misspelling them could get a much better [inaudible 00:47:23] cells that are needed [inaudible 00:47:27]. Does that answer your question.

Question:                  

Yes.

Interviewer:               

We have time for one more quick question if anybody has one. I want to thank our panelists very much, very salient, very understandable presentations.

[applause]

 

The Art of Translation Panel

Jason:                         

Very good. Thank you very much. We have one more panel before a break, so there will be a break after this panel discussion. This panel is called the Art of Translation. As we said a little bit ago, the program today is going to follow the lifecycle from the preclinical world, which is where we just work through the translational into the clinic and then obviously later into the biotechs and companies. To moderate this panel, we have Dr. Amy Laster. Amy has been with the foundation [00:00:30] for 10 years. She has her PhD in neuroscience from Purdue University, and did her postdoc fellowship at Johns Hopkins. So please help me welcome Dr. Amy Laster to the stage.

[Applause]

Dr. Amy Laster:          

Good morning, thank you Jason. Again, I am Amy Laster [00:01:00]. I am the Senior Director of our Grants and Awards program for the Foundation Fighting Blindness and welcome to the Art of Translation panel. A little events going on in the back. This morning we are joined by four outstanding academic scientists who will share their perspectives based on their experiences in advancing academic research to clinically relevant therapies. Each lead [00:01:30] innovative research programs that have been or is in part supported by the Foundation’s Translational Research Acceleration Program. I just want to start a little bit to talk about the process of creating medicines. It is complex, time consuming and costly. The early laboratory research that established a drug discovery really is the first [00:02:00] step in a very rigorous development process. During this stage scientists search for or create biological tools and compounds. We've heard about that earlier, that may eventually become approved medicines and therapies.

These initial therapeutic candidates then progress to preclinical testing, which is extensive laboratory and animal experiments that will determine their safety for testing [00:02:30] in humans. Researchers, they must show regulatory agencies such as the FDA, the EMA that the results of these studies and describe how they will plan to test these drugs or therapies, candidates in clinical trials. The regulatory agents, they really bear the ultimate responsibility for deciding whether a compound or therapy is reasonably safe, [00:03:00] enough to move forward in a human clinical trial or to test in humans. From there a potential treatment will undergo progressive phases of clinical trials to gather the evidence of safety and efficacy needed to gain these regulatory approvals. Drug candidates or therapies, they can't be disqualified at any step of the process if they are found to be unsafe or ineffective. It's a bench to bedside bridge [00:03:30].

In the next 45 minutes, our guests will kind of pull back the curtain and highlight the successes and challenges of advancing academic research programs across this bridge into treatments for patients. First I'm going to take a moment to introduce our panelists. Joining us on stage we have Dr. Karina Guziewicz, she is a professor in the Department of Clinical Science and Advanced Medicine at the University of Pennsylvania. [00:04:00] She has 15 years of experience in retinal degeneration research. Also joining us Dr. David Gamm, he's both a clinician scientist and entrepreneur. He not only directs the McPherson Eye Research institute and serves as Chair in the Eye Research and is a professor of ophthalmology at visual science at the University of Wisconsin Madison, but he's also co-founder and chief scientific officer of [00:04:30] Opsis Therapeutics.

Dr. Shannon Boye a Professor of Ophthalmology at the University of Florida, holds numerous patents on technologies that stems from her research to develop gene augmentation and replacement strategies. Most recently she successfully licensed technology to a pharmaceutical company, to benefit LCA1. Last certainly not least, Dr. Jean Bennett, a world renowned expert in molecular [00:05:00] biology vector development and gene therapy translational studies. She really is known best for her work along with others that recently culminated in the first FDA approved gene therapy treatment for retinal degeneration due to mutations in the RPE65 gene. This will be a conversational panel, so we're going to get started with Dr. Guziewicz who will [00:05:30] walk us through the typical next steps that's required after academic program that’s kind of shown proof of biology. Just kind of give us a sense of what's happening. I'm going to join you guys at the table and then we'll start our conversation.

Dr. Karina Guziewicz.  I also would like to thank the organizer for the invitation on this exciting event together with my colleagues we are going to show our experiences from the translational journey. [00:06:00] But let me start with the most I think the fundamental aspect that the Art of Translation will not exist without the beauty of the basic science. How you develop this research project from scratch and what it takes and how do you learn about the translational volume? It always starts with an identification of an animal model. In general, in model that can be a model for instance, [00:06:30] genetically modified rodent model commonly used, that can be the state of the art in vitro model system, which David is going to elaborate later on. Like for instance, human derived iPS cells, but in our case at the University of Pennsylvania in our group, we based our research on naturally occurring canine models of human retinopathies, which is a very important. What it takes to identify [00:07:00] the model? First of all, a very experienced clinician and can recognize a novel phenotype. Then a group of molecule biologist best with expertise of ophthalmic genetics. First to exclude a genetic defects known already segregating in this breed and then pinpoint the genetic defect, which very often is not as a simple task. It requires management large [00:07:30] data scale, genomic data.

If you are lucky, then there is already a human disease characterized. The characterization of the new phenotype in the dog is obviously very more facilitated. Still, this is a long way before you can talk about the translation of volume. Next, there is a group of a biologists and cell biologist tried to determine the mechanism of action of the mutant gene on the [00:08:00] DNA, then RNA and of course protein level. You need to develop and characterize them on actual history of the disease in the dog in comparison to human and only this based on this knowledge we can talk about the strategy, therapeutic strategy. I was always laughing as they say, it takes maybe a village to raise a child, but what we know for a fact it takes an army of determined scientist to restore the vision [00:08:30] of this child. I just want to comment, this is the most important.

I would like to also highlight some of the therapies which you might well remember that always is a collaborative effort. This is the most important thing I want to say. It's [inaudible 00:08:51] group as I mentioned before, group of molecular biologists or geneticists and clinicians. But the most important thing is also collaborative effort [00:09:00]. Obviously nothing is happening in the one lap. This is something which we know exactly and we have well established collaborators and in the Scheie Eye Institute Dr. Jacobson and Sebastian, of course, in Westfield, Florida this is the group of [inaudible 00:09:16] and also this investigators present here. As you might know this, I was lucky to find this army of experienced investigator when I joined [00:09:30] laboratory of Dr. Gus Aguiari [PH] in 2005. A lab that the boldest ideas and hypotheses are being tested and the impossible becomes possible.

As you might know that the first RPE65 affected dogs were injected in the collaboration of University of Florida by Dr. Aguiari group but also [00:10:00] since that was published in 2001 and I will let Jean Bennett comment on the latest. But since then we also have two project already in the clinical trial. This is CNGB3 associated achromatopsia. It was a study led by [inaudible 00:10:19] and also RPGR retinitis pigmentosa this is study led by Dr. Beltran [PH]. This study was [00:10:30] also supported by AGTC but in terms of RPE65, as you’ve already heard before, the proof of concept study and preclinical safety study were made possible by the support of the FDA of course.

Recently we have two new developments this is Rhodopsin associated with retinitis pigmentosa and the canine best disease, both entering the preclinical study and the pre IND enabling [00:11:00] study in the [inaudible 00:11:02] agreement with [inaudible 00:11:02]. None of this would be possible without your support for all these years. I specifically want to highlight the canine basest disease study, which FFB supported us for 10 plus years. Prove of concept, identification of the mechanism and pretty much the model support of the model for OTS will be possible having evolved. Thank you and also [00:11:30]on behalf of future patients.

Dr. Amy Laster:          

Karina, you speak about the collaborations. How are they different from when you're doing your, your preclinical work and it's your laboratory and now you're moving into the kind of (IND)-enabling study. What happens in the collaboration? Do you bring on more investigators? Is it bigger? What's necessary in terms of really advancing your therapy from the laboratory and getting it ready for clinic?

Dr. Karina Guziewicz: 

Well, as I said [00:12:00] I am very lucky to have joined the laboratory that establish collaborations. If we can keep the collaboration and expense depends what's the study becomes that is exactly what we plan to do.

Dr. Amy Laster:          

And so you also have collaborated with David Gamm.

Dr. Karina Guziewicz: 

Absolutely, absolutely

Dr. Amy Laster:          

What kind of lead -- David Gamm kind of pick up a little bit and give us just a little bit of insight on moving those early stages of research [00:12:30] into clinical trials. It's a lot of animal studies as Karina mentioned. It seems like you almost have to repeat them when you're getting ready to take it to the clinic. There's this thing called GMP studies. David you want to share a little bit with us about that and how we move the studies forward?

Dr. David Gamm:       

Sure. There are a lot of gaps between what you do in the laboratory. In my case, I'm a stem cell researcher and making those basic discoveries and ultimately translating that into something that can [00:13:00] safely be put into a human patient. That's what people call it the valley of death. It's hard to cross, there's a lot of elements to that. One of the aspects of that that I was asked to talk about was something called a GMP or CGMP requirements. For the folks that have been here and gone to a lot of these meetings, you've probably heard those letters. it's called-- well the C is actually debatable, it's either clinical or current, but good manufacturing practices.

What CGMP is, are the practices and procedures necessary to [00:13:30] document that your product was manufactured in a way that's safe for humans. It's concerned with the process. How did you get from your raw materials to ultimately the product that's going into the patient? It also cares about the end product, but really it's more along the lines of the process. Why is that important? It's important because yes, you can test the end product, but that's going to be a sampling, right? You're going to pull a few things off the assembly line and you're going to test them. But it doesn't mean that every single one of the batches [00:14:00] there could be batch to batch variability. How do you know the quality assurance is there every single time you make that product that's going to go into a new patient?

One way to think about that, and I think one of the ways that we all whether we know it or not question CGMP practices is food poisoning, right? You would have a pizza, it makes you horribly, horribly ill. That same place that manufactured that or made those pizzas probably mostly make pizzas that don't make people sick, but the one time that you got it, [00:14:30] it did. You probably sat there thinking, well did they wash their hands? Where did they get their tomatoes from? All this kind of -- those little pieces that go into making sure every one of those pizzas aren't going to make you sick. Clearly the same processes are deserving to go into manufacturing of a product that's going to go into your eye or otherwise into your body. Ultimately the goal of all of this is to do no harm, so to prevent harm to the end user.

For me personally, one of the first times that I ever thought [00:15:00] about CGMP was the first time somebody tried to get me to drink Kombucha. I looked at it and I said, this looks like something somebody made in an old boot in their living room and I was reluctant to drink that, right, so just, I drank it anyway I hated it but it's whatever. But anyway, you go through these processes and certainly if you're first in line for a new therapeutic, that's something you should think about. Who's overseeing this process? The agency that oversees in the U.S. is the FDA, the food and Drug Administration [00:15:30] although worldwide there's different agencies, the European Union has one, UK has one, Japan, India, so on and so forth. They’re tasks with making sure that that process is consistent and that there's not this batch to batch variability. The elements that go into that start with the facilities, so where are you making your product? Does it pass muster? What was the equipment that you use? What's the maintenance of that equipment? Are the personnel [00:16:00] that are doing the work that are monitoring the equipment, are they well trained? Are you documenting the process appropriately such that if there's something that goes wrong, you can go back and pinpoint it? Also, so that when they have different shifts that come in, that one group of personnel do it exactly the same way as the next group of personnel.

For some of these new therapeutics there's an art to it, it's not a manufacturing in line where you have robots doing everything exactly the same way. There are people behind [00:16:30] the manufacturing of these products, and so that's a very difficult thing to do to make sure everybody is doing it the same way. Then there's the products that go into your product and where are they sourced? You have to trace back that pizza example, right, where the tomatoes came from. It's not just the pizza guys, but how are they sure that the tomatoes that they're getting are not laced with E. coli, for example. This is a daunting task, the FDA gets a lot of heat for doing this -- drives up cost, what have you.

In 2013, which [00:17:00] is the most recent one that I could find, there are over 4000 GMP facilities worldwide, that's a lot. What percentage do you think of the products or the key ingredients that go into the things that you put into your body from a drug standpoint are outside of the U.S.? Not a quiz, 80%. Outside of the U.S. 80% of the key ingredients that go into the drugs that you take come from outside the U.S. those GMP facilities have to conform and they have to register for FDA approval to be sold in the U.S. [00:17:30] The FDA does go out and do a pre-inspection, post-inspection and then continuous inspections along the way, but there's not a million people in the FDA either. That's where it's a daunting task.

The FDA also is not a law enforcement agency, so it can't come in with guns blazing and shut people down. It has to work through the courts and the legal systems. It can seize drugs, it can also warn the public and ultimately bring things to trial as well. They're there [00:18:00] really to make sure that the process is stacked in your favor as ultimately an end user of them. In addition to that, you think about, my particular road that I've traveled since I started in my lab first looking at pluripotent stem cells like Trevor talked about earlier, embryonic stem cells and ultimately induced pluripotent stem cells where you're taking something that can make essentially any cell type in the body.

But you're trying to direct it in one particular [00:18:30] place, in this case, photoreceptors -- retinal pigment epithelium. How do you know that you are -- and that takes a long time, and there's a multiple different ways developmentally that that can go into different directions. You have to assure that the end product is actually authentic that it's not this adipose tissue that somebody is trying to sell snake oil with, but it's an actual cell type that’s authentic for the human retina.

Along the way you have to develop a lot of practices and processes to assure that to yourself but ultimately to the FDA and that's important. [00:19:00] My particular case I was very fortunate that two floors down from my laboratory, the University of Wisconsin had its own GMP facility. The folks there given that UW-Madison has always been a Mecca for stem cell therapies and cell therapies in general, they had expertise specifically in that area because not every GMP facility can do everything. Some will do food, some do drugs, some do gene therapy, some will do cell therapies, but not every one of those 4000 is equipped to do everything the same way and to the same [00:19:30] level of expertise.

The facility I had a couple of floors down from me was, and that was very important because what it taught me was you have to approach what you do with a thought process of can what I'm doing ultimately get into what humans? Are the ingredients that I'm using is the process that I'm using translatable to a GMP process? If not you're going to have to go back to the drawing board and it's going to have a lot of time and cost down to the ultimate exercise. Those conversations were important [00:20:00] because I could say, well I can make it this way. I can make A, B or C and I'll say, well, B and C there's no way to obtain those reagents in a safe manner that can be put into patient so go away. It also taught me to keep things simple because every element that you put into the product manufacturer has to be vetted. If you don't need something, if it's not critical for the end product, then don't use it.

Also, you have to have multiple sources, so every step along the way, if you need a particular ingredient [00:20:30] you want to have more than one manufacturer of that ingredient, because what if that manufacturer goes bankrupt or goes belly up or if they have a problem and they're shut down because they don't comply to CGMP. You want to have a backup to that. All these things then go into ultimately making a safe product for you. It's not foolproof, but it's done in your interest and it's been an education along the way from me I'll tell you that.

Dr. Amy Laster:          

So I want to go back to you Karina. A lot of the therapies and drugs [00:21:00] that are generated are tested in multiple animal models. Maybe they're in small animal models and they're large animal models such as the canine models that you work with. Based on what David said, so for the animal models that you're testing particularly the dog, do you use GMP? Is that required? I mean, how does that fit into making sure that you're using GMP practices? Do you do it at the preclinical stage [00:21:30] or it's a little bit later?

Dr. Karina Guziewicz: 

This is of course project dependent and this is the FDA decision. One of -- this is important if you have alternative model to compare to, obviously this is a -- like we had to look [Inaudible 00:21:44]. In terms of -- for instance maculopathy that in the end you will want to try your product in the, for instance, nonhuman primates. There is always a project to that.

Dr. Amy Laster:          

I can imagine that that also having an impact on [00:22:00] the cost of the research.

Dr. Karina Guziewicz: 

Absolutely.

Dr. Amy Laster:          

Can you talk a little bit about that?

Dr. Karina Guziewicz: 

Not really. It’s just the beginning of the journey.

Dr. David Gamm:       

Well, I can mention that. These aren't sequential things. If you waited until you had a GMP process to then do the preclinical studies, that would add millions of dollars on and then you wouldn't kind of know. You're doing these things smartly, hopefully. You're developing the basic [00:22:30] research, you're doing that with a thought towards, yes. I want to help patients some day so where I can mold the process into something that could be more streamlined into patient’s use, that’s great. You interact with the folks through the FFB through regulatory agencies kind of trying to educate yourself along the way. You test that then in small and large animals and then you hopefully are developing these things at the same time, that saves time and that saves money.

Dr. Amy Laster:          

Right. I mentioned it early [00:23:00] that if something advance as it goes through multiple phases of clinical trials and the first phase is really to test safety. Dr. Boye, can you give us a little bit insight on what are those safety concerns? One thing that we constantly hear is that the eye is immune privileged. How does that benefit research scientists and using the eye to advance therapies?

