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National Science Call - 12/4/2019

PowerPoint presentation with audio from the Foundation Fighting Blindness National Science Call recorded on December 4, 2019

Full Transcript

0:07

Hello everyone and welcome to today's national science call: Foundation Fighting Blindness. Before we get started, I would like to go over a few items so you know how to participate in today's event. Your control panel is located on the right hand side of your monitor. This control panel contains multiple panes, which I will explain in just a moment.

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0:42

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0:57

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1:07

You may send in your questions at any time. We will collect these and address them during the Q&A session at the end of today's presentation. For all questions not addressed during today's webinar, we will follow up individually to answer your questions within two weeks.

1:25

For those of you that were able to call in but were unable to join the webinar, please submit your questions by emailing scullen@fightingblindness.org.

1:38

Before we begin our science presentation. I would like to introduce Shane Cullen, the associate director of chapter development with the Foundation Fighting Blindness for a brief welcome.

1:52

Good morning, or afternoon everyone. Thank you very much for joining today. This National Science call is one of the ways we like to try to engage our communities across the country.

2:03

We also have additional efforts that happen throughout the year through our local chapters, which a list can be found on our website at fightingblindness.org. if you would like to learn more about your local chapter or have a starter chapter, please either email me at scullen@fightingblindness.org or type it into your questions pane and we'll follow up after the call.

2:31

With that, I would like to go ahead and introduce Dr. David Birch, scientific director at The Retina Foundation of the Southwest and professor of ophthalmology at the University of Texas Southwestern Medical School in Dallas, Texas. Dr. Birch, I pass this on over to you. Thank you very much Shane, and it said pleasure to be with you all speaking. Good afternoon to those in the on the East Coast, I guess, and good morning to those on the West Coast.

3:01

I'm going to talk about clinical trials, primarily gene therapy trials, talk about early results and patient experience. The last National Science talk was by Ben Shaberman. He did a great job of summarizing all the ongoing trials, so I'm not going to try and do that.

3:21

I'm going to try to sort of focus in on a couple of them and talk about the kinds of experiences of patients have. So what I'm going to talk about it is, given the enormous growth in the number of trials that are going on, being conducted. I'm going to talk about how you might find out about a trial. How do you get into a trial. Talk about what a typical visit is in a clinical trial and then, you know toward the end, we'll talk about the results to date of some of the trials and what we can expect in the future. Where we're heading.

4:00

What's on the horizon. So, you know, I think that there have been several trials ongoing and many of these trials are gene-specific; what we mean by this is that it's only for patients that have a particular mutation. So I've just listed some examples here, you know, you've heard about the trial for Leber congenital amaurosis. It does now have a proved product for RPE 65 patients.

4:35

We have trials for x-linked RP for patients that have the RPGR mutation; starting up trials with dominant RP with rhodopsin mutations all the way down to Usher 2A, which is a common cause of RP and deafness, and retinoschisis, which is a problem that leads to a splitting within the retina linked to the RS1 gene. So with all these genes, and if we look at the genetic heterogeneity, we've got something like 260 different genes that have already been identified as causing retinitis pigmentosa. How do you find out which gene you have? Some of these genes only occur in very few people and it's, you know, you just need to find out what gene you have and that really helps you to get in sync with the clinical trial trials that are going on.

5:31

So the main way that people in the community are now getting their molecular typing and finding out what gene they have is through My Retina Tracker and this program has been fantastic. It's sponsored by the Foundation Fighting Blindness and it's been expanding pretty dramatically in the last few months.

5:55

It's now available to many many many retina specialist throughout the country and what it is is a patient controlled registry, so patients that sign up for My Retina Tracker consent to having anonymized information sort of available; there's no way anyone can track you without your consent but this information becomes valuable for these clinical trial development programs.

6:24

So as part of enrolling in My Retina Tracker you can have your genes, your DNA typed by 285 gene panels. So Blueprint has this nice panel that has 285 genes and pretty much all the genes on it. And now, with this many genes on the panel, there's about a 70% chance of having your defect identified.