Dr. Shannon Boye:     

Yeah, that's a good question. Can everyone hear me okay? [00:23:30] How about this one? No, that's a very good question. The eye is indeed immune privileged and that's the reason that people like Jean have gotten their gene therapies approved. The first approved gene therapy in the United States is for an ocular disease, and that has a lot to do with the fact that the eye is immune privileged. But what does that mean? Think about [00:24:00] if you get a scratch on your arm and you get an infection, you get a germ inside that scratch that scratch is going to become red and inflamed. There's going to be inflammation. You've got an infection, right. But the eye has evolved essentially to develop a mechanism to not become inflamed every time it gets exposed to antigen or a germ, because if you think about it. If our eyes became inflamed every time they saw something foreign like a germ, then we would lose our vision and obviously that is not an evolutionary [00:24:30] adaptation.

There are other tissues in the body like the testes that have similar types of immune privilege for obviously evolutionary reasons. In terms of how the eye is immune privileged, one reason is that it's compartmentalized. You've heard of the blood brain barrier most likely there's also a blood retinal barrier, a blood ocular barrier, meaning that if we develop a drug whether it’d be an AAV gene therapy or a small molecule, we can potentially put that in the eye and it doesn't leave because it's compartmentalized. [00:25:00] Now there’s caveats to that which I'll get into in a moment. If you take too much of anything, it can be bad including water.

The eye is compartmentalized. It's also small so you don't have to deliver a lot of drug to that tissue compared to some of the systemic diseases that gene therapies have been developed for. There is also a lot going on molecularly in the eye. There’s molecules, immune modulatory molecules that are equipped to see a germ in the eye and tell the body to react to it [00:25:30] differently than if you get a germ in your skin, for instance. There’s are all these mechanisms in place. You don't have lymphatic drainage around your eye the way you do around other tissues. There’s multiple steps in there to make sure that the eye has this immune privilege.

But again if you deliver too much of anything, you can have a problem. This is where it becomes super important to take the material that you're ultimately going to put into the patients in the clinical trial and test it in a GLP [00:26:00] toxicology study. GLP stands for Good Laboratory Practices sort of another acronym like GMP. That's where you take potentially a GMP level material that David has made and test it in a GLP tox study. To do this ideally you use a macaque a nonhuman primate, and the reason for that is because macaques have a phobia. Really they’re the only species aside from humans that has a phobia and as everybody knows the phobia [00:26:30] is a cone exclusive region of the retina, it's a very specialized structure.

[Informal Talk]

Anyway, the macaque exists and it's very much like the human. There are other ocular structures in monkeys that are very similar to man. Ultimately when you want to move these treatments into the clinic, you need to test these products in a species that's most similar to man. What we do is depending [00:27:00] on, there are various injection routes you can inject subretinally, intravitreally, intracamerally. There are multiple different products that can be tested, AAVs, small molecules, cell based therapies, but you inject them into your nonhuman primate. Now importantly these nonhuman primates are not disease models. With the exception of some studies that are being run by Trevor and others where hopefully we will have monkey models of disease soon. Right now GLP tox studies are being performed in just normal monkeys, so they're not diseased. [00:27:30] The goal isn't to rescue vision in these monkeys, but just to test whether that clinically representative material that you're going to put into those patients are safe.

What do you do after you inject the monkey? Clinicians come in or vitreoretinal surgeons or veterinarians and they use all of the same clinical outcome measures that would be used on patients. They do gross ophthalmological exams, they look in the eye, they look at the fundus, they look for any haze that might be popping up in the vitreous that would be indicative of inflammation. [00:28:00] They use OCT, Optical Coherence Tomography, which Joe showed images of to look at whether or not any retinal structural changes have happened as a result of that injection. They also use ERG to look at whether or not that drug caused any loss of retinal function and possibly you can bring your monkey to Joe's lab and he can look at whether or not the cones are hanging around using AO [PH]. There's lots of different ways that you can test safety in these tox studies.

But of course at the end of that study [00:28:30], the animals are humanely sacrificed and the retinas are sectioned. Someone that's very experienced in histopathology in other words looking at the retina on a very base like microscopic level, cellular level will come in and look to see whether there are any signs of inflammation. There are various ways to do that. But it's looked at very, very carefully before the FDA will approve taking that drug into a phase one, two trial.

The other part of GLP studies typically involves a biodistribution analysis. What that [00:29:00] means is we look for where outside of the eye, the AAV vector, the small molecule went to, focusing on AAV because that's what I do. What is usually involved is the vector is injected into a rodent or a primate eye and then various tissues from the body of the animal are sampled and we look for the presence of the vector DNA in those tissues, so just the DNA not the therapeutic gene product. Very typically you do see some shedding of virus [00:29:30] DNA outside of the eye. It's compartmentalized but some can't get out. But what's important to understand is just because you have vector DNA in a peripheral tissue does not necessarily mean that you have the protein encoded by that vector DNA. The way that we can kind of control that is by incorporating cell specific or retinal specific promoters so that we can restrict expression of what we're trying to deliver to the eye, to the eye. Again biodistribution analysis is really important [00:30:00] to look at the safety of these drugs.

One thing I think that is worth mentioning is that the eye is immune privileged but the most immune privileged site in the eye is the subretinal space. Trials like the one that Jean ran have been applied subretinally and that's a very quiet space in the eye. You can put things there, they kind of don't make the eye angry. But we're moving into a phase in research for ocular gene therapies where we're trying to inject these things intravitreally and that's not without its challenges. [00:30:30] When you think about injecting a drug in the vitreous it’s going to get diluted immediately in the vitreous body. There's a lot of fluid there as opposed to in the subretinal space where you can inject just a little volume and it stays there and it's not diluted. You have to deliver kind of a lot of virus. Again if you deliver too much of something, things can go wrong. A lot of attention has been focused on the immune response to intravitreally injected gene therapies.

There's a lot of work going on in research labs. Again [00:31:00] to repeat what Karina said, the basic science is so important to all of this because the basic science looking to understand the immune response is really going to come into some of these clinical trials. But we're working, for instance, in my lab as is Leah [PH] to develop AAV capsids that can avoid causing inflammation. You make special designs on the AAV capsid it's called, that help to prevent causing that inflammation. There’s also really cool things being developed [00:31:30] by George Church, for example, at Harvard. He has this technique where he can put in what's called a [Inaudible 00:31:36] into the vector DNA that prevents it from being recognized by what's called TLR9 and initiating that really fast immune response. There’s modifications being made in research lab to the outside of the AAV as well as the inside to sort of address this inflammation issue.

Essentially once you've done all of that, once you've gotten your GMP product and then you've done [00:32:00] a GLP study in the nonhuman primates, then it's time to do a lot of paperwork. If you're lucky, you have an army as Karina mentioned, if you're even luckier you have a biotech company that has a huge staff of people that are going to help you do this. But it's a huge paperwork load and you submit the investigational new drug application to the FDA. Then you wait on bated breath for 30 days for them to tell you whether or not you've got the green light to go ahead [00:32:30] and initiate your phase one two trials. We were excited because on January 18^th we got our IND approved for LCA1. That was a success story 15 years in the making. Thank you.

[Applause]

But then at that point we take all that we've worked on. We really pass the baton to the physicians, the vitreoretinal surgeons, and the biotech companies that we've been fortunate enough to [00:33:00] align with.

Dr. Amy Laster:          

Thank you. I know we've been talking a lot about gene therapies as well as cell based therapies. But can any of you comment if the process is any different or any different concerns for small molecules and drugs that are being developed?

Dr. Shannon Boye:     

I'm not a small molecule person, but I can tell you that just within the AAV field. AAV can be made in a billion different ways. You can make it in [00:33:30] one cell type, you can make it in another cell type, you can have different helper systems. Depending on what your GMP process is, your vector might be more or less potent than another vector. One thing that's kind of coming to the forefront, at least in the AAV gene therapy space, is that you really -- if you have the money, you should be doing your IND enabling preclinical studies with the material that's made in the same way that is going to be applied clinically because of those potential differences and [00:34:00] potency.

Dr. David Gamm        

Yeah I think -- mentioned a little bit too. If you think about it simply for a small molecule, you’re talking about chemical. For AAV gene therapy you've got a lot of different parts that are being put into an AAV so you could think of that exponentially increases the complexity. Then for a cell you have all of those parts within a cell that you're putting into patients. The complexity goes up tremendously when you go from say, a small molecule to a gene therapy [00:34:30] to gene editing to cell therapy. One of the things -- this goes back again to the Sham [PH] stem cell clinics is that at some point the FDA goes, well, you know we can't monitor every thousands and thousands of things that go on into a cell. Sometimes they kind of back off and say, well, just show us two or three things. That's where it can get a little bit dicey.

When you're talking about -- sometimes it gets to a level of complexity where they kind of back off a little bit and while you can't be assured [00:35:00] of every single part of that cell, you have to be cognizant enough of the parts to make sure that you're actually putting something and that's going to be beneficial to the patient. It's a little bit of a complex thought, but I think it brings up the issue of how important it is to do GMP and to do -- and to vet these therapies. The FDA isn't going to do that necessarily. They're looking at the processes, they're looking to make sure it's safe, right, but doesn't have a chance of working in the patients. That's where foundations, that's where advocates come in, right. [00:35:30] I think that's a very important role in the FFB to vet these processes along the way, because the FDA is not a retinal cell therapy or retinal AAV expert. That's the scientist, that's the clinicians and they're oftentimes overseen or brought along by the FFB.

Dr. Amy Laster:          

We're so fortunate to have a scientific advisory board over 50 experts from around the globe to do just that. They give generously of their time to [00:36:00] come in and evaluate the programs that come before us for investments for just that reason. David and Shannon and Jean have been served on our advisory boards and we appreciate your time. Jean, for the therapies that kind of make it through the clinical development programs, what stands between that proof of concept in humans before it becomes available as a [00:36:30] prescription? What are some of those processes that have to happen?

Dr. Jean Bennett:       

Well, good morning everybody. First of all, Shannon mentioned the IND that has been mentioned by several -- the other speakers. This is really a threshold moment. It's the gateway to begin a clinical trial. A lot of the work builds up to the submission of this IND. The whole process, the interaction with the regulatory body [00:37:00] in the United States the US Food and Drug Administration FDA that there are a series of meetings typically before this big opus is submitted to help define what this trial will look like and what the IND package will look like. There are typically what are called pre-IND meetings that investigators can have with the FDA where the team can ask specific [00:37:30] questions to get formal feedback from the FDA on how they can proceed in order to be able to submit this IND.

In my experience, the FDA has been extraordinarily helpful. For example, in our pre-IND meetings for the Luxturna clinical trials, we asked them specific questions about our plan for testing safety of the injection, which was done by subretinal delivery that had never been done in [00:38:00] humans before delivering a gene therapy reagent. How we could be sure -- be as sure as possible that this was going to be safe and what doses to test and so forth. Using that format, and several back and forth with the FDA, we had a pretty good -- we developed a set of data which gave us that information which then became part of that IND package. [00:38:30]

What else is in this IND package? Typically one includes a natural history of the disease section describing what is known about the disease, the genes that are involved, modifier genes, the strategy that is proposed to be used for running the clinical trial. The rationale for that, what has gone into the experiments in the laboratory to show proof of concept [00:39:00] and safety of the intervention and the design of how to show whether this is going to be effective. The safety data includes the -- what is carried out in the preclinical toxicity studies. Typically those are the studies that are done after getting advice through the pre-IND meeting with the FDA. As Shannon mentioned, a favorite target for looking at safety [00:39:30] is the nonhuman primate because only primates have a macula. That's where we, we feel that we can get the most accurate safety data to predict what would happen in a human retina as we're also a primates.

There are a host of documents that go into this IND including standard operating procedures, how steps are going to be carried out in the clinical trial. [00:40:00] All of the data reports from the pre -- from the informal preliminary proof of concept studies and then the formal preclinical data reports. Not only are the data summarized in this IND, but the IND also includes many, many appendices which include just incredible detail. Every detail relating to each eye, each species of animals that’s been injected, [00:40:30] what has been injected in them, what the findings were both when the animal was alive, whether it was imaged, whether there was retinal function studies including electro retina grams, the appearance of the retina.

Then the formal histologic read out, which is typically done by somebody who is neutral to the study and so is not -- does not know which animals were treated and which were control so that we can get the best assessment of the data. [00:41:00] Then as Shannon also mentioned, looking at biodistribution, how does the delivery to one part of the eye effect the spleen or the liver or the skeletal muscle or particularly the gonads. The FDA has historically been really worried about gene transfer to the sperm or to the eggs, to the ovaries, because it's been worried about vertical transmission. I think those concerns have died down now that there's a lot of data from humans. [00:41:30] In fact, humans, at least in our clinical trials have had children and they have not shown evidence of vertical transmission. In other words, vertical transmission is it passing on the gene therapy reagent to their child.

The IND also includes the plan for the trial including details such as who will be included [00:42:00] and who would be excluded. Of course, one of the inclusion criteria for a gene therapy trial for a genetic disease would be that the person actually has copies of the mutant gene in question. For the Luxturna studies, if people did not have two bad copies of the RPE65 gene they would not have been included. As far as exclusion criteria that can include, of course, [00:42:30] if they did not have those disease causing genes. If they had another disease which might impact the interpretation of the results, for example, or that might affect the safety of that individual in enrolling in the trial.

Early on, we were concerned particularly that people with immune deficiencies might be at risk by delivering a recombinant virus, so there were exclusion criteria for those individuals. There are some people on medications [00:43:00] which might interact with the gene therapy reagent. For example, people who were enrolled in the trials for that led to Luxturna could not be taking Accutane a drug which acts by the retinoid pathway to treat acne because that could have impacted the results in the retina. The IND includes information about the dosing and the volume of material [00:43:30] that is injected and the route of delivery, whether it's subretinal or any of the other routes of delivery that are carried out and how specifically how that delivery is administered and the safety of that a approach. It includes material about the devices used in the gene transfer.

What type of syringes is used? What type of a needle or cannula is used to deliver the reagent? [00:44:00] What kind of studies have been done to show whether your gene therapy reagent binds to the internal surfaces of those device? How that impacts the dosing that is used in the study. One typically does not want to use an unapproved device. For example, if you developed a specialized cannula that you thought would deliver this material really efficiently to the subretinal space, and that device [00:44:30] itself had not been approved by the FDA. You would have to do special studies and get special dispensation to be able to use that test device. It generally is much harder if you're running a trial which involves two new entities, a gene therapy reagent plus a device that has never been used in humans.

The IND includes a schedule of administrations and attesting including baseline test [00:45:00] the type of tests, how many of them, how many days, how long before the reagent administration those test occur. It includes the details about the administration itself and which is usually day zero. Then the schedule for post administration testing whether the person is evaluated day two after the administration day 30, day 60, day 90 [00:45:30] and how long this testing goes forward. It used to be that the FDA mandated long term follow up of 15 years. That follow up has recently been reduced substantially, which will be a big boon for all of us because that's a huge amount of effort to imagine that the team is going to stay together and people are going to be willing to come back yearly for 15 years.

The outcome measures are described the types of tests that will be used. As [00:46:00] you've heard phase one is safety study. The typical safety measures will include, test that are used in the clinic ordinarily for measuring visual acuity, visual fields, looking at imaging, making sure there's no inflammatory process that's going on. Then phase one is an opportunity to explore a whole number of different areas to help define ultimate efficacy endpoints,[00:46:30] how well does this drug work? in our phase one studies for the RPE65 gene therapy, we included a wide range of tasks including pupillometry, electro retina grams, immobility test, fulfilled light sensitivity threshold testing etc.

Ultimately we went forward with mobility tests that we then we had further modified during a follow on stage of phase one to use as our [00:47:00] outcome measure for phase three. This is a great opportunity and typically it works the best if you're using a piece of equipment to do that those exploratory measures that you pick equipment where you're going to be able to get it for the next 15 years. Unfortunately our pupillometry testing looked fantastic, but there was only one company that made the pupillometry we used and I think they made it in their garage. [00:47:30] Within a couple of years after we initiated phase one, that company went out of business. It would have been impossible to carry on using pupillometry as a final outcome measure in phase three.

The IND also includes a monitoring plan, how are we going to be sure that the data is maintained, it's not tampered with it that it’s robust that it's put into checkboxes. Now there are electronic medical records, electronic data records [00:48:00] where the data's entered right away and so it can be also analyze really quickly. The plan also includes stopping rules. What happens if there is evidence that there is a safety concern or where there's, for example, if there is summit level of inflammation after the delivery of the reagent, how bad is that inflammation? Typically it's graded in terms of categories, [00:48:30] no inflammation level one, level two, level three, level four. You don't want to get to level four. Those stopping rules are spelled out in terms of both the ocular parameters as well as systemic parameters.

Then data is also included in the IND about the all of the test that have gone on to make sure that the reagent is sterile, [00:49:00] lacking contaminants, that it is monitored over time for its stability and its punch the potency assays are described. Those potency assays don’t have to be finalized to phase three, but early on they are -- the initial plan is given. The methods of making sure that the facility that is generating this clinical grade vector is monitoring [00:49:30] the environment in that room doing swabs of the walls and the tables and all the other equipment that may be in there to show that there's no bacterial contamination, and that the product fits the limits that had been pre-designated.

Just to sum up then this the IND is just an enormous document. It is -- and it takes a long time to compile it. Shannon's right, [00:50:00] it's really helpful if you actually have a team of specialists helping to work on this people with regulatory expertise or familiar with the format and what needs to go into these documents. It certainly has been an education for me as a scientist, learning about this. At a certain point also you want -- in going through this whole process, as a scientist we are trained to ask [00:50:30] questions to say, well what if we do this? What if we changed this variable? What if we increase the volume of delivery? We learn early on at a certain point when we think we have a -- what's called a clinical candidate. You don't change anything. You keep everything constant and you don't do extra experiments to ask your creative scientific questions.

You don't hand it off to other people to use because what happens is every experiment you do [00:51:00] using that clinical vector then has to be reported to the FDA. There's a penalty to doing these extra experiments. The reason that it has to be reported is because it could also impact the design of the trial and the safety. Two other points about, the IND, it's a really good idea to include plans or details that are consistent with the regulations in other countries. [00:51:30] For example, the European medicines agency is the European equivalent of the FDA. Some of their rules are a little bit different. Some of their interests are a little bit different than those of the US FDA. But if you can cover both categories, then ultimately if you are lucky enough to get to phase three and get a drug approval, then it will be a much easier to get that approved worldwide or internationally. [00:52:00] The other consideration is that the FDA does actually not approve an IND. What you do is you submit the IND and then 30 days later, if you have not received an answer, you have a green light. The FDA does not actually approve it. When you submit that IND you hope you don't hear anything back. I'm happy to stop here.[00:52:30]

[Applause]

Dr. Amy Laster:          

Jean, thank you so much for kind of sharing us all -- sharing with us all of the kind of nuances that happens in developing. Just the last few minutes that we have I would invite our other panelists to share with us anything that you've kind of found surprising or enlightening on this journey to developing these site saving treatments. Good thing.

Male:                          

I think everything is surprising. I don't do this every day, right? Just probably good, you got a healthy sense of kind of [inaudible 00:53:08] get some people around you that are mired in all of this, right? Which sometimes can be -- can bring you down because they're more than willing to sit there and list the 5000 regulations and you can just walk away and say, I could. It's a lot easier for me to stay in my lab and obviously all of our [00:53:30] discovery started there, right? It's kind of good, I think ignorance are like marriage and children. You don't want to know too much, you want to just enough and you don’t get scared off in the beginning.

Dr. Amy Laster:          

Right, Karina.

Dr. Karina Guziewicz: 

Well, I just want to say this maybe sound like same also, but please do invest in basic science because if you don't there won't be nothing to translate in not very too distant future, this is very important. We know for a fact that without understanding [00:54:00] the principle of the disease and the progress in development of effective therapy [Inaudible 00:54:06]. Yes, we all want to see new therapies and treatment on the market as soon as possible. To this end cutting edge science, yes, cutting corners? No. The latter is simply counterproductive.

Dr. Shannon Boye:     

Okay. I think one thing surprising for me is when you're developing something in a research lab, [00:54:30] it's just you, your mice, your Erg machine, you've got total control over what you're doing. You feel like you're doing it pretty well, and then you align with a company and they have a completely new set of ideas about how things should be done. They have maybe read about your study, but they haven't spent 10 years doing it. Striking a balance between, getting feedback from the people that are giving you the millions of dollars to bring this forward and making sure that you can [00:55:00] affect the type of study that you know is best because you're the scientist and you've been doing it for a long time. I think finding that balance is important and finding the right people to work with on advancing these therapies are super important.

Dr. Amy Laster:          

Great. I want to thank all of our panelists for this insightful information. If you could just join me and --

[Applause]

Dr. Amy Laster:          

Thank you very much, [00:55:30] so we will now have a brief 10 minute break in our programming. Please do use this time to check out of your rooms if you haven’t done so. There’s coffee and other refreshments in the back of the room but don’t go too far because we’ll be continuing in our programming shortly. As a reminder tuck into your chairs and just clear the aisles, thank you.

Retinal Degeneration Fund Portfolio & Emerging Company Updates

Male:                          

Few questions to some of our panelists. So maybe Christina, I can start with you. I know you've worked in some other areas of orphan medicine like a spinal muscular atrophy. Maybe you could just comment a little bit about some of the differences you've seen in working with inherited retinal disease compared to spinal muscular atrophy.

Christina:                    

It's not the exactly [inaudible 00:00:28]. I [00:00:30] would talk more about the -- what is similar, so we are in both case in a rare disease area. To push the program further there is always difficulty to found the company and its programs. What was more difficult with ACMA [PH] was that we did not had -- we had no [00:01:00] proof of concept, right proof of concept. It was very difficult to sell the idea to firm for that. We are more looking with our programs today, especially for PDE6 Beta for example. But on the other hand what is more difficult for us is that we are talking about very rare disease, very small population if we consider that we have a pearl gene approach. [00:01:30] For example, [inaudible 00:01:35] is a population estimated to roughly 1000 patient in U.S. plus EU five. This is very narrow and this is very difficult to sell to the investors. Considering that maybe one way is to mix the way of funding the company from both [00:02:00] traditional VCs and maybe the foundation can help. We are also trying to mix with non-dilutive funding from [inaudible 00:02:13] organization for example, from the Europe. Yeah, financing is a bit difficult.

Male:                          

Okay, got It thank you. I think we have a question in the back.

Female:                      

Hello, Holden this is Evon Chester [PH]. [00:02:30] Can you explain the differences between NEC and NECA and the effect those two different things have in the eye?

Male:                          

I will certainly try. I'm not -- I may call on Steve to tell you that the real truth. But basically it's considered that NECA is a pro drug to NEC and its primary advantages when the MI group is added to NEC it [00:03:00] becomes more lipophilic. You simply deliver more NEC through the blood brain or the retinal barrier. Did I do that all right Steve?

Male:                          

You did it perfectly. The MI gets cleaved off the active molecule is NEC, but it gets more concentration into the eye with the MI because of the transport, and as you said lipophilic.

Male:                          

I'd mentioned that one of the reasons Dr. Campochiaro had turned to us is out of all of the [00:03:30] attempts to experiment with antioxidants. The only one he got any reaction in the lab was NEC. It wasn't adequate and so he was looking for a better delivery technique.

Male:                          

Got It. Great.

Male:                          

Is there any reason why [inaudible 00:03:56] [00:04:00]?

Male:                          

Probably not, but then you don't know what you're getting is typically not GMP and you can't make any label claims. Typically that's not been a route that a series drugs followed.

Male:                          

Yeah, I’m just more concerned about in the real world of high price drugs versus readily available sort of -- [00:04:30].

Male:                          

Yeah, and the only other thing I would mention is that as we found out after a year of work formulating in a reliable and lasting manner was not easy. It isn't just a molecule, it can be thrown together without it being very impure and having no shelf life.

Male:                          

Great. All right, I think we have another question [00:05:00] in the back.

Male:                          

Yeah, I think you have a lot of patients and constituents across the Foundation Fighting Blindness who would be very interested in participating in a phase one safety trials. In part, because of their age, they may not be able to wait until 2029 or 2030. I guess my question for the panel and for FFB is how do you get the word out to prospective phase one [00:05:30] safety trial patients who could enroll?

Steve:                         

Really Brian should be talking about this, but the My Retina Tracker registry that is part of the foundation is really an important part of that, Jim, in that we have advertise My Retina Tracker. Quite a number of companies have come to [00:06:00] the foundation and asked who do you have in My Retina Tracker that would potentially be interested and have the particular gene or whatever. At that point, we can let those individuals know we never give out to the company or researchers any personal information. It always goes back to the individual and say, you know, here is a trial you may be [00:06:30] interested in, and if you are, this is who you contact.

I know that in quite a number of cases I know for AGTC, I know for some others in the room as well, that that actually has allowed enrollment to go much faster and to keep people in. In fact, the classic case is from years ago Neurotech with their implant of their neurotrophic factor after [00:07:00] the foundation advertised that Neurotech was looking for people instead of enrolling the trial in what they thought was going to be 18 months it was enrolled in six months. The bottom line is that My Retina Tracker registry is really the place where people should be putting their profiles in the genetic testing that's involved in that. It really is the gatekeeper [00:07:30] these days for clinical trials.

As you were saying, Jim, for people who are at a certain point where they have to make a decision, am I going to go into a phase one safety trial or am I going to wait further? That's where My Retina Tracker and the foundation are really out in front. We have companies coming to us on that in order to answer that. If you come to www.fightingblindness.org and you look at My [00:08:00] Retina Tracker and register in it and also in the eye on the cure blog, we always announce when a clinical trial is in fact starting.

Male:                          

Great. Thanks Steve.

[Informal Talk]

Male:                          

I think one of the key points in recruiting patients for [00:08:30] clinical trials is to have patients that are fully phenotype from the clinical point of view and then also fully genotype from a genetic point of view. In some of these classical studies this wasn't really done. What you then end up with having is a mix of different genotypes. Some may actually respond to the treatment, but most probably won't, and then your statistics in the end are completely messed up. A key [00:09:00] point is to have the right patient preselection to go into the clinical trial. This is, I think we're, the new trials are all going now.

Male:                          

Great. Maybe a question for Lynn [PH]. Since you've been in biotech for a while, you are successful CEO at some exits and you're sitting in RA Capital and sort of like an entrepreneur in residence, and you have a lot of things you can look at. What attracted you to Tom Ray’s technology [00:09:30] and to jump into IRDs for your next move?

Male:                          

Yes. When we looked at Tom Ray’s Publications, it was really a novel mechanism of action, the potential to have a mutation agnostic approach as well as having a small molecules that potentially could be delivered systemically. Those were the three key features. I mean the level of science is just phenomenal [00:10:00]. I think what Tom has done is spectacular and trying to understand how inhibition of these nuclear receptor hormones can affect rod cone dystrophies.

Male:                          

Great. Thank you. Francois, so you were working in a consortium of different academic centers to find new treatments and cures and you found something really cool. But can you just talk about some of the pluses [00:10:30] and minuses of being in a consortium like that? How do you manage it? How do you all get along and collaborate with such a diverse group of collaborators?

Francois:                     

Yeah, that's interesting of you to ask that. Yeah, it's not easy. That's the bottom line. No, but I think it all depends on finding the right people. If you can get along on a personal level, then it's probably okay. If you [00:11:00] have a feeling, oh, this person I'm not getting along with, then you should probably drop it even before you start thinking about it. In this drug for consortium, I was quite fortunate, this whole thing was set up from writing, from starting to think about it to submitting the application in five days, a 5 million euro grant, five days., and those five days were [00:11:30] very busy I have to say. This was really a chance event.

We just had an idea. We had three academic partners we wanted to put together so that we knew that, but we also needed to have industrial partners and we needed to have two industrial partners. When you think about that one is okay, but if you put in a second one, if that's a competitor, how's that going to work in a consortium? It won't. It has to be some other company [00:12:00] that has a complimentary something. We were lucky enough to find that and get them interested and they work really, really hard in those five days to get everything done. Yeah, if you start off like that then I think you can be hopeful that the rest will also go like that.

Male:                          

Great. Thank you, so we are out of time, so give me a quick round of applause for all our panelists.

[Applause] [00:12:30]

Male:                          

Thanks everyone. We're going to have a 10-minute break, we're going to break and basically clear for lunch. There's going to be a mad rush to get the tables ready for some food for you guys. Then we have a lunchtime speaker. Take the time for a quick break, and we'll see you back here in a few minutes.

Summit Luncheon Featuring Keynote Dpeaker Omid Karkouti, MS

Jason:                         

We have a very special treat now, we are going to take some time at the end of lunch, we’ll have probably good 20 minutes towards the end of lunch for everyone to certainly to socialize and have a nice little break from the day if you haven’t checked it out, that would be a great time to check out of the hotel as well, but we do have a really special opportunity here over lunch to meet someone. [00:00:30] His name is Omid and Omid has a unique story. So like many of the folks here today he has a career in biotech, he’s actually an entrepreneur like many other folks today, but he also has the unique perspective of not only being interested in this space from a business perspective but also from a very personal one as well. He’s a patient advocate because his mom suffers from Retinitis Pigmentosa and on the heels of leveraging his professional experience and his knowledge and his [00:01:00] personal passion, due to his mom. He’s created a brand new company called Perception Therapeutics. He’s just founded it this past year and like many of those in the room is learning the trials and tribulations of starting a biotech from scratch. In this case, the unique experience of a biotech focused on developing AAV-based gene therapies, which brings along with it its own unique experiences. I am anxious for you all to hear his story. So with that, [00:01:30] I’m going to do introduce Omid to the stage. Mr. Omid.

[Applause]

Omid Karkouti:           

Thanks so much Jason for the introduction. It truly is an honor to be here to speak with you all about my experience as a patient advocate for my mother who suffers from RP and then further, really to talk to you about the founding story of why [00:02:00] I came to be an entrepreneur in this space, which is also closely tied to the Foundation Fighting Blindness as I crystallize really in it from, my attendance of the Visions Conference last year in San Diego.

We’re all here because someone in our lives, [00:02:30] someone that we’ve met, someone we’ve treated in the clinic, someone we’re sitting nearby here in this room has lost vision or is losing vision. Really the point of my being here and the reason for my being here is, is to think about a model where we can develop retinal gene therapies with patients in mind. The patient that I’m thinking of and for more than one reason. She’s the reason I’m here, it’s my mother, who suffers from Retinitis Pigmentosa [00:03:00] due to mutations in the CNGB1 gene. My experience with Retinitis Pigmentosa has really been, well, my mother was diagnosed in the 70s in London. She traveled from Iran to London to get her diagnosis. At the time, as many have alluded to here today, there was really nothing, the physician said you should try to wear sunglasses outdoors and prepare to lose your vision over time.

                                    I’ve been looking at [00:03:30] gene therapy since I started grad school at Baylor College of Medicine in 2004. At the time really there, it was a really interesting research tool. I worked in the virology department, so I had a lot of lectures on it and learned that, you could cure mice of different forms of blindness using AAV-based gene therapy. So since then really been thinking about that, but up until the regulatory approval of Luxturna, [00:04:00] it was still in my mind a really, really interesting research tool that was, you know, moving its way towards, clinical trials. Then perhaps one day there would be an approval of a gene therapy. You know, December 2017 we got the amazing news of the regulatory approval of Luxturna.

You can have a gene therapy based on AAV in the United States for diseases caused by mutations in RPE65, which is amazing. Around that time [00:04:30] is when we looked at, actually we did the genetic screen offered by Spark Therapeutics. My mother’s gene was not present in their initial panel of 31 different genes, so we worked really hard to try to find someone to help us find out what was the causative gene of my mother’s disease. We’re fortunate enough to connect with, Jackie Duncan at UCSF, who actually signed us up on that [00:05:00], my retina tracker patient registry. So we were the beneficiaries of that service, and got the affirmative diagnosis of her RP. There’s a CNGB1 because of that. Once we knew that I went straight into the literature, well what do you do there? I have enough science I guess to be dangerous and I looked and saw that CNGB1 is actually likely one of the best modeled and also as far as preclinical efficacy data, at the top of [00:05:30] having data that shows that you can treat this with an AAV in mice and we showed that in 2012 and further a spontaneously occurring mutation in Papillon dogs, that was discovered at Michigan State University and Simon Petersen Jones lab and later showed that you could treat those animals, effectively with AAV as well, expressing the multi-type gene.