6:50

So 7 out of 10 patients that go through this program now end up knowing what their mutation is. And the best part of it all is this is free and so far we've thousands of registrants join this program. So once you know your gene, you're in a position to search for a clinical trial. And so the next question is: how do you find a study and the best resource for that is clinicaltrials.gov. Just something you should know about.  clinicaltrials.gov is a website.

7:26

It's not, you know, it's not FDA-supported or approved or anything. It lists lots of trials. Some of these trials are not as valid as others, but all the good trials are there and if you search by disease or by mutation, what you'll find is a listing of the different trials that are taking taking place and the listing for the trial will tell you about the recruitment status.

7:54

It will tell you whether the, you know, the trial is still recruiting patients or whether it's filled. It'll give you contacts and locations where the trials being run, different sites. It'll give you most of the inclusion and exclusion criteria and I'll explain that in a minute and then it'll tell you the sponsor: who the sponsor of the trial is.

8:16

So one thing to know about these trials is that they're fairly specific in the kinds of patients that are included, and there are lots and lots of reasons for this, but the main reason is patient safety, you know, we want to do everything possible to be sure that the appropriate patient is in the trial. So this is just an example from one trial and what the inclusion criteria might look like. So this particular trial is for male patients with RPGR mutation within exons 1 through 14. So this is the stuff that you get from My Retina Tracker and then you have to have a clinical diagnosis of x-linked retinitis pigmentosa.

8:59

There are usually restrictions on the visual acuity.

9:02

So in this particular trial if your vision is better than 20/32, you're not going to be able to get in. If you have 20/20 vision, you're not a candidate. You've got to be able to perform all these different tests and you've got to have somebody to help you with the study instructions or comply with the protocol if you need it, and then finally the most important thing is that you have to fully understand the trial and consent before even being screened for the trial.

9:36

So that's kind of the inclusion criteria list. We have the same thing with exclusion things that keep you out of a trial; that would be anything like other pre-existing eye conditions that would interfere with the interpretation of the study endpoints, the output, anything that would increase surgical complications like glaucoma or diabetic retinopathy, retinal vasculitis.

10:07

Usually trials avoid patients that have complicating systemic diseases; medical conditions causing immunosuppression or any kind of sensitivity or allergy to medications. So you also probably would not be able to be on anticoagulant drugs, agents.

10:28

And usually you have to agree to use contraception during the course of the trial, so you don't - we can't have patients in trials that have  been in other trials within the last 90 days or so. And usually if you're in the gene therapy trial you definitely can't have had a previous gene therapy product. In this case, in this particular trial, they don't want patients that have acuity of below 20/800 in the fellow eye.

11:02

So you can get some feeling from clinicaltrials.gov, whether you might be a candidate, you know, if you feel like you can kind of fit the this particular pattern, you can contact the trial, and the way to do that is to is to contact the sponsor, who's listed on clinicaltrials.gov and typically the patient advocate working for any of the sponsors of these trials and they'll help you hook up to one of the sites in the trial.

11:32

You can go through the Foundation Fighting Blindness. They can help you coordinate with getting into a trial or you can go approach the site directly. If you know a site in your part of the world that that is doing one of these trials and you are interested you can compact contact them and see if you can get in for an appointment. So there are different ways to make contact.

11:57

So once you do make contact, get involved, you're going to have a screening visit. And this is probably one of the most important parts of being in the trial. What we do here is we send out a consent form, a pretty long document, several pages to any particular  candidate for trial. We send it out ahead of time so they can read it and get other opinions and talk to other people about it. 

12:27

Um, but when you come in with the screening visit, we have a long discussion of the consent form and we talk about everything that can go wrong. You know, what what your expectations are, what the safety of the procedure has been up to this point, try to answer any questions that you might have and the key is to ask a lot of questions, get second opinions, talk to other people about this because it's a big decision.

12:58

And then after you, you know, where everybody's content and everybody is comfortable with the whole consent process, we have several tests which will be used to determine eligibility and I'll show you some of these. We'll usually get a full medical history, comprehensive eye exam. So what what kind of tests do we do at screening? What are we looking for? What kinds of information do we need about a patient before the file screening begins?