                                    So this was really lined up for me. I thought, okay, I’m going to find out what company I can convince [00:06:00] to do this or if I can’t convince anyone to do it, then well, I’ll figure it out, see if I can do that myself too. So that really, also Dr. Dunkin [PH] introduced me to the, the Visions Conference and said that you should definitely try to attend. Last June I went to San Diego. I traveled there with my wife who’s a proper scientist with a PhD and she helped me a lot in going through the literature before we got there. I think I bugged [00:06:30] lots of folks in the room here and others who aren’t here and a couple of who I’ve been closer to, and so there I met, Benjamin Yerxa, Jason Menzo, I met Trevor McGill. I met Brian Mansfield and then a bunch of other clinicians and scientists that I wrote ahead of time. I actually had 14 meetings in two days during that conference besides attending the programs, which is awesome, and everybody said, yes. Okay, I’d like to talk to you. Let’s talk about your approach. So really, truly coming from different industries coming from, [00:07:00] you know, more recently working in oncology, this is the ophthalmology community. The IRD community is amazing. I love you guys and thank you for being welcoming.

So, the initial funding for my company, it’s a small amount of funding from the Y Combinator startup accelerator in the San Francisco Bay area. I’ve really learned about company building, company formation and venture funding from those guys. That’s the same accelerator that has like companies [00:07:30] like Airbnb and Dropbox if you’ve heard of them, but the purpose of perception is to, to enable gene therapy development for blinding genetic diseases that are not presently industry priorities and for personal reasons and also for practical reasons. We’re focused on Retinitis Pigmentosa. So RP, as many of you know, affects more than 2 million people worldwide, and it’s a phenotype [00:08:00] . So it’s really not one disease but rather 94, at least 94 different diseases that have a similar clinical presentation, leading to progressive vision loss and in many cases blindness.

So, I looked at this and looked at the genes and started saying, well, if I was going to treat these and thinking about CNGB1 as something that’s a personal priority, how do I prioritize other ones to work on, to make a pipeline to make a company? [00:08:30] Looked at really what AAV gene therapy compatible with in terms of the method of in, the mode of inheritance of the disease primarily focused on recessive and, and more specifically autism or recessive RP. Then also what fits in a single AAV vector because that is the current paradigm, the current technology. What kind of modeling after Luxturna further can we drill down a bit further and see which ones have animal models [00:09:00] and there’s more than 50 genes compatible with the current AAV gene therapy. Technology and further there’s reasonable animal models for 28 of these, and beyond this, with the approval Luxturna we know AAV is safe. There’s an established scientific path. There is a clinical development path with the end point that is a primary clinical development end point that is applicable to r Retinitis Pigmentosa. The FDA will approve gene therapies in the eye, which is, [00:09:30] pretty much everything that you could possibly ask for in terms of scientific, clinical and regulatory de-risk.

                                    So that makes the question, why isn’t anyone working on my gene? Not only for CNGB1 because there are many people who are working on that in terms of the preclinical studies and, but this applies more broadly to more folks who are affected by RPs, as these different knife or different diseases. Many of them are ultra-rare with less than 3000 affected [00:10:00] U.S. patients. I keep hearing these snippets, these words from folks and these, these kind of stick to me. There’s too many genes. Well, you know, 94 is a lot. 50 of those are compatible with existing technologies. It’s a lot. Sure. But, you know, does that mean then you need to do 50 clinical trials? Well, probably that’s a lot, but there’s a significant opportunity [00:10:30] to and economic value in developing therapies for patients that are effective.

                                    The other quote here is really something of my making, and in that we ran a lot of financial models on looking at AAV gene therapy and ultra-rare inherited retinal disease and focusing on RP. After a certain point, the therapies, the diseases become rare enough that it becomes hard to make an economic case to work on them, but I’m not really solving [00:11:00] for an economic case for standing up one. I’m trying to solve for an economic case for how can we treat all. I think that there is a ton of value both economically and for patients in using the existing, the playbook that works, that leads to regulatory approval. So how do we redefine financial priorities? First looking at this and solving for, financial models to treat every [00:11:30] gene and is that even possible? Well, I luckily have friends who are better at financial modeling than I am and we’ve looked together at this really closely and saw that the economics really improve as you, if you can develop a portfolio of assets in this space and especially if you can use efficiencies that you gain from the first example of this or the first group of examples of these types of therapies.

                                    Second, we really did have an exhaustive [00:12:00] review of the gene therapy preclinical through clinical development path and saw lots of areas for potential improvement and we’re really, really targeting efficiencies that enable scale because sure this is going to work and you can treat one and I might be able to benefit personally, in some way my family and then people who are affected similarly, but what about everybody else? You have to make a scalable model in order to address more patients. You know, through this financial modeling and also looking at the opportunities [00:12:30] as a portfolio and looking at potential efficiencies, we have an initial pipeline that, we believe covers about 15% of autism are recessive RP. We’re still very early. This company, I’ve started working on it full time, truly last October. So we’re in the stages of really modeling and starting the clinical studies, but I’m very hopeful that this will be very impactful and this will be a model that other companies can use to. So how do we get there? [00:13:00]What makes it scalable?

On the left we’ve got a couple of challenges here. Obvious ones, what’s the development cost and what is the market size? I look at these challenges as instead opportunities to break up part what we think is true, try to remove bias from the discussion as what we think we know as far as the development of gene therapies and see what parts we can do, we can potentially innovate. So can you break off the development in two different [00:13:30] modules? Looking at preclinical efficacy, looking at IND-enabling safety pharmacology and toxicology studies. Looking at the IND itself and writing the IND at which, which Dr. Bennett was, kind enough to go through exhaustively and say how much work that is, but if you have a pipeline and you’re treating similar diseases, could you make all that documentation effectively copy and paste from the first one you do or the second one you do?

Opportunities for manufacturing efficiencies in terms of both research grade material [00:14:00] and clinical grade AAV production and then also how can we engage more actively with the FDA in order to get them to agree to different things like a clinical trial design or different kinds of CMC methods that translate across different forms of therapy that use the same type of background, AAV vector background. Then second for market size really well, we heard about my retina tracker today and I truly believe that in order to make, to build the market in gene therapies for inherited retinal disease, every person with RP needs to get a genetic diagnosis. In some cases we won’t find it. We want know what the causative gene is, but the more people that we identify and promote this to it really the result is you have patients for clinical trials, as we all heard today. So, my goal is also [00:15:00] as part of perception to invest early in this type of activity and work closely with FFB to promote their programs in the space too.

This is a super obvious statement, but the economic model improves a lot as you drive down costs of development costs and you drive up the market size for the therapies that you’re developing and the patients that you can treat. So I apologize for the using a diagram here, but I’ve tried to overly simplify this and also think of this [00:15:30] as a very, very aggressive model in terms of timelines.

                                    Let’s say you have a whole portfolio or a whole pipeline of assets in this area. There’s certain things that you have to do. You have to do preclinical efficacy studies. You have to do some form of manufacturing the product that can work and research animals, safety pharmacology and toxicology in clinical manufacturing and can you make this efficient and pretty much the same for every single gene therapy that you intend to develop for this [00:16:00], for autism or recessive RP. If so, then once you have the clinical grade material and you have the IND package set up so that it is not a monumental amount of work each time, can you take that into clinical trials where patients have already been screened? So many patients have already been prescreened that it doesn’t take you a long time to recruit for this day. Then further is there a clinical trial designed that the FDA will accept that is shorter [00:16:30] with potentially a longer follow up period and then taking advantage of things that are available for orphan diseases, which we heard very exciting news about the accelerated pace that the folks at [inaudible 00:16:40] doing in developing their antisense oligonucleotides.

Can I be optimistic? Yes, because I don’t want to be held by the same. I don’t think that we need to be held to the same rigorous standard and it cannot take 16 years for the next therapy, next gene therapy [00:17:00] from start to finish to go to market. We don’t have that much time and the patient community doesn’t have that kind of vision left.

                                    So, our plan is really to use CNGB1 because of its extensive preclinical data. Yeah, the proof of concept data having a relatively high prevalence amongst autism or recessive RP and running the financial model and actually seeing that it stands up as its own [00:17:30] as a therapy to build the tools to make this process happen and be reproducible and further validate this development engine that if we can build all the component parts, turn the crank on and make more gene therapies happen. So, I have limited knowledge but I have a lot of really good friends and through FFB have been able to connect with a lot of excellent scientists as well. This slide just shows photos of [00:18:00] different folks who are working with me on the company now.  They include Joey Leatham [PH], Chief Scientific Officer. Johnny Chan, who’s actually my college roommate, I’ve known him for 20 years as Chief Operating Officer and my wife Elizabeth IORNS, who is cofounder of the company with me. Then scientific advisors. Some of these faces are probably all of these faces you all know except probably Mike on the right represent Simon Peterson-Jones at MSU.  Trevor McGill, who’s sitting here at [00:18:30] OHSU, Dr. Hauswirth at University of Florida. Your FFB’S own Brian Mansfield and then also a friend of mine who’s kind of a regulatory wizard that’s Mike Curly as scientific advisors. We’re really just getting started. So, I think about our progress and we’re moving as fast as we can on the limited resources that we have at the moment, but we have recruited a team and advisors. We’ve licensed key IP and we’re demonstrating its performance in multiple different species [00:19:00].

Further, we’re planning to conduct our preclinical efficacy studies. They’ve not yet kicked off, but that’s in the works.  Beyond that, we’re looking forward to shortly an intro call with the FDA in order to talk about a lot of the different ideas that we have in terms of process efficiency and also we are further developing a patient centric online community where we can use some of our [00:19:30] insight and in-house knowledge, in terms of industry best practices for marketing, outreach and lead generation that I’ve used in the past as a business person and our CEO Johnny has used in the past to. Market consumer products, to get the most - the word out about resources available for inherited retinal diseases and drive more people to get their genetic diagnosis.

So, you know, at the moment, we’re meeting with, [00:20:00] different folks as far as potential investors, investing in some technology and trying to move forward some of our preclinical data in CNGB1, but fundraising to progress up to, to make progress in that program as well as, move forward some of the additional pipeline of assets and also validate the platform.

                                    So, really in closing, what I want to impart and impress upon you is that this is a, I believe that this is a singular time in biomedicine where [00:20:30], what was yours not too many years ago a research tool, can be used now to effectively treat disease and be approved by the FDA. We’re not trying to be out there trying to be like the most brilliant minds here who are innovating and inventing the new technology, but instead we are thinking of the best way to apply existing and current technology to the development of as many therapies as we possibly can for [00:21:00] and make it possible to treat a disease that doesn’t have too many patients out there. Further investing in the infrastructure in order to be able to find everyone in the community, and working with existing organizations like FFB too, to get the word out about those resources as well.

So, I thank you very much for the opportunity to speak to you all, telling you a little bit about my new company and I would be happy to field any questions. Bear in mind, I’m not an ophthalmologist [00:21:30] , a business person who knows something about virology, but the other kind folks that I showed you before are - follow up with me and I can get answers to most of the questions through the, through the friends and the advisors that we have. Thank you.

[Applause]

Jason:                         

[00:22:00] Are there any questions?

Omid Karkouti:           

Okay, thank you.

Public Company Forum

Male:                          

Please take your seats we are going to start with the afternoon session now. That was very good everybody that was impressive. I expected to see that at least five or six more times so that was terrific. We do have a fantastic afternoon program scheduled. We’ve been on a journey so far right, so we [00:00:30] started this morning with Brian [PH] giving us a really good landscape and current state of affairs with regards to the IRD marketplace and the landscape. Then Steve moderated our panel on preclinical. We have the Art of Translation and then we got to meet some of the portfolio companies and some of the companies that could be in the portfolio of the RD fund. Those small biotechs that are coming out and making their way, and now we’re transitioning to [00:01:00] a different stage. We’re going to be speaking with some publicly traded companies and to moderator is our very own Dr. Rusty Kelley.

[Applause]

Dr. Rusty Kelley:         

All right good afternoon. I’m Rusty Kelley for those who weren’t at the earlier session. I’m the Vice President of Investments & Alliances in the Foundation and work closely with RD Fund and the RD Fund board as well [00:01:30] Ben Yerxa. Welcome to the public company forum. During this session you will hear some updates from various leaders of publicly traded companies who are pursuing both preclinical and clinical programs, inherited retinal diseases. Joining us on this panel, we have Sue Washer, CEO of AGTC, Bob Ward CEO of Eloxx, Dr. Bill Marshall CEO of miRagen, David Fellows CEO of Nightstar Therapeutics and Dr. Kourous Rezaei CMO [00:02:00] of Opthotech.

We had a six speaker Zandy Forbes, the CEO of MeiraGTx, but she is busy in London integrating the new partnership with J&J so it's exciting times for our industry. The market is starting to heat up. We're happy for Zandy and her team and some of her representatives are here, including Blair [PH]. We have five companies representing this panel that cover some of the genetic strategies [00:02:30] that Eric Pierce discussed earlier. In this case we have three gene therapy companies and two RNA modulating companies.

To begin, I'd like to welcome Sue Washer. Sue Washer is the President and Founding CEO of AGTC. She's an accomplished executive in the Biopharma industry and she has transformed AGTC from a small academic spin out to a leader in gene therapy. A shameless plug for FFB, we have funded the RS1 program [00:03:00] and this is via the Martha Neuringer’s lab at Oregon, Robert Molday University of British Columbia, Bill Hauswirth at University of Florida and Jeff Chulay of Walter Reed, who is now a staff at AGTC. Welcome Sue.

Sue Washer:               

I know everyone's had trouble with this mouse, so I'm going to see what I can do. Look, it works. Forward looking statements this is a slide that every public company has to get [00:03:30] put up and no one's supposed to be able to read it, so don't worry about it. We just have to put it there. The next slide is talking about how we need to keep the patients need insight. We are a very patient focused organization and it comes from our very early, as Rusty mentioned, relationship with Foundation Fighting Blindness. We have a very active patient advocacy group in it. We feel this is very important even from the very beginning [00:04:00] stages because one thing we learned through our active work with patients in one of our areas, which is achromatopsia is that the thing that the achromatopsia patients cared about the most was light sensitivity.

Yes, they'd like better visual acuity. Yes, they might like to see colors, but light sensitivity was the one thing that really caused them to have difficulties. That allowed us to work with the patients, work with people at Bascom [00:04:30] Palmer to come up with a quantitative light sensitivity test. This has been very, very useful in our clinical development, it’s something the FDA is very open to. But I point that out as an example of why it's important for companies from beginning to end of the life cycle of a product to keep the patients need insight.

This is our comprehensive product profile. What you'll see here are some yellow bars on a dark blue background [00:05:00] and hopefully you can see those. What this points out is that we have three programs in clinical development that are right now in phase 1/2 clinical development. Achromatopsia, there’s two different genes that cause achromatopsia so we have two trials in that indication. We have a trial in X-linked retinitis pigmentosa caused by the RPGR gene. What these bars tell you is that we are in that phase 1/2 development and our guidance has been that we'll [00:05:30] complete enrollment and be able to provide the interim six month data on all three of these programs by the end of this year. This is going to be a very, very exciting year for AGTC. We're thrilled to be at this stage of development.

As Rusty pointed out, we've gotten lots of support from the foundation through the years. I want to point out two ways, not just the funding to the academic researchers that did some of this work early on, but also funding to us to help us [00:06:00] with development of preclinical models and testing in the preclinical fashion. Then most importantly to the current stage of development is My Retina Tracker that the foundation has put together. We have found to be incredibly useful to identify patients because you think about these trials, there's only 24 to 30 patients in each of these trials. But we really have to screen through hundreds of patients to be able to find the patients that are the right patients to have [00:06:30] in these very early trials. You want to give yourself the best chance to get a clean signal that you can take to the FDA to be able to advance the trial. Your inclusion, exclusion criteria are usually set quite carefully.

While a patient might not be appropriate for the first in man trial, we keep track of those patients for later clinical development. For instance, in between achromatopsia -- the two achromatopsia programs and the XLRP program, we [00:07:00] have been in contact with almost 700 patients that we have talked to and talked to their care provider. Then have made it some part of the way through the screening process. Some of them meet all the criteria that are very strict in these first in man trials and some do not. But again, they may be eligible for later development.

The other thing I did want to briefly point out on this slide is the optogenetics program. Some of you heard about the optogenetics technique earlier today. [00:07:30] We are going to be filing an IND in this first half of this year such that we'll be treating patients by the end of the year in an optogenetics program. This is a program that is more forgiving of the specific genetic defect. It is a way to put light sensitive proteins into the eye and help create vision through transducing of retinal ganglion cells. We have a very carefully engineered version [00:08:00] of this light sensitive protein that holds a lot of promise.

One thing I wanted to talk about and kind of this ties back to why it's so important to have a connection to patients. That is this, I know this audience is well aware of is that there are many, many different inherited retinal diseases. I think that many in the general public would say, well they're all the same, they’re similar, they are diseases that cause vision loss and cause poor vision. But what we [00:08:30] all know is that these diseases are extremely different from each other. Depending on which part of the pathway that allows vision has a genetic mutation, the specific phenotype can be very, very different. It can affect different cells, whether they're retinal ganglion cells or cones or rods or unfortunately in some cases both rods and cones. How you develop the product needs to be specific to the genotype [00:09:00] phenotype of each indication.

It unfortunately -- it would be easier for all of us if it was more of a one size fits all. But the physical delivery, the nature of the vector, the nature of the promoter that drives expression and what cells you're trying to get at is all very, very different. That's what something we pride ourselves on is to take those differences into account as we're designing and developing therapies. This slide provides a little bit more of an [00:09:30] explanation about the different parts of a gene therapy vector. You heard some of this, this morning. There's a lot of talk about the capsid, which is the outside of the vector and that capsid interacts with your cells and hopefully delivers genetic information. There's something called a promoter that allows the gene to be able to make the protein and that's very important.

Manufacturing, we heard about GMP manufacturing [00:10:00] and how important that is because regulatory agencies think of the process as the product. How the process goes is how the product gets defined. Then finally, vector administration I think there were a lot of good talks this morning about intravitreal versus subretinal injection and how that affects the response to the vector. All of these things, just again, taking it back to the patient, you need to understand what the specific patient's needs are, the specific characteristics [00:10:30] of the clinical indication and develop your product accordingly. Again, we are thrilled to be at this stage of development through the support of the Foundation Fighting Blindness. This is going to be a very exciting year for the space and, and we're excited to take part in it. Thank you.

[Applause]

Dr. Rusty Kelley:         

Thank you Sue. Our next speaker is Bob [00:11:00] Ward. Bob Ward is the chairman CEO of Eloxx Pharmaceuticals. Bob previously served as the President and CEO of Radius Health, Inc. the top performing IPO in 2014. Prior to Radius he served in various executive roles including NPS, Schering-Plough, Pharmacia, Bristol-Myers Squibb and Genentech as well. Eloxx is a clinically staged company and their lead is in cystic fibrosis and they're developing their ophthalmology program. [00:11:30] Thank you Bob.

Bob Ward:                  

Thank you very much Rusty for the invitation to participate. It's our first year here with FFB and we're launching our new ophthalmology program. But I wanted to say that the reception we've had from FFB has been fantastic. When we think of having worked with patient advocacy groups or foundations and a variety of therapeutic categories over the years, the experience we have with FFB has been fantastic. It's part of what played a role of us prioritizing ophthalmology in our portfolio. During the course of today's [00:12:00] presentation I will be making forward looking statements that I'd asked you to refer to our recent filings with the SEC. We will have an earnings call this upcoming Friday for those of you who would like an update on the program.

Eloxx focuses on a cluster of small molecules that were invented by a medicinal chemist and a university. Based on the understanding that we knew that Aminoglycosides led to a low rate of improvement in rare diseases when patients [00:12:30] are being treated for bacterial infections, that first observations are probably 30 years old. Today we know that because of the way the Aminoglycosides interacted with the ribosome, that they restored protein production where proteins were not being made that had an essential function, and that's because of a single nucleotide change in the gene. Here's an example of inherited retinal diseases where you can see that the nonsense proportion says, of all of the [00:13:00] changes of the genes of interest, what percentage of the individuals have one or two copies of the gene that would have a nonsense mutation? It typically ranges from one out of ten to as high as four out of ten patients in different disorders.

Now with these small molecules, when we have the right concentration of drug in the tissue for the right period of time, we can restore protein production. When we think about [00:13:30] intravitreal administration, much like Lucentis or Eylea, with monthly administration we anticipate that the molecules would be able to restore protein production across a number of different inherited retinal disorders, while one will be selected for clinical development. Because in the original development program we need a patient population that's sufficient to meet the regulatory standards. We will be giving more information about our ushers program, on our call this upcoming week. [00:14:00]

Now, the way the molecules were selected is that the binding site is been known so 170 novel molecules were created and then screened to ask the question of do they affect the ribosomes in our cytoplasmic? If you pictured your cell like an egg with the yellow part of the egg being the nucleus and the white part of the egg being the Cytoplasm, protein production happens in the cytoplasm. But when gene's first manufacturer messenger RNA [00:14:30] in the nucleus, if there's a premature stop code on that messenger RNA may be degraded. One of the reasons why premature stop codons limit protein production is the message itself can be degraded. We selected molecules that had strong activity in the cytoplasmic ribosomes, but no longer carry the baggage of Aminoglycosides. Remember Aminoglycosides cannot be taken for a long period of time and we're looking for molecule suitable for lifetime [00:15:00] use.

In the course of Eloxx which started as a company back in 2013, various molecules have been shared with academic groups around the world. Six different molecules have demonstrated the ability to produce proteins in a variety of different inherited retinal disorders, but much of that work was demonstrating the potential utility. At the end of 2017, I came into the company as well as a group that had [00:15:30] many of them had worked with us previously at Radius where we led approval in 2017 of Tymlos [PH]. Over the last five years, we've raised about $189 million for medical research, including up-listing Eloxx earlier this year. We're really looking for now how can we drive development and successful registration so we can take some very interesting preclinical compounds and turn them into approved therapeutics that can be used for managing patient health.

So [00:16:00] when we think about what do we know about the molecules today, we know that they have a defined structure that binds to the target of interest. We have completed screening on retinal safety parameters looking for preservation of electroretinogram, limited impact on the retina itself, stability of intraocular pressure. On this Friday's call we'll mention that we've hired our lead ophthalmologist, a very experienced [00:16:30] clinical scientist who's led programs at a number of major companies, we’re excited about having her join the company. Then once she's on board we'll be out with an update of our timeline for IND, and entry into the clinic in Usher syndrome as our lead focus program.

In our portfolio itself we currently have a program focusing on cystic fibrosis that will be in phase 2 this year. We'll report top line data later this year. We're really delighted to have an opportunity to [00:17:00] participate with FFB, to be in ophthalmology at a time where the next 10 years are going to be so dramatically amazing when it goes from area where symptoms might have been used to describe disease. In the future it will be a molecular medicine where people want to know what is the molecular basis of what's happening? There'll be specific target interventions for different [00:17:30] molecular changes. Remember we're working on small molecules that affect basically just a single nucleotide change in a gene. It's very likely that for our children or for our grandchildren, those will be edited and cured. We’re working on treatments today. The future is very bright and we should expect that changes will be dramatic over the next 10 to 20 years. We couldn't be happier to be here and I want to thank FFB for including us today.

[Applause] [00:18:00]

Dr. Rusty Kelley:         

Thank you Bob. You've probably seen Eloxx and MeiraGTx’s name sponsors of this meeting. We really appreciate our corporate sponsors. In Eloxx’s case we are working very closely with them on the preclinical side, pairing them with the right KOLs and models including [00:18:30] those models that are in cell culture. They've been very successful in their cystic fibrosis program with the organoids. The same is unfolding in the ophthalmology space where we have retinal organoids that can be screened for these read through technologies. Our next speaker is Bill Marshall. Bill is the CEO of miRagen. This is another [00:19:00] RNA modulating company. Prior to miRagen he was the VP of Technology and Business Development for Biosciences at Thermo Fisher which was acquired. Bill was also one of the founders and executives of Dharmacon. Welcome Bill.

Bill Marshall:             

Thanks Rusty. I want to thank the FFB for the opportunity to speak with you today and talk to you a little bit about [00:19:30] miRagen Therapeutics. miRagen is working in an area, we're a pure platform technology company and I'll make the disclosures as well that we are -- I'll be making some forward looking statements today. I would encourage you to access our SEC filings. miRagen is focused on the modulation of microRNAs rather broadly and people probably wonder what is a microRNA. When the genome sequenced almost 18 years ago now, what was a really fascinating observation [00:20:00] was we thought there was going to be a lot more genes in humans than other organisms. It turned out that if anything we may have fewer genes than mice, but we make almost 75% to 90% of that genome into RNA. A very small percentage of that gets converted into protein.

What we've been trying to figure out for a long time is what is all this RNA doing? We started miRagen in 2007 to begin the task of really going after what is [00:20:30] likely the bigger part of the genome here. One of the interesting subsets of these non-coding RNAs is something called the microRNA. As the name suggests, they're small RNAs. They bind to a ribonucleoprotein particle within the cell, and the cell actually expands about 5% of its energy just making these complexes. When that molecule binds in that ribonucleoprotein complex, instead of acting on a single [00:21:00] gene at a time. What it does is it orchestrates, coordinately orchestrates the expression of entire pathways and networks of genes.

What we've been able to identify over time is that there are certain microRNAs that become pathological because their expression is reinforced by - their miss expression is reinforced by the deficiency in the pathway that they've now introduced. What we've done, [00:21:30] is spent a lot of time, we have three clinical stage assets at this point. We are a bit agnostic to therapeutic area. One is in hematological malignancies and oncology more generally, the pathologic fibrosis asset, which is currently in phase two, scarring study is one that we intend to move into the ocular setting. Then, the third asset is one that's focused on the generation of new blood vessels. This is partnered with a European pharmaceutical company called [00:22:00] Servier and that's being analyzed in heart failure.

We are looking at a broad spectrum of opportunities, but the eye and the high unmet medical need, the fact that we could actually orchestrate complex multigenic events culminate in something that could really be disease modifying, really was an extremely exciting opportunity. We have really moved in trying to demonstrate that these microRNAs carry out [00:22:30] a important regulatory route n various diseases. We have, you know, as I said I'll talk about are a REM Larson asset, which is a for pathological fibrosis, should have broad applicability in ocular fibrosis. But I wanted to start with an earlier stage program. This is again in preclinical studies at this point. It's called the microRNA 183 cluster.

This is a really fascinating, a microRNA cluster. It's a, [00:23:00] a non-coding gene. Essentially when we began to talk about these things, we're not actually making proteins. We are making -- the cells are making transcripts and these transcripts then, as I said, dictate complex biology. The miR-183 clusters are a very interesting transcript of this type. It's only expressed in sensory organ cells and it's expressed at very high levels in photo receptors. If [00:23:30] you have a sort of a homeostatic condition in place, this microRNA is making sure that the relative expression of different genes in that pathway are all controlled and business is occurring as usual.

What you'll find with this particular cluster, it's expressed in photo receptors, it's expressed in hair cells in your ear, it's expressed in your olfactory system where it regulates smell and taste. In the photo receptor system [00:24:00] what's been observed to some very compelling evidence to suggest that this microRNA is an important player in retinal degeneration and retinitis pigmentosa. Again, this particular target is one that should be rather agnostic to individual gene mutations. When we look at the set of genes that is regulated by this particular set of microRNAs, you can see there's a whole host of different networks that are regulated [00:24:30] involved in photo receptor maturation and maintenance, programmed cell death, phototransduction, membrane trafficking, ion transport. It really is going across a very broad range, coordinate regulation of a process. This is a very powerful opportunity.

The genetic disruption of this cluster results in syndromic retinal degeneration and increased susceptibility to light damage. It's been implicated in both dominant and recessive forms [00:25:00] of RP. What we also know is that if the simple expression of this microRNA cluster is sufficient to maintain adult cone photoreceptor inner segments cilia, outer segments and normal light response. There's a lot of good supporting evidence that this both from genetics, and observations actually in human genetics, that this is a vital cross gene factor in maintenance of [00:25:30] photoreceptor function.

What we've been able to do is now really look at can we take out oligonucleotides that replace this microRNA cluster and put them in the disease context. What we've been -- I want to thank Dave for the introduction today was the -- the most entertaining a introduction I've heard by far I would say. Dave was obviously an important part of miRagen for many years, but what he also pointed out today was that oligonucleotides, [00:26:00] synthetic oligonucleotides are really -- it's a preferred compartment. Again, much like with gene therapy where we can have long term effects of single administration of these compounds.

What we've been able to show with the synthetic replacements is we can do single intravitreal injections. This pharmacological replacement we can show that we actually modulate all the downstream biology, which we would anticipate from this particular cluster. When we've put this into a [00:26:30] couple of different models of retinitis pigmentosa, what we found is that we're able to preserve function and vision, visual acuity in these animal model systems. We are currently at a point with this molecule. This is the earlier stage of the two assets I'm talking about today, is really those preclinical systems that will allow us to move into the IND-enabling studies to be able to move this forward. We believe that this is a real opportunity to effect [00:27:00] a broad range of different causes of retinal degeneration with what should be a significant disease modifying therapeutic agent.

The other thing I wanted to cover quickly today is actually an asset that is in phase two now. This is an asset called REM Larson. it is a replacement of microRNA 29. microRNA 29 has been very broadly implicated in a pathologic fibrotic conditions including in the eye [00:27:30]. The microRNA itself, we've shown is that, and others have shown is that it inhibits inflammation, it affects TGF-Beta activity, the full fibrillogenesis cycle. What we did in phase one and now in phase two in humans is demonstrate mechanistic proof of concept. What we can say now with confidence is that REM Larson can replace miR-29, and it's able to regulate the entire [00:28:00] fibrillogenesis pathway as well as various factors that appear to lead to benefits in terms of healing and reduction in scarring.

The agent is in phase two now it's ready to move to the next stage. There are two opportunities that we have afforded in the eye with this particular asset. The first is in retinal degeneration, we've been able to show a variety of different stresses actually cause miR-29 to be lowered. When miR-29 [00:28:30] is lowered we see fibrosis in the eye. In a variety of retinal fibrotic conditions, we see this, we've been able to do intravitreal administration of mimetics in this area and shown that we can actually invert that entire fibrillogenesis pathway.

Another area that is likely not as interesting to this group, but one of very high unmet need in the eye is actually in the area of corneal fibrosis. This an area of, [00:29:00] again, very high unmet need. It's a large cause of blindness in the world. What we've been able to show in this context is that REM Larson windows topically is able to enter all the relevant cell types. We get a massive reduction in scarring and hazing in the eye. Not only that, it appears as though this asset actually facilitates the healing of the eye, in these settings. We're very excited to move REM Larson into opportunities and ocular fibrosis [00:29:30]. Again, whether it's in the setting of retinal fibrosis where multiple ideologies could induce fibrosis that becomes either limiting to current therapies, for instance, in the area of AMD and also in the areas of things like retinal detachment. Then again in the area of corneal fibrosis to be able to provide a pharmacologic agent that may actually be able to address this condition that can really only be addressed today, with transplantation. [00:30:00]

We're very excited as a platform technology company, we need to work with partners. The FFB has been a great asset to us. We're very excited to continue the discussions with the FFB and also interested in partnering with companies that might be interested in continuing to push these assets forward. Thank you for your attention. It's been an absolute pleasure to be at this meeting. It's my first time and it's a phenomenal group at FFB. So thank you very much. [00:30:30]

[Applause]

Dr. Rusty Kelley          

Thank you Bill and it's worth noting that some of his team came out of, GlaxoSmithKline here in the park and he's also on the board of Ribometrix [PH] which is a Hatteras funded company. Our next speaker is Dave Fellows, he’s the CEO since January of 2015 of Nightstar. He was previously the VP of J&J, he’s head of marketing, global marketing. Then prior to J&J, he was with Allergan for 20 years. [00:31:00] FFB funded, several programs at Nightstar, some of the early work out of Miguel Seabra’s Lab, Lisbon, Portugal on REP1 and XLRP. Dave, welcome,

Dr. David Fellows:      

Thank you Rusty. I wanted to thank FFB for the time, but also their flexibility. As many of you speakers probably know they're very rigorous on their slide count. I was fortunate [00:31:30] to be able to convince rusty after extensive negotiations that my disclosure and disclaimer slide does not count against my slide, So thanks for the flexibility.

One of the questions I often get from people is where did the name Nightstar come from? Actually it comes from one of the very first patients that was treated in our choroideremia trials in Oxford. This patient happened to be an astronomer and very active [00:32:00] trying to look at the stars. In choroideremia one of the first problems people face as they lose their night vision. Early in his 20s this particular patient was no longer able to see stars. Fast forward 20 years, he had enrolled in Professor MacLaren’s choroideremia trial. Literally four weeks after the injection of the REP1 gene, he was out on his patio in London looking up into a clear night [00:32:30] and actually saw stars for the first time in two decades.