13:27

At screening we'll measure the visual acuity, and you've all done this typical eye chart on the right, or sometimes, more and more in clinical trials, we're starting to use monitors where we actually present a single letter, and you have to read the letter and if you get it right smaller letters are given to you if you get it wrong a bigger letter; you kind of track along back and forth until we find the place where you really just right on the edge of being able to see it and that's your visual acuity. So we monitor that and make sure that your acuity fits into the inclusion and exclusion criteria. The other important screening test and outcome test that we use a lot in these trials is automated perimetry and I think many of you probably had this test. The most common device is the octopus

14:27

perimeter shown on the left and it's a device where put your head on the chin rest and look straight ahead.

14:37

There's a what's called a fixation point right in the middle there and lights are presented all around the dome one at a time and if you see a light you press the button. There's two ways of doing it: one is called kinetic perimetry when the light is moving, and the other is called static.

14:59

So this is an example of kinetic perimetry results from a patient that has pigmentosa. It shows each eye. This is the left eye here, this is the right eye and it shows all the regions that you can see the spots. So this is the big spot and there's a region around the outside where it can be seen and then, as is quite typical in retinitis pigmentosa, there's a region in this kind of mid periphery

15:30

where there's a blind spot or scotoma where you can't see the light and then as you get toward the middle, you can see smaller lights and in the center you can see the smallest lights. It kind of maps out your whole visual field and shows you where you can see things of different sizes. It's incredibly useful and something that we are using quite a bit now to follow to see if things are advantageous.

15:57

The other kind of visual field testing is called static perimetry. It's on the same device - the Octopus - but instead of moving the lights and having you push a button when you see it, in this case

16:11

the lights are presented against the background and you see a flashing light and you have to push a button if you see it and the more sensitive you are the dimmer the light is that you can see and it figures out the dimmest you see and then it puts a number there and the higher the number the better. So this is a static perimetry field and this patient has a nice central field - lots of high numbers. We can expand this but these are high numbers here in the center. And then there's this mid peripheral region where the patient's not seeing and then there's an outer region where the vision's pretty good. So we need to know this as well and this is another of the potential

16:56

measures that we can use to study if the treatment's working.

17:02

Many of you have had an electroretinogram and we don't do this as often, you know, we can do the fields quite frequently. Electroretinogram we usually do once a year or so look to look for change. An electroretinogram is nice because it doesn't require any input from you. We put a lens on the eye and we just record the electrical signals that are produced when we stimulate the eye. So we can stimulate the rods

17:31

and get a rod response; stimulate the cones and get a cone response and the amplitude of the response is a pretty good indicator of the number of healthy rods and cones in the retina. So we're looking for an improvement in the electroretinogram with with the treatment.

17:51

There's a lot of imaging that we do and the imaging has become very sophisticated. We can now use OCT or optical coherence tomography to get a very nice cross-section of the retina.

18:12

And in this particular example, what I'm showing is a normal cross section up above and you can see a nice layer of photoreceptors marked out by the yellow here in a patient with retinitis pigmentosa. The receptors are only really nice in the center. And then there's a region just away from the center where the photoreceptors are much much smaller and much less healthy so we can visually see now the healthy part of the retina and map that as part of the measurements.

18:57

Okay. So those are the tools that we use to screen patients to identify patients that are good candidates who would be good for the trial and a lot of these measures are also what we use to follow after treatment to see if something has been beneficial.

19:16

So let's talk about trial design and the kind of schedule that you would see as a patient and this depends a lot on the type of trial it is - the type of intervention, so that when we talk about gene therapy, the two approaches that are common right now, being done right now, are called subretinal and intravitreal. Okay, the two are quite quite different. Subretinal means putting the gene - the gene therapy vector -

19:57

under the retina, so you actually have to go in as a surgery and you have to go in and make a sort of a little bit of a detachment under the retina and put the viral substance under the retina and then it goes into the cells and puts it close to the photoreceptors of the cells that you want to treat and then it goes in there and provides the gene.