[Applause]

Dr. David Fellows:      

If you hear him tell the story, he said I ran into the house and it was past midnight. He'd called Professor MacLaren or as he says, I gave him a tinkle on the blower. Thanks Professor MacLaren profusely for the ability to see stars, so that is where the name Nightstar came from. We are in a phase three registration trial [00:33:00] for choroideremia. This trial is currently enrolling. We finished the investigator sponsored trial data about a year ago and we finished dosing 32 patients in that trial, which led us into our phase three trial. Importantly, we were able to secure, one of the very first designations RMAT designation. This is the regenerative medicine advanced therapy designation very similar to breakthrough therapy that the FDA grants. [00:33:30] This was the first ocular gene therapy program that was able to secure this designation. Importantly, what it means is that we're able to have an ongoing regular dialogue with the FDA. We were also able to have an expedited review and as we prepare our license application, otherwise known as a BLA, we're able to submit certain sections of that as we complete them as opposed to waiting till the entire BLA is put together and then [00:34:00] submit it. That should actually expedite the approval process.

Our second program is in X-linked retinitis pigmentosa. We finished a dose escalation trial in 18 patients earlier or late last year. That gave us the opportunity to see an efficacy signal, which prompted us to move forward into a phase 2/3 trial for that program, which is ongoing right now. The third program is for Stargardt’s disease, ABCA4. [00:34:30] One of the challenges with Stargardt that many in this room would know is it's a very large gene that's not capable of being packaged in a single capsid. We're working on a dual capsid, dual vector approach to that where we split it up between the upstream and the downstream and we’re able to put those in two different capsids that recombine in the eye. Some really exciting work there and some data has been published earlier this year showing the correct localization of the ABCA4 gene and expression [00:35:00] the full length protein being expressed in animal models.

All of the programs have come out of Oxford University. We have another four programs and are currently active, but we have been focusing on monogenic diseases of prevalent populations. Our first program is for choroideremia and this was the data that essentially it was presented to the FDA that allowed us to garner the RMAT designation. What this shows is that the treated group of patients [00:35:30] in the investigated sponsored trial of 26 patients and the high dose. You can see that at one year, two out of 26 loss more than one line or 92% of the patients maintain their vision, and essentially this is what these patients are looking for. If you compare that to the natural history trial, so we have 308 patients that were in a natural history trial. You can see at one year, 13% had lost more than one line of vision.

Go forward one year [00:36:00] and now we have two year data on those patients, you can see the treated group continuing to maintain their visual acuity, at least 90% of them or more. However, you can see the untreated group continues to lose more than a line of vision. Obviously in a slowly debilitating disease like that you would expect to see continued separation of the treated and untreated group. In terms of our X-linked retinitis pigmentosa program, we were very encouraged in the phase 1/2 dose escalation [00:36:30] study to see a efficacy signal. What you're looking at here is a microperimetry reading. Many of you are probably familiar with this instrument where the patient puts their chin in a rest and has a button to press and mapped on their macula, which is depicted here. They have 68 points, and machine goes through an algorithm where it varies the light level and the patient has to pick up various thresholds of light level.

A normal functioning patient, this map would be all green [00:37:00] essentially saying that this patient or these patients like us who have normal vision would be able to see the lowest level of stimulus. This particular patient was one of the early RP patients and you can see that they have very little retinal sensitivity, and what little retinal sensitivity is left is right over the phobia. If you're looking for an improvement and improvement would look like changes in the color of this map, meaning the patient is now picking up less bright stimulus as well as area. [00:37:30] You can see here's a baseline patient, top one image is the treated eye, the bottom image is the untreated eye.

You can see at baseline this patient’s pretty much similar in both eyes. At month one you can see not only the color changing suggesting that the retina is becoming more sensitive, but you can also see the area starting to grow. That's been persistent up to three months as well as six months. We now see one year data on some of these patients and it continues to persist [00:38:00] this improvement, so very encouraging. If you talked to these patients, particularly this patient, he will tell you the reason I knew my visual acute or my vision was improving is I have a rack of kitchen utensils. I sit in my living room and as I look through the door to the kitchen, I was previously only able to see one of those kitchen utensils without having to move my head. He said, I'm now up to three kitchen utensils [00:38:30] now, so he has a kitchen utensil algorithm that he goes through. It's very sophisticated, but very encouraging.

We shouldn't forget, we talked a lot about the efficacy of gene therapy, but we've now treated well over a hundred patients, both in our choroideremia trials as well as in our RPGR trials in total. We continue to see very well tolerated safety profile. [00:39:00] In fact, in our choroideremia trial, we've only had two serious adverse events. One of them is inflammation, largely related to reflux of the vector into the vitriol cavity. The other one was related to a gas bubble in the surgical tubing. Beyond that, we've really seen no significant safety issues at all. We're very encouraged not only by the efficacy signal, but also continue to see strong safety profile as well. Thank you very much.

[Applause]

Dr. Rusty Kelley          

Thank you very much Dave. That concludes the speaker presentation, so we'll move to Q and. A. If you have questions from the audience, please look for one of the mic presenters. I'll kick things off while you guys are preparing yourselves for a few questions. One thing for the folks that aren't exposed to these company transactions in the early stage, companies that are looking for an exit.

This term exit as a is a financial term that really is about liquidity. You have these companies that are backed by number of investors, and stake holders, and at some point they need to harvest their investment. There's two primary avenues for that. You can be acquired as Spark was by Roche or you can go public.

There's pros and cons to going public, and some of the pros are that it increases your company profile. There's this perception of legitimacy and arrival. If you get lucky, you might get to ring a bell on Wall Street, you're attracting talent through stock incentive plans. Of course, there is liquidity for your investors. You can raise money at a cheaper cost of capital, it's easy to do business with others. This is a very important point.

Once you're public and once you're filing on a quarterly basis, there's transparency around your company and that tracks the ability to transact. You can use your stock as currency for strategic acquisitions. There a few cons I think by far the pros outweigh the cons, but the cons are that it's expensive and it's time consuming.

You lose some control with more investors to answer to and with greater scrutiny in some cases. There's the downside risk of going public. You can always have, a failed public offering. you can end up as a penny stock or you can be delisted. Of course, there's the burden of financial reporting that I mentioned earlier.

I guess one laid off question for each of our guest are, for the companies that are thinking about going public, what advice would you give them based on these advantages and disadvantages or other considerations that you might think of?

Can we start with you?

Answer:                    

My biggest piece of advice for people considering taking their company public is not to think of it as an exit event. It's really a financing event and it's a way to get a much larger amount of money in to really fuel the growth of the company. If you're thinking about an exit event then I would maybe take a step back and think some more.

The other piece of advice is that I think that, especially lately with the CRISPR/Cas9 world. There's been a lot of companies and ideas that have gone public very, very early in development, and that it's challenging to manage. That's going to be exceptionally challenging for the management team, because you are required to report every quarter on what's going on.

If you don't have trials in the clinic, if you don't have which indications are going to go after solidified and it's going to make that much more challenging. I think it's really fast to go public and have this liquidity event as you're moving into clinical development, which is where you need that financing. Those would be just a couple of pieces of advice.

Answer 2:                 

I think traditionally the lobby IPOs would be on a Phase 2 data delivery. Clearly a lot of companies are going public earlier than ever, but it's really a unique time in the industry. There's more biotech companies today than ever before in the history of the industry. It's a question of recruiting talent and what's happening in the sector. If you look at ophthalmology and you think the fantastic success of Spark, it's great for iResearch as a whole for a couple of different reasons.

We see companies that as I've looked at whether it's Knightstone are or ProQR, or even AGTC did. If you look at who are the scientists that are joining the companies, many of them have limited industry experience and they're coming out of academics' centers now to jump into iResearch, if you think of Philadelphia today, it's really an emerging center where we start to see an integrated network of people in academia, venture capital, biotech coming together. That drives innovation.

As a early stage company, if you're thinking about how would you then move to the capital markets and take on all of the exciting challenges of quarterly updates and full disclosure making sure your sox compliant on all these other things. It's also about building relationships with whole new groups of investors. Some investors only invest in companies with revenue. Some will only invest in companies after proof of concept.

Some will only invest in companies where someone like FFB has stepped up and said we would come and vast or validate your program. As you think about who the different stakeholders that you'll be reporting to, because there are a number of them that are very happy to help you think of the 25 questions you didn't ask about your program when you go and talk to them. You want to be thinking also about for your initial investors, are they going to be with you for a lifetime?

Do they need to have an exit because of the life of their fund, and who can you be introduced to that will help you continue to build the company over time? The fortunate news is that the capital markets today I've been very supportive for biotech, and it's the reason why we see some really fantastic opportunities.

CRISPR Cas technology, we may not know today which technology or which company is going to create the next great breakthrough. The fact that there's many technologies going right now is the reason why there's such high promise. Capital markets are really important for biotech. The cost to take companies to market remains high because of meeting all of the regulatory burdens, especially for programs that we intend to register globally.

Meeting the needs, not just of FDA but [inaudible 00:06:31] or CFTA or other global groups. Without the capital markets, we wouldn't have the ability to take products all the way through. going public is an important part of the company growth.

Answer:                    

Yeah, those are really echo kind of both comments there. The balance that you have to think about a lot is how much overhead and burden you're going to put on the company versus how much additional access to the capital that he gained. I do think there is also something where you have to look very carefully at where is your story?

Are you a story or are you data? The CRISPR is a story today, data will be coming and I'm confident it will be exciting, but reception in the public marketplace is going to be different dependent upon essentially how hot the story is. As you move along the access to the capital and the mechanisms to access capital that allow you to continue to push things forward and perhaps get a program to a point where a validating or important partnership in some of the more large market indications is really a necessity. 

In overall terms, I think the balance of the access to capital, the ability to highlight our technology platform really that I thought the decision was appropriate for miRagen, but it has to be taken on an individual basis.

Answer:                    

I would say one of the things when you go public you need to be prepared for is getting on the hamster wheels. Once you get on it you really have to keep pedaling because one of the things that I've certainly found with investors is they're always looking for that next data point. You've got to continue to produce that data and be prepared if you don't produce that data to be punished.

It is really critical that you have your milestones really well laid out when those data events are going to occur. More importantly, you deliver on those data points or you really will have significant issues with the investors. One of the little dirty secrets on going public, I didn't do it on the New York Stock Exchange, did it on Nasdaq. Nobel, it's a buzzer.

More importantly, it's really a like a TV set. You go in there, it's in a fairly small room, you can bring whoever you want to come up on the stage with you. In our case, and in many cases, they really need to make a lot of noise because you see the events on TV and it looks like a huge amount of people are screaming and shouting.

All those people come from Nasdaq and just go to the back of the room and they make noise at that point in time. They're really actually-- It's well set up, it's a fun event and I'd  encourage anybody to do it or at least watch it if you have an opportunity to do it.

Male:                          

Radius Health is the only biotech company in the history of IPOs to have successfully completing IPO on the third try. The first IPO was before my time, it was on the date of Hurricane Sandy and strangely enough that wasn't a great day to go public. Two other companies were supposed to go public that day. They both went bankrupt. When I came in Radius and there was 30 days of cash and six employees and we needed to take the company public. I was a little disappointed on a road show when the Friday [00:00:30] before we were supposed to price our deal the next day, there was a report that we’d pulled our IPO. I had actually just finished meeting with Venn Bio. The banker from Cowan was already calling me already goes, did you see this Radius cancels their IPO?

The first thing I was thinking of is who would have canceled it and not told me? It turned out that one of the junior lawyers had pulled the old registration statement on that date and not simultaneously put in the new one. That immediately got reported out as the IPO being pulled. As [00:01:00] you might imagine, no investor believes that something as simple as a clerical error could have resulted in a story like that. We had to take the IPO down, wait 90 days, and then bring the company public. But it's not where you start it's where you finish, so we brought the company out at eight bucks a year later at $74 a share. People who didn't like us at eight loved us at 74, so it was a success story.

Male:                          

Well, are there any questions from the audience?

Male:                          

Yeah [00:01:30]. I’ve got a question. First of all, thank you all for being here. Really appreciate it. Each of you are – it seems that each of your companies are doing multiple trials. My question is for each of you, what are you doing internally or what have you done to try to create efficiencies or economies of scale for a shortening the time period of the clinical trial process [00:02:00] because obviously [inaudible 00:02:02] is not as patience as other. Interested in hearing what you’re doing internally?

Female:                      

I'll start, one of the things that we've done is in the time it takes from when you identify, I want to work on this genetic deficiency in this patient population to when you filed the IND, there are some things you can do to shorten that time up. Like, take risks and make your [00:02:30] clinical trial material and do your tox study at the exact same time, don't wait for the tox study to make your material. There's many things like that you can do to shrink time, and we've worked really hard at doing that. But I get the question a lot. Can you get that to the clinic faster? Well, I can't do a 90 day tox study any quicker than 90 days. I can't analyze all the data from those dozens and dozens of animals really any quicker than an additional 90 days to analyze the data.

There [00:03:00] are some constraints to how you can push that to be compliant. We've been lucky and that the IND for the optogenetic program will be our eighth IND that we file. We feel we've gotten really efficient at that and that the FDA has been very accommodating and understood that our data has been sound through that experience. We no longer have to do safety studies in nonhuman primates. They have allowed us [00:03:30] to go to one species in our last two INDs that’s been very helpful. I think a lot of it is experience building a reputation with the regulatory agencies of excellence and compressing as much as you can. But I heard somebody say earlier, you want you cutting edge, you don't want to cut corners because in the end, what we care the most about is the safety of the patients.

Male:                          

I think the other area where we've made a lot of progress, certainly Sue would know [00:04:00] this is really in the surgical training and preparation at these centers that are doing the subretinal procedures. Only two years ago or so very few centers were doing this and the preparation needs to be extensive, the training needs to be extensive. But because so many subretinal procedures and so many genes are being developed we've now I think at a point where the surgical centers are really well qualified up to speed, know how to do subretinal, know how to prep the patient. We [00:04:30] know how to now train the pharmacist if they have to do dilutions. There's really a whole ecosystem around that surgical delivery that now is I would say up to a steady state and only getting better.

Female:                      

Yes it’s because they've got gone through your training, they've gone through our training, they've gone through Spark’s training. They are well trained at this point.

Male:                          

They are ready for us now.

Female:                      

It's very important. It's something that I don't think was really appreciated at the beginning. We [00:05:00] -- I'll just say one of those foot faults that you made, we were some of the first out there, other than Luxturna doing subretinal injections in our very first achromatopsia trial. We thought it was a really great idea to use three different surgeons so we had more surgeons across the country. Well we dose three patients and we've got three different surgical outcomes because it wasn't well understood that just following a surgical manual was not quite good enough, you needed to have the training. That's something that the field -- we're competitors [00:05:30] on some level obviously, but it's some of those kinds of things that we should agree to agree to and to help each other with.

Male:                          

Other questions from the audience.

Male:                          

I'll throw out one more question here. One thing that's of concern for the foundation is that there are over 270 genes that are affected [00:06:00] within RDs. Is there a threshold of prevalence and incidents that I realized you can't speak publicly about some of your future plans, but is there a model within your organization to tackle ultra rare indications?

Male:                          

Yeah. If you think about the evolution of development in general [00:06:30] for rare diseases, we're still requiring a randomized control trial for approval. But quite frequently it's a single trial and it may or may not have a placebo arm. If you said for expansion of the level, is it possible to take smaller groups of patients with variance and cluster them together and that while the trial has a patient population might be heterogeneous that the outcome of the trials added to the trial, yes that’s occurred already. Today we're seeing now label extension based on [00:07:00] preclinical data. In a case where we can provide compelling information to the agency that leads them, first of all, to answer the most question was make sure that it's safe because in terms of answering safety, it's still dependent on patient exposure, how many years of patient exposure is available. There's always going to be a requirement on the safe side.

Then on extending the efficacy benefit it’s what's the reason to believe the translational model [00:07:30] is truly predictive of clinical outcome. We just entered into a collaboration that's funded by the European Medicines Agency. I'm sorry, it's collaboration, European Medicines Agency funded by the EU and the hub to take organoids and then test patients drug response in the laboratory and run a prospective clinical trial to identify whether the laboratory test is predictive. That is the type of work that will enable us to work more rapidly to extend [00:08:00] therapeutics to ever smaller patient population.

If you said for CRISPR today where a single nucleotide change requires a full development program, we should expect that as the technology matures, the ability to apply it to a new gene or a new change, the burden will become smaller so the technology would be more accessible and the development path will be faster. But to make that happen [00:08:30] we need patients to share the patient experience with regulators, having gone to meet with the FDA on numerous occasions with representatives of the patient population. The people at the FDA want to hear from you because when we create an NDA the last one we did was slightly taller than the empire state building if you stacked up the piece of paper. We hand it to the folks at the FDA and they have to read it all and make a critical assessment that they think everything there is correct [00:09:00], knowing that people are waiting for the therapy is as inspiring to the folks at the FDA as it is for those of us who work in drug development. Please share your story, talk with people about what we're doing.

The second piece is having from a company perspective, a solid dialogue with our regulators. I once asked Steve Kozlowski in the antibiotic division, why are there delays in drug development programs when we know so much about antibodies? He says because we at the FDA [00:09:30] ask a company to do three things. When they come back they said number one, we heard what you said and we did it, and we say thank you. On number two, we heard what you said and weren't sure that you had the best idea so we did something slightly different. On number three, we decided you are wrong and didn't do it. He said, well then as the FDA we say, tell us when you get the three things done and we'll continue with your program. Being sure that we're listening to what regulators share with us is very important.

Male:                          

I would just really [00:10:00] echo this and this is actually in a -- and we're treating a very rare hematological malignancy. One of the aspects of this is there's an important aspect of patient reported outcomes pruritus and pain that occurs. The agency is very interested in these patient reported outcomes today. We set up a second meeting with the FDA, collaborate with the FDA as much as you possibly can. When we had that discussion, we had proposed [00:10:30] a rather broad range of tools that we are going to employ in the study. We were fortunate enough to have the CEO of a patient advocacy organization actually join us for our FDA meeting and it was an amazing difference in the response to our proposal. At the end of the day we got exactly what we wanted to in terms of guidance from the FDA on how we move forward. Collaboration is a key component moving forward.

Male:                          

Well, I believe we are out of [00:11:00] time, so please join me in thanking our speakers.

[Applause]

Male:                          

We're going to take a vote. It's kind of a fun audience participation point of the day -- opportunity for the day. By a round of applause, who would like to take a 10 minute break or who would like to maybe just stand up, clap your hands and move into the last [00:11:30] panel and maybe end a little bit early today. So who's in favor of taking a break? No clap, clap, take a break? Clap, a little bit, little bit, little bit of break, all right. Who wants to push on through maybe stand up, take a quick 30 second minute and then bring the next panel up?

[Applause]

Male:                          

All right, good we got a consensus. Let’s bring up the next panel. But in doing so, do we have a -- figured it's perfect time for a joke.

 

The Ecosystem Panel

Male:                          

We’ll jump right into this last panel for the day.

[Informal Talk]

Male:                          

All right, well I do want to thank everyone. This has been a power packed day. We’ve had a lot of meaty content, a lot of conversations [00:00:30] obviously and a lot to digest in a setting. I want to thank everyone (a) for their time and (b) for their attention because this is a lot. It’s a lot, this is the first time we’ve done this and just want to get a sense. What do you think? Has this been a good day? Enjoyed it?

[Applause]

Male:                          

It is a classic case of just asking for applause just for the sake of asking for applause. I really do think this is a good start. We intend on [00:01:00] doing this meeting with frequency and we’ll look to get feedback from everyone who’s here whether this is an annual thing, maybe it’s more frequent than every other year type of thing that we’ve done in the past. I think it’s nice and we’ve said this quite a bit in this. Next panel is actually a perfect example of it where it brings together the cross-sections of all the different components to be successful in helping us meet our mission. This panel is the exemplification of that. It’s moderated by Ms. Kelly Lisbakken. I’m going to [00:01:30] read some information about Kelly which is just super impressive.

Kelly is a Managing Director and Head of Biopharma Investment Banking Groups at Wedbush. Since joining the Pacific Group Equities in 2004 she has completed over 200 transactions and raised over $20 billion, which is fantastic. Probably most important she's on our RD Fund board and so we're thrilled to have you on the board Kelly and getting to know you. Your energy is infectious and I'm anxious to hear this last panel today.

Kelly:                          

Fabulous. Well, thanks everyone for [00:02:00] -- is that on? Thanks everyone for making it to the end of the day. I know it's been a long one, but I really wanted to bring everybody together for this last panel and talk about different perspectives and how we can translate some of the disruptive technology that's occurring at what the state of play is, how we can get that commercialized, how we can get these drugs developed. We have a power packed panel here. I'm going to ask each of the panel members to introduce themselves and just give the perspective that they're bringing to the current state of play.

Sue:                            

No you're not seeing double and I am sitting on the [00:02:30] same chair and I'm still Sue Washer, President and CEO of AGTC. What I'm bringing to this panel is the perspective of a public company CEO.

Kali:                            

I'm Kali Stasi and I’m with Novartis so I represent a big pharma I suppose today. I come from a University of Pennsylvania so as it was correctly pointed out earlier it has actually [00:03:00] contributed a lot to the gene therapy field. I have the academic perspective as well as the industry perspective.

Christy:                       

Hi, I'm Christy Shaffer I’m with Hatteras Venture Partners and I've been in the ophthalmology space for a number of years. In fact, I’ve worked with Ben Yerxa for 15 years and some other people in the room here. I'm representing the venture and entrepreneurial perspective, but also I've been on a number of nonprofit boards for the years including the Cystic Fibrosis Foundation. I know [00:03:30] how much the patient advocacy groups help, this been said several times today and I see a lot of parallels in terms of what FFB is doing relative to the CF Foundation, which has been a role model for venture philanthropy.

Eric:                            

I'm Eric Pierce. I'm a clinician scientist with colleagues at Mass. Eye and Ear in Boston. I see patients with inherited retinal disorders and I also run the Ocular Genomics Institute where we're trying to develop -- really have a whole translational program to develop [00:04:00] gene and genetic therapies for these disorders. I guess I also -- so I’m representing the clinician scientist perspective on the panel. I also after 17 or 18 years being with FFB think of myself as part of the FFB family, so thank you.

David:                         

I'm David Nierengarten I'm a Head of Healthcare Equity Research. I work with Kelly Lisbakken at Wedbush Securities and I've been following gene therapy companies for more than half a dozen years now. On the ophthalmology side I’ve covered and saw several of the companies [00:04:30] here AGTC and Nightstar among them, grow from a private company to a public company attracting public investors, so that's my perspective.

Mark:                         

Hi, I'm Mark McClellan I'm a former federal worker. First as a commissioner of the Food and Drug Administration, more recently Administrator for the Center for Medicare and Medicaid services. Currently I'm the director of the Duke-Margolis Center for Health Policy, which is a university wide program at Duke with offices in Washington [00:05:00]. We work on very much of the same kinds of issues at the Foundation for Fighting Blindness does. A lot of work related to promoting health care transformation and innovation. For example, projects on new mechanisms for paying for gene therapies and other kinds of curative or transformative therapies. It's a pleasure to be here and John a little bit of you.

[Informal Talk]

John:                           

I am John Corneille. I'm director of Legacy Giving at the Foundation Fighting Blindness and I am not here in that [00:05:30] capacity because how shameless, tacky and self-serving would it be for me to come before this group and give a self serving plug to consider creating a legacy gift to the foundation. Shameless, tacky and self-serving is not my style, so that's not why I'm here. I listened to Dr. Joe Carol [PH] this morning talk about feeling like an outcast, I think he said. Ever since I heard that I thought what word best [00:06:00] describes being farther out there than an outcast?

About three weeks ago, Ben Yerxa sent an e-mail to this group introducing each other to ourselves and telling a little bit about what we're doing today, what do we hope to accomplish? I thought, wow, what an impressive group of people. I forwarded it to my significant other Julie and said, hey, take a look at this panel. Isn't this cool? The response comes back, you're the only one without a PhD. I'm here to give the [00:06:30] patient's perspective and I'll do the best that I can to represent all of you out there and Steve, thank you for that question. Hurry up, right?  That's all I have to say. Thank you.

Kelly:                          

Thanks so much, we got this. I want to remind the audience as well that we do have microphones. This is an interactive panel. We'll start with a few questions, but if you have anything that you’d like to discuss, please raise your hand we'd love to take here from the audience. First thing, maybe we can talk with Christy and Sue a bit about [00:07:00] how does venture capital look at early stage companies? What do you need to see in order for something to be an investment worthy? Then on top of that, how have things changed over the last 10 years in terms of liaising with early stage researchers and giving them the funds that they need to make early steps? [00:07:30]

[Informal Talk] [00:08:00]

Christy:                       

In terms of what early stage investors are looking for because that is what we do every day is the first thing we look -- there are three things we're looking for. The first thing we look for is outstanding science. We usually find that in the academic setting. You've heard many great academic researchers today [00:08:30] and we often find they published a paper, they're about to publish work. We began talking with them and figure out that they are wanting to either form a company or have just formed a company just getting ready to license the technology out of the universities. We've had great success doing this with a number of companies across therapeutic areas. But I'm particularly interested in ophthalmology and also rare diseases. This fits perfectly in terms of what we like to do.

First is outstanding science. [00:09:00] We figured that out in part because of the fact that hopefully the scientists have published in good strong peer review journals. The science is often validated by a lot of government funding, maybe the NIH, NCATS etc. Then also it's really important to us if a group like the Foundation for Fighting Blindness are already fund invest because it means you've looked at it, it really validates the technology. First is great science.

The second is its ability to be translated, [00:09:30] you heard a lot about the art of translation. I love the comment made about the beauty of basic science, we have to have that first before it can be translated. I'm going to use a word that Adrian Graves used at a glaucoma meeting recently. We're in a renaissance period right now, there's just so much fantastic science and we now know better how to translate it. We have to know as an investment firm that in a pretty reasonable period of time [00:10:00], maybe two years, we can translate the science into something that looks like it's going to work.

The final piece, the third piece is team. It's very important to know that there is a team of scientists, usually a combination of academic experts, perhaps the founder along with maybe the Foundation for Fighting Blindness, along with some of our help as a venture company. Also industry experts, particularly on the regulatory side, all those things come together [00:10:30] to allow it to really succeed. It's really those three things that help us know it's worthwhile.

Now, I've heard a couple of comments today about what's too small? We are called to rare diseases for a lot of different reasons. But I do think there are some investors and certainly maybe 5, 10 years ago, no one would have invested in indications this small. That has really changed and Spark has been a part of that. [00:11:00]

Sue:                            

I'll just add to what Christy said. AGTC went through several rounds of an early stage financing from private investors and VCs before we went public. I'll emphasize the team part. I think most entrepreneurs don't believe that. Most entrepreneurs believe that an investor is investing in the science. It is critically important, don't get me wrong, but what they really are investing in is the team because if you look back through the life sciences [00:11:30] history of biotech companies, very few of them ended up being successful on their first idea. One of the very few was Genzyme so Henri Termeer got that right for sure. But you look at Amgen or Genentech or any of the big names, they became successful on their second or third idea. That's why it's so important if you're an academic scientist that you build the expertise around you and you put that team together.

You know what made a big difference for [00:12:00] us was the Foundation Fighting Blindness and we got funding from them. But we also got recommendations from them on how to put together our scientific advisory board, how to pick our principal investigators because that's -- it's not just the team at your company that they're going to look at. It's the team of people you're interacting with and they're going to go talk to -- your early stage investors are all going to go talk to your principal investigators and your scientific advisory board members. I think that that's critically important. It has changed a lot. [00:12:30]

I've told this story before that when I was first at AGTC and going out and raising that first amount of money, I wanted to get like at least 10 minutes into the conversation before I uttered the words gene therapy. Because I didn't get somebody excited about the indications we were working at, excited about the team, excited about the great animal data we had. If I started with gene therapy they'd turn off because there'd been a really serious safety event and no investor wanted anything to do with gene therapy. Now that's the [00:13:00] first thing that comes out of my mouth because it’s -- so everything has changed and it's changed because of all the great science that everyone's been doing. It's changed because of all the great translational and it's changed because of the first gene therapy product getting approved.

Kelly:                          

Great thanks Sue. Eric, we would love to get your perspective as a clinician and an investigator. How do we bridge the gap between commercial investment in early stage research? Is there still a gap? How have things changed over the years? Any lessons you've learned from tech transfer or other experiences? [00:13:30]

Eric:                            

thanks, so let's see the first of those questions, bridging the gap to commercial interactions between take an academic program, develop a commercial partnership so we can bring therapies to patients. This is getting easier as you've heard throughout the whole meeting today, but it's still, I wouldn't say always easy. The ease is correlated to some degree with, as you would imagine, disease prevalence. For ultra rare disorders we still get [00:14:00] requests from companies we're trying to develop partnerships with to de-risk the investment, meaning do more science. In some cases even bring things towards IND-enabling studies so there's a more clear path for our potential commercial partners for their development. That can be hard because as you also know it can be hard to attract academic based funding for IND-enabling type studies which are not traditional research. We hope that continues to get easier. We're certainly excited about hearing all the engagement and investment on the [00:14:30] part of commercial entities here today.

We did form a nonprofit company Odylia Therapeutics to help try to bridge this gap where as academic scientists we haven't been able to get the funds to do, for example, IND-enabling studies. But with this additional nonprofit and trying to tap additional sources of support through Odylia we’re trying to do that and we'll hopefully see if that works. Tech transfer does definitely play an important role in this regard. We thought we were doing pretty well with this, right. You have to secure the intellectual property [00:15:00] for your program so that you can really attract commercial interest.

I thought we were doing well filing intellectual property disclosures and then patents on some of our programs, but I learned recently we're not doing well enough. We got scooped on one of our patents. Usually we were to use for publications but it happened with one of our patents by a company we're partnering with to develop a therapy for one form of inherited retinal disease. Clearly we needed to be a little more aggressive about getting the patent filed, [00:15:30] but we also needed to communicate more clearly with that company about expectations around intellectual property for a program we were developing jointly. I would say we need to file early and often like we like to vote and communicate a lot.

Kelly:                          

Thank you. Kali maybe you can talk to us a bit about strategies with working with the current regulatory bodies. How have they become more collaborative [00:16:00] interacting with both patients and drug developers to come up with innovative strategies to get drugs on the market quicker.

Kali:                            

Thankfully things have changed a lot. It looks like, so interactions with the health authorities both in the U.S. as well as in Europe or other countries have become much more, how shall I call it, they understand the field much better. [00:16:30] I think this is because of all the work and all the programs that have now presented to them, so that's one of the positive things. I would advise anybody who considers bringing something to the clinic to start very early interactions with the health authorities. Take advantage of pre-IND or indirect meetings, how they are called now or the equivalent in Europe, if you plan to go to Europe or in any other [00:17:00] area. Start when you think it's extremely early and maybe you think that your colleagues would be laughing at you, that's the time to go, I'm not kidding.

They actually appreciate that and they want anybody to go very early because it helps them as well to be prepared for the later stage. They don't want to be surprised at the last moment with seeing something that it may not make sense. [00:17:30] Also they are not prepared about that specific disease or the specifics of that disease. Also prepare to be ready for launch. What I see, because I also participate in a lot of due diligences for companies or academic programs for collaborations or acquisitions. A lot of times they go to the health authorities, but they don't have [00:18:00] a program that can be supportive of the drug all the way to launch. That means that maybe the formulation is not okay or something else is missing or some part of the clinical plan is not formulated. That means that if you start -- if you focus only on when I can get the first patient treated in the phase one, two study and you have not thought of the rest, it's going to be a problem at the end. That is going to be a problem [00:18:30] potentially with the regulators as well because they can cut that when you go to them.

Now a huge amount of support is patient advocacy. I have actually been to a meeting with the regulators where they were supporting one -- actually they were supporting more limited patient population. They were of the idea that the most advanced patients will not benefit so let's not even try on those. [00:19:00] We had actually a patient advocacy representative. It was good that they actually brought one from the health authority. The two patient advocacy representatives both from the company and from the health authority they both supported that we should try it on everybody. Even if somebody has limited amount of physician for that person it is extremely [00:19:30] viable. I actually saw the health authority people changing in the middle of the meeting and say, okay, we are convinced you can go ahead and try it on everybody. They are flexible and I'm actually very happy about that.

Kelly:                          

John, maybe you can talk about the patient experience and interacting with regulators as well as for clinical trials. [00:20:00]

[Informal Talk]

John:                           

I don’t have any personal experience with regulators but I think, [00:20:00] once my memory phased with age I remember the story fairly accurately, Steve goes telling it to my mom. But I seem to remember Steve telling the story that I think it was at the final hearing for the approval of [inaudible 00:20:14] before the FDA that someone on the FDA panel asked a question something to the effect of well why -- what's the point in us marketing this because you're never going to get 20-20 vision. Never [00:20:30] really going to get vision [inaudible 00:20:32]. My understanding there was one or two people there who were actually affected with these diseases and were able to tell the FDA that for those of us that experience life with diminishing eyesight, constant transition of vision loss and the adjustment in life. We don't expect perfection for [00:21:00] someone like me who -- and I never had 20-20 vision, most of us probably never had. Can you hear me okay?