20:25

So that's the subretinal approach intravitrial means it's put into the vitreous - into the gel of the eye. So this is exactly the same kind of thing as a treatment for macular degeneration. You you inject into the vitreous, a much simpler office type procedure in doesn't involve surgery, but it has some disadvantages and advantages but depending on which type of treatment you're going to get the time course and

20:55

sequence will be a little bit different. So let's just take an example of a trial design where we're using subretinal injection. Here you would be seen at screening, you'd qualify for the study basically, and just get all your consent issues worked out and everything comfortable.

21:20

Then there would be a baseline visit with all the all the tests are done as at baseline. That's sort of the standard of comparison. We want to look and see if things are changing relative to baseline. And then day zero is when you have the subretinal injection, that would be usually a half morning - you'd usually able to go home after three or four hours, but it it does involve anesthesia. It is a it is surgery. So the subretinal injection you come back the next day and then you come back in

21:55

three days, seven days, fourteen days, and you can see, you know, repeat visits - the initial visits are for entirely for safety to make sure that there's nothing been disturbed, nothing ,no inflammation. No complications from the treatment, but then we start we're testing one month, two months, three months, six months, twelve months, every six months after that

22:23

to see if there's a response, a benefit and if that benefit is maintained.

22:28

You know, do we we get an improvement in acuity, does it last the entire three years? Then, years four and five are just sort of made to follow on and make sure there's no sort of surprises way down the road. But you can see it's a major commitment, you know, it's a commitment for everybody involved but especially for patients that have to travel and you know, it's tough, and as we start thinking about kids, and doing kids, that's missing a lot of school, you know, and it's a lot of considerations here.

23:05

So, the busy schedule, lots of visits, and on a typical visit - and this would be for a typical gene therapy type trial - you would arrive at the clinical center at something like 8 o'clock.

23:25

Basically you talk about any changes in your health or medical history, any changes in medications. All these things have to be rigorously documented. We then would spend some time making sure you had the best correction, the best glasses and what's called best corrective visual acuity and that takes a while. Around 10 o'clock or so, we'd probably start with visual

23:55

fields and that usually can take until lunchtime. So a couple of hours for that. After lunch, we actually do a lot of things dark adapt - we dilate the eyes, do the ERG and sometimes do what's called scotopic perimetry, which is a test for the rods, the full field sensitivity test, FST, and then towards 3:00 o'clock, 3:30, you would get a full

24:24

dilated eye exam to make sure everything is looking good and then leave later on in the afternoon. So it's it's a commitment, it's a commitment in time for each visit and there's a large number of visits.

24:39

Okay, so let's look at what's what we're getting so far with with subretinal gene replacement therapy. So here the goal is to replace a defective gene. Okay, if you have a recessive or an x-linked disease, like x-linked retinitis pigmentosa or choroideremia, you're missing a normal copy of the gene.

25:02

You've got a bad copy and the goal is to replace that with a normal copy and the way that's done is to inject this subretinal vector under the retina.

25:19

And what this what this vector is a sort of a safe virus that's been been given a new gene and the virus actually attaches to the nucleus of the cell, in this case by the photoreceptor or the pigment epithelium, and it attaches and it injects the gene into the nucleus.

25:43

So the gene kind of sits in the nucleus and then it just starts making the protein that hasn't been made from this eye for it so it's a way of allowing the cell to make the new protein and it's been fairly - we have been getting pretty optimistic about some of the results. This is the approach that works so well for the rpe65 kids, you know Leber's. Another condition that has had a lot of experience with now is choroideremia and choroideremia is closely related to retinitis pigmentosa.

26:26

It looks a little different, but the key thing is that the photoreceptors and the pigment epithelium or are lost progressively just like in RP and and you end up with a small central field and in the initial study - so this shows actually the remaining portion of the retina - this part here is all that's left in this particular patient. And so the idea is to put the treatment under this this remaining part in the very center and in the initial trial that was published a couple of years ago

27:03

it was pretty encouraging and it was a small number of patients but you can see that in some of these patients, there was a 20 or 18 letter increase in the study eye, and in most of the eyes, if you looked at the change in study eye versus the control eye it was  impressive.  The control eye was was was getting worse and the study

27:33

eye was getting better and that was kind of unexpected, you know, the the original goal of any of these trials is to is to try to preserve what's left. But here in choroideremia, we have evidence that it's actually improving the vision in some of the eyes. So because there were a couple of trials small trials like this that showed a nice benefit Biogen which used to be Nightstar is conducting a large

28:06

international phase 3 study. It's called the Star study and they recently completed enrollments. They have a hundred and seventy patients from many many countries. It's a randomized trial now, so we get to phase 3 you need a placebo control.

28:24

So some some patients get the treatment and some patients don't and the people that do the testing are unaware of which group the patient is in, so the patient knows but he's asked not to tell anybody that's testingwhether he was treated in which eye, I so it's done as masked as possible.

28:48

And in this particular trial what Biogen is trying to do is improve the vision - the acuity of the patients that are treated - so that the endpoint - what they're looking for - is the  proportion of patients showing 15 letters and more improvement at 12 months. So you see, if they see many more patients in the treated group showing this improvement of 15 letters and they're going to go forward and try to get approval for this as a treatment. So it's different.

29:22

It's a little unusual in that they're focused on an improvement and you know, that's encouraging, but you know, I think a lot of us would be just as happy if we had a treatment to stop things from getting worse, you know, that you could arrest a condition and stop it from getting any worse.

29:43

So the choroideremia program is fairly advanced and there are several other groups also working on some retinal gene therapy for choroideremia. Another condition that has been getting a lot of focus is x-linked retinitis pigmentosa. It's the most common gene actually causing retinitis pigmentosa.

30:10

It's in about 80% of the x-linked patients, but there are also a lot of patients that have no family history to actually turn out to have an RPGR gene linked disease. So the numbers are fairly substantial and so it becomes one of the most common and obviously makes it a nice nice target for going after. And AGTC,

30:40

for example, to give this this one example of a Phase 1/2 trial, so this is now when you talk about and early trial, which is what this is but it's in part B, and it's called open label, which means that everybody knows who's being treated, they're all being treated. There's no no attempt at masking, or no control group. So one of the issues in x-linked RP is whether to treat in the center or in the periphery.

31:13

And so one of the unique aspects of this is that it has both, you know, it has some patients that are treated centrally and some that are treated peripherally. So this is kind of a great typical design for a Phase 1 study where you have dose escalation, you have different groups or different groups of patients each with three or four in each group. And as the as the dose goes up before each new group begins,

31:54

there's a review with the independent safety committee to make sure that everything is is going well. So to show you just an example of peripheral treatment in a patient with an x-linked RP. This is an example of a 45 year old male who's treated about a year ago in the left eye and this is a patient that had low central acuity and because he had a nice a nice visual field out in the periphery, the decision was made to put him in the in the peripheral group to give him the peripheral treatment.

32:30

So he qualified by having the right gene and having a clear media and all the other characteristics that we were looking for.

32:39

And so this is where the treatment was given, so you can see you can't really treat that much of the retina. The bleb - the region that the subretinal surgery is - the gene is placed in a fairly small region of the retina and this these case this is in the periphery, but it's in a place where he had good visual field.

33:02

So this shows his field - all these high numbers here - where we're putting the treatment and what we're following for the next few years ias whether or not this gets any worse, you know, does this treatment prevent this peripheral field from decreasing, because he'd  love to hold onto this side vision, this peripheral vision. In other cases we treat centrally and here's an example of where the bleb is placed.

33:33

It would just start making the putting the needle in just above the fovia, but the whole central region of the retina is being treated. So we have some preliminary results. Actually AGTC released some some six-month results just like a month and a half ago. And just in the in the small, fairly small number of patients that have been treated so far, we've had no serious adverse events, and of the eight patients treated peripherally, they've been stable, their fields and acuity have not changed. Not surprising,

34:11

it's only six months, we need to look at this over a couple of years, but it's encouraging. And then actually, what's surprising, a little like the choroideremia surprise. We have nine patients we treated centrally and about half of them have shown significantly improved acuity. So we're getting a benefit from this gene therapy that we weren't really expecting. You know, we would have been happy with preservation. But improvement is is even better.

34:42

It's good. Okay, so very quickly, the advantages of subretinal are that they get the gene close to the cells that you want to treat but there are some disadvantages to this too, so the other approach that we talked about was intravitreal, putting the gene into the vitreous and allowing it to make its own way into the retina

35:12

to transfer cells and so there are lots of advantages of doing it that way if it can be done. It's a standard office procedure - every retinas specialist

35:30

does this. It is a very low risk from the procedure. It's an intraocular injection. Because of that we can treat earlier stages of disease, you know, we can consider treating patients that have very good vision still, kids, you know, it becomes much more feasible if it is low risk, and then there's also the possibility of treating the entire retina. Remember on the previous slides how small

35:59

the area that we were treating subretinally was, well, when it's intravitreal it can go to the entire retina and perhaps treat all of the cell.

36:09

Disadvantages are that it may not even get to the outer retina, you know, we have to make sure that it's actually getting to the cells that we wanted to get to and sometimes because in the vitreous it can cause more inflammation. So we have to kind of be aware of that. So I just talked about the first intraventional trials that has been reported on and that was a trial in x-linked retinoschisis.

36:36

And this is a splitting of the retina and it has a very characteristic appearance and the electroretinogram is typical of x-linked retinoschisis. So what's happening is you have splits in the retina and it prevents information from getting through so you have a reduced signals from the eye and you have reduced visual acuity.

37:00

So in some of the early lab work, it was shown that you could put this gene into the vitreous and it would go into the into the retina and it woulde Express itself in the Müller cells in the inner retina and the protein that it made would go out and it would would stop the schisis and it would improve the electroretinogram.

37:26

So in mice it was very effective in treating as animal model. In the human trial there were certainly examples of where it might have, you know, improved the quality of the retina. So here's one example of a patient with retinoschisis. And what we're looking at is the right eye, the top section there. You can see all these little gaps - these are the schisis cavities. These are the Müller dissociations. This is what's leading to this breakdown in communication between cells and these these cavities are sort of the hallmark of retinoschisis.

38:14

So after four months after the treatment you can see the cavities are much better in this particular patient. It certainly seems to have an anatomical effect and 12 months again. Same kind of thing. The cavities are much better. Unfortunately, it didn't make any difference to the vision. So we looked at acuity, for example, and this is a complicated slide, but all you have to know really is these lines are all flat. There's no improvement in the study eye.

38:44

From the vision. This is by different groups. This is by individual patients. So there was no improvement in acuity, no improvement in the visual field, it's all flat. So it's disappointing. We were two trials with retinoschisis where there was really no benefit. So we were able to show that it was feasible to do the intravitreal injections.

39:14

But in this particular case, it didn't seem to benefit. One of the things that we have to do to improve the the intravitreal approach is to get better vectors, better better ways of getting the gene into the cells.  And currently we're using some of the original first and second-generation vectors, these naturally occurring AAV vectors.

39:44

They don't really target any particular cell type so they're really inefficient, you know, they only get in certain percentage of the time. So one of the solutions has been to develop libraries containing millions and millions of variants of these vectors and then to study which ones get into which cells and that's something that's been ongoing for a while and it's called Directed Vector Evolution and basically out of thousands and thousands of vectors that are made, two or three will always end up being the most effective. And so now we have vectors that are capable of getting into the photoreceptors from the vitreous. So they're now trials beginning with intravitreal injections

40:27

for things like x-linked RP. Another new development, a recent development in the clinic, is what's called antisense technology. Instead of targeting, instead of trying to put in new copies of DNA, what we're doing is targeting the bad RNA.

40:48

So in this case, what we do is we produce a ribozyme or produce an antisense oligonucleotide that binds to the messenger RNA and prevents the translation of the protein, and so we've got now a trial coming up in autosomal dominant retinitis pigmentosa where the goal will be to block the defective copy of the dominant gene.

41:19

Another sort of variation of this is with therapies for Ushers. ProQR has a program where they are binding to just a small part of the gene. So rather than knock out the entire transcription their binding to just a small region and making a protein that doesn't have the defective

41:47

part in it. And this has been very effective in trials in Leber congenital amaurosis, in the recently reported trial with patients that have a particular gene for LCA and they found that an increase in the acuity from this treatment and that increase was maintained for at least six months and now we're hoping to get new data soon. So I think you know with in intravitreal approaches

42:17

there's a lot of opportunity, and there are several trials that are going to be up coming in the next year or two. 4D Pharmaceuticals has these next generation evolved vectors and they'll be looking at choroideremia,  x-linked retinitis pigmentosa. And then we have this antisense technology with ProQR and they'll be tech running a trial or starting a trial with Usher 2A0 and with autosomal dominant RP.

42:48

They're going to be other approaches coming to the clinic soon, they're not there yet. But gene editing for example is very powerful and has a few more safety hurdles to clear but it will certainly get there. So in summary, I think, you know, there's been an ever-increasing number of trials. The subretinal approach is pretty well established. Now, it's the FDA approval of Luxturna,

43:17

for rpe65 LCA we've had some initial reports of benefits in patients with choroideremia the next thing to RP. So, I expect, you know, they'll probably be some approvals for those two. I think, you know in the future you'll be more perhaps more emphasis on the individual approach.

43:40

We got these promising new vectors and you know, the risk-benefit relationship is the key to approval and so if we can do this continue to evolve this in a way that is less and less risky, then it can only be a benefit for patients and I think with that I will end the presentation and I think we have time for some questions and see if we have any questions to follow up.

Alright. Well, thank you. Dr. Burch. We're now going to begin answering the question submitted during today's presentation.

44:17

As a reminder you can still submit your questions through the questions pane in your attendee control panel or by emailing scullen@fightingblindness.org. If your webinar control panel has collapsed, please click on the orange and white arrow at the top of the control panel. Okay. So our first question is my son has x-linked RP and has been trying to participate in several x-linked RP clinical trials.

44:48

What are the eligibility criteria to participate and what about stem cell x-linked RP clinical trials? 

Well, that's a great great question. And as you probably know there are actually several trials with different sponsors and the trials all have slightly different criteria for eligibility.

45:13

So which one you get into depends a little bit on your son's vision, your son's age. For example, some of the trials are only including patients over the age of 18. Usually involving minors is a later later stage in the development of the program. So you have to find which one of these companies is sponsoring a trial that includes minors.

45:43

You have to be sure that It fits with the visual acuity and the visual field that your son would have, and as far as a stem cell treatment for x-linked: actually, the nice thing about stem cell approaches is that they don't depend upon any particular mutations. They're gene neutral. If you have an RPGR mutation, you're eligible. You might be a candidate for stem cell trial.

46:15

But if you don't even know your mutation you still might be a candidate because it doesn't really matter what your gene is. You have to be really careful with stem cell trials in there are only a few, only two or three or four that are really legitimate and I think one of the key distinctions between a legitimate trial and in one that you don't want to get involved with this is whether you have to pay.

46:44

If there's any kind of suggestion that it's proven effective and that you're paying several thousand dollars for this benefit, then I think you have to sort of be very suspicious and the FDA as some of you probably know has become much more aggressive about trying to regulate some of these stem cell shops in places like Florida.

47:13

Thank you for the question. 

Thank you, Dr. Birch. Our next question is: my question is regarding any clinical trials or treatments for the disrupted pde60 gene. I am registered at My Retina Tracker.

47:31

So another good question. There's no there's no trial that I know of in the United States. There is a trial in France: Dr. Guylène Le Meur at Nantes University Hospital is conducting a trial. It's sponsored by a company called Horama

47:57

and it It is evaluating the benefits in a small number of patients. So it's a phase one trial, but I think it's a standard, it's a typical sort of subretinal therapy trial trying to replace the defective gene.

48:22

Okay. All right. Thank you. Next question. I am an adult patient affected with non-hereditary RP. I