[Informal Talk]

John:                           

Probably never had 20-20 vision some of us never had more than 20 degrees of peripheral vision. Many of us, and I've heard others say this that depending upon where you are at the stage of vision loss, you will say, oh if only it won’t get any worse, I’m adjusted to that. I have adapted to that. I can deal with this. Then six months later you would go to some place [00:21:30] that you’ve been six months before you think it's a little darker in here. It's continuing to get worse. A lot of people would be very happy with stopping or slowing the progression of the disease. You go to somebody at my point where all he have is like perception left, that’s not going to make me very happy. But I don't have any desire to drive on a road, the roads today with text messenger with all the other idiots out there.

I learn to use jaws, I'm uncomfortable with that. I would like to get back to where [00:22:00] I was even five years ago where I could maybe see faces and see the faces of my kids and my grandkids. I'd be happy with that. I guess the -- I want you to -- and I tell this to -- I've told this to Eric Pierce and his team as any researchers that I get a chance to that please don't think that you’d have to restore perfect vision to us. I don't think that we require that. As far as the clinical trial experience I think many of you know that I participated in and around clinical trial [00:22:30] [inaudible 00:22:30]. I don’t have time to go all the details there, but I want to tell you that from a patient experience going through that after volunteering for the foundation for a number of years and then becoming staff. Only think about always wanting for us to get to these clinical trials because we know that's necessary to even had a chance of a treatment.

To then actually experienced that was life changing. To have experienced [00:23:00] with Eric Pierce and his team the way they were so professional and so accommodating and made me feel so welcome. The three and a half years believe it or not that it took from the date of the press release on May 6^th of 2015 I think, until last September 2018 when I finish my commitment. I can't believe that three and a half years went by that fast. A lot of it was because of the experience that we get with Eric and his team. [00:23:30] So while we all want it to move faster, and many times I don't care about safety, but I really do, I understand it and I get it. But when we hear things like they have 10 more years or 20 more years. I’m like, all right guys it's a little bit discouraging but we get it, we understand that the foundation is our only hope. People like you and the investors are our only hope. [00:24:00]

Eric:                            

Can I jump in and make one comment?

[Applause]

Eric:                            

Something we sometimes forget to say -- is this on? Is how important the participants in clinical trials are. They are pioneers in our field and I'm thrilled that John, you're participating in this panel and get to represent that critically important part of this endeavor, because without those pioneers we wouldn't be able to do this work. [00:24:30] It's like being the first people on the moon. It's really important we recognize that, so thank you so much for your contribution.

Female:                      

I also want to reiterate that and also say that I think the Foundation for Fighting Blindness clinical consortium that you have is fantastic. That helps so much. One of the reasons that [inaudible 00:24:53] likes even likes the ultra rare diseases are when they are -- or organizations like [00:25:00] FFB they can help us to identify patients. From the registry to the clinical consortium, that makes is possible and therefore we want to do it.

Kelly:                          

Great thank you. Maybe a small shift David, could you talk to us a little bit about public market perception of these types of therapies, opportunities for future consolidation, the role of manufacturing and other concerns that a public market investor [00:25:30] might have versus an earlier stage private investor?

David:                         

Yeah so stepping back for a second, I mean the public company investors and private company investors too view of the world through risk reward that comes up repeatedly. That's really the focus of any public investor and private investors also. What we've seen recently with, of course, a value creation over at Spark among others, successes and clinical trials adding value to a [00:26:00] gene therapy companies throughout is of course now if there's a better quantity of a reward that has been experienced by public market investors. The question is what's happened to the risks side of things?

The risk admittedly has improved and yeah I think there are some discussion of that earlier too on a regulatory flexibility so there’s biology risk, clinical regulatory risk and commercial risk. The FDA has gotten more flexible I think with [00:26:30] the approval externa and other more innovative clinical trial designs. Biology risk is always biology risk, there's hopefully less of that as the companies progressed in their lifetime, but it's never really ironed out. Now actually with the launch of Luxturna among other gene therapies, maybe not in the ophthalmology space, but other gene therapies. There's going to be a question of commercial viability for the gene therapies to the earlier questions on how big of a market is a commercially viable[00:27:00] market. That's going to provide some brackets I think in the near future for working backwards what investors, what opportunities, what disease areas investors are more willing to invest in.

Kelly:                          

Thank you. I think that segues nicely into a conversation that we've all seen in the news, which is around drug pricing and how do you start thinking about reimbursement. Luckily we have Mark who is intimately involved with these topics. Mark we’d just love to get your perspective on where things stand now and, [00:27:30] and how you see them changing the next 5 to 10 years.

[Informal Talk]

Mark:                         

David said reimbursement uncertainty is there, the investments companies have made to get to the point of the market depend on things like how effective they can interact with FDA, [00:28:00] whether there is that, I don’t know, smooth and easy path on the regulatory side and having a lot of reforms. Doing many building on that critical path initiative that we watched for a while, I was there it’s been great to see those come along lead to more early investment in products including for very rare diseases. We're just starting to get the clear picture on how reimbursements going to work for [00:28:30] the gene therapies though. I think Spark did an excellent job of kicking that off the right way.

It's not an inexpensive therapy, but Spark did not price the level that [inaudible 00:28:41] we're expecting or looking for good solid return on investment and capacity to support further research and try to reflect that value as John tell you much more clearly that I, of their treatment of eye restoring 20-20 visions don't make a tremendous difference [00:29:00] in the lives of our kids and people who have that particular form of blindness. I think that's a good start. The other real challenge that gene therapies create is not just kind of what the level of the payment is, but what's the form of the payment? Most of the treatments that we've had today for a range of conditions, including rare diseases, and others treated with drugs involved kind of chronic treatment, [00:29:30] treatments that you need to keep taking to offset a gene, defect like cystic fibrosis or correct some other physiologic abnormality. If the treatment doesn't work, may be expensive, but you stop it, you stop incurring the additional cost associated with continuing to pay for the treatment.

Gene therapies -- one time, one and done treatments are different, if you apply this the same old historic ways of paying have a very high price upfront. That's been [00:30:00] challenging for many payers, both because of concerns about whether the treatment is going to really work over time. Certainly many patients have responded, but we're not yet perfect on long term response or some heterogeneity out there. I think that's going to get better as the science continues to improve and get better evidence on effective techniques. But that's going to take some more effort and applied research and [00:30:30] evidence collection registries and so forth to track how to actually improve the effectiveness of the therapies.

The second problem is just a big lumpy payment. Many of the patients that are going to benefit from Luxturna are on Medicaid. That's a program for lower income Americans paid for by Federal Government and the states. The states that are paying for Medicaid face fixed budgets and rising cost in other areas, especially health care. A big bump [00:31:00] in their expenses can be difficult for the states to sustain. Those two features, the uncertainty about long term benefits in practice and the big payment upfront have lead to pressures for a different way of paying for gene therapies. This is another area where Spark and Luxturna really led the way. They have been part of a collaboration with us through Duke around value based payment [00:31:30] for new transformative therapies that help develop some of the regulatory changes that were needed and some of the models for paying based on results over time for medical treatment.

Kind of a different approach to a payment, not just one price up front, but a payment that occurs over time based on how the patients who are getting the treatment are doing. Spark was willing to stand behind their treatment in these models by saying that, instead of having a, [00:32:00] they have a one and done upfront payment option. But they also have a option for payments that can extend as far out as five years and the payments only continue if the treatment continues to work. That's a company standing behind whether that they do think that their treatment is going to be effective in practice. That creates a different kind of model. It creates a more collaborative model for working with not just payers, but also the clinicians [00:32:30] who are using the treatment and practice. It creates a different kind of incentive and support for developing better evidence on how well the treatments are working after they come to market.

You can't implement programs like this without a good reliable registry approach to learn more about the actual experience with patients and what matters to them. I think to reduce and eliminate the uncertainty that does exist about the wave of gene therapies that are coming many for conditions involving [00:33:00] blindness. More work to adopt and implement the kinds of steps that Spark took would be really helpful. Thinking about a reasonable price to set based on the value of a treatment and thinking about ways in which the company can stand behind the treatment and an outcome based approached I think are important ways to reduce that uncertainty and help make sure that these treatments do really reach the patients who need them so much.

Kelly:                          

Great. [00:33:30] Thank you -- I know that's a hot topic for a lot of people. Any questions from the crowd on that? Okay. One of the other things we wanted to touch on was the value of patient registries, across the board both for drug developers, clinicians as well as investors. Sue do you want to start? What defines value in a patient registry? How much data do you need to have? What are you looking for in that?

Sue:                            

Well, at the minimum what we're looking for is how do we understand and how do we reach patients [00:34:00] to be in trials, and whether that's a natural history trial or an active trial. Before the advent of things like my retina tracker, this was done by reaching out to clinicians across the country and you had to talk to clinicians and say, have you heard of achromatopsia? That was the first question that had to be address. Then if so, do you have patients that are in your system that have achromatopsia? Sometimes they didn't know, and you had to describe [00:34:30] the disease to them, what the symptoms might be, etc to get down to whether they might have seen those patients. You can imagine that that is exceptionally time consuming. We're all concerned with getting these products to market quickly, and so to take that much time just to identify your patients.

As we're getting more and more sophisticated, ideally what you want in a registration -- a registry is you want the information about the patient, how to get to them, their phone number, their e-mail, their address, etc, which is kept anonymised [00:35:00] by whoever holds the registry. But then you want to know what disease do they have? What is their genetic mutation? What has been their specific phenotype? For many of our indications, we want to know what their last ERG looked like, what their last fundus exam look like, etc. You can't always get all of that information but the closer you can get such that you can work with the holder of the registry to pull out patients are going to most likely meet your inclusion [00:35:30] exclusion criteria. That means the faster you're going to get your trial enrolled.

The other part of it though is that I don't think registries solve the whole awareness recruitment problem. I think because not everybody drives to a registry. I think it would be shortsighted of us all to think that just having the registry was the end. I think that there has to be driven a lot of awareness to everybody and all of us need to be advocates within [00:36:00] our communities about that there are trials going on and help people figure out the way that they learn about it. Whether it's through clinical trials.gov, whether it's through checking the web pages of all the companies you've been introduced today. Whether it's through companies working with the foundation to drive out information and newsletters and blogs, etc. We need to go through every avenue because not every patient accesses information the same way.

We have to think about this as being kind of multimodal [00:36:30] in how we get out there. As I said earlier, we've touched for our -- for active trials, we've touched close to 700 patients. We're only enrolling about 25 patients per trial. We still have to reach out to more patients because not all of the patients initially meet those initial criteria. That's why awareness and as many interactions as you can have are critically important.[00:37:00]

Kali:                            

If I may add one step further from the registry is a formal natural history study or end point study. That's also a kind of study where we are really thankful to the patients who devote their time and energy and effort to come to these non-interventional studies, which are extremely useful. They can speed up the development of any product to get to the market [00:37:30] a lot, even if it's not very obvious sometimes to people hearing about it. But if we don't have the right end points and the right way to test them, and to be confident that what we see as efficacy, these are actually efficacy.

What we see as one end point changing can be a new end point that we can use and we can potentially correlate it with patient reported outcomes, which is going to [00:38:00] make all the difference to the payers because the payers, they don't care if whatever endpoint increases or decreases. They care what does it mean for the patient? You need to actually breeds all these together to make sure that you have a picture that you can actually use to harvest the whole effort and make sure that it will make it to patients eventually. Really thank you to all the patients who consider participating in natural history studies because these are critical [00:38:30] for the overall development.

David:                         

I just like to add to that too far from the investor side, a natural history study or patient database really helps the quantification of the commercial opportunity. Population genetics, extrapolating any rare ultra rare disease from population genetics is not -- just leads to error. I mean, there's just no other way to put, it just leads to an erroneous, population count. It really helps to provide the quantification of that opportunity. [00:39:00]

Mark:                         

Just from the policy side, I think we alluded to this earlier that FDA has taken a lot of staff, especially for rare ultra rare diseases to have a clear pathway to demonstrate safety and effectiveness and the natural history, controls that kind of -- these kinds of registries can provide as you all emphasized is now pretty commonly done by -- pretty commonly used by FDA. There are some -- obviously some standards of quality and the like that are important, [00:39:30] but I really does help with the regulatory science behind development. Then that is also a foundation for tracking how patients are doing once the treatment is available.

As I emphasized earlier, there are a lot of questions and you all said, well, they’re not going to be fully resolved at the time of treatment as approve. What difference does it really make in the lives of patients? How can we make the treatments even more effective than they are at the time they come to market in complex areas [00:40:00] like gene therapy administration. Very important from both the regulatory process and payment standpoint.

Kelly:                          

I think we're getting towards the end of our time. If there are no questions from the audience, maybe I'll just ask John as a patient, what would you want to leave us as drug developers, researchers, investors with from your perspective as we try to prioritize projects to take forward, investments to make [00:40:30] and, and really striving to create medicines to help the community?

John:                           

Again, I guess I just want to reemphasize about how important it is to realize that there's a broad range of patients, people that are affected. I mean not just the people that are affected, but the parents that are -- have affected children [00:41:00] and maybe 10 years in 20 years it doesn't seem as bad for them. But, trust me, they have pain every day to watch their children grow up with these diseases and think that by the time they're 60 years old they might end up like me or some of the other of my friends out there that have light perception only. Know how much we are depending upon your commitment to what you're doing. It really was encouraging [00:41:30] for me and I've talked to several others similarly affected, to know how many different levels, different ways that we're approaching these diseases. Our philosophy at the foundation, I know I'm not here for the foundation, but I'll say this, obviously we do not put all of our eggs in one basket.

We support a broad range of research that could lead to treatments and that's what we stress to our constituents. That's what we stress to those of us that get discouraged [00:42:00] from time to time that we love it, that we as human beings are competitive. We want you guys to be competitive. We want as many type A personalities that we can get in the field. We hope that you have a spirit of collaboration between yourselves. We think we talk about that often, how much information are you sharing between your peers and your colleagues, we understand the competitive nature of it. [00:42:30] We just want you to keep working at it, know how much we appreciate it. Know how much that we're out there doing everything we can to promote your work and raise the much needed funds to help it become success for you.

Kelly:                          

Great. Thank you, thank you to the panel and thank you to everyone in the audience for sharing and be with us.

Male:                          

All right folks we did it, we’ve got just few more minutes. I do want to say thank you to everyone for your attention today. It has been a lot of great information. [00:43:00] I do have one housekeeping note, one of our commitments here at the foundation is to be as transparent as we possibly can. We, I guess it was in the fall, we launched a new initiative it was called the Quarterly Insights Forum and I want everyone to know that our next one is scheduled. There'll be an e-mail going out to all of our constituents but it is scheduled for Thursday, March 21^st at 11:00 a.m. Eastern. It's an opportunity for Ben and myself and the leadership team to talk through kind of the latest updates [00:43:30] on what's happening with the foundation, answer any questions. It's just -- it's in the spirit of trying to be as open and transparent with the news what's happening with the foundation. Our last presenter who's going to send us off is Mr. Warren Taylor [PH] who is the chairman of the RD Fund. I'm going to bring him up here to say a few final words. Thank you.

Closing Remarks - Warren Thaler, MBA

Male:                          

Well I only have about 15 slides I can put up, but three things I'd like to do. We talked about the history of the FFB and what the plans are for the RD Fund. But the key thing, you look at the history, one person has been celebrated today who's imminently critical to the history of making [00:00:30] everything possible and that's Lulie Gund like everyone a round of applause for Lulie Gund.

[Applause]

Male:                          

The key to the FFB’s future is engagement it's always been with the past, with everything Gordon and Lulie have done for the FFB. Two thoughts to leave you with and -- we could talk a long day about what great time [00:01:00] what’s happen and how much we've learned, how much we want to thank you all for spending couple of days with us. Ben, Jason, Rusty, Steve, the team behind the team. The details of the food, we want to thank all those people, we’re not going to spend any time on that.

One quick thing to think about between now and when you next go to your FFB event, next FFB event you go, homework assignment. Two questions, first question, how can I productively spend more time helping Ben, Jason [00:01:30] and the team behind the team the FFB get the message out. The second is think about who your smartest friends are or your smartest family member or someone you're really impressed by who has nothing to do with the FFB and just tell him how you spent your day today, how you spent the day yesterday. Tell them something you learned. Tell him something you want to read about in the paper. Tell them about the Baron's article that talks about gene therapy you're going to [00:02:00] read tonight when you get home.

But I just wanted to thank you all for coming and if we ever do this event -- if there's any interest in doing one of these events, again, let them know. But I hope if we do have an event like this, you'll all show up and we'll have a few more sponsors and we can find cures to blindness and we can make a lot of money in the RD Fund for everyone to get their blindness cured as soon as possible. Thank you for coming.

[Applause] [00:02:30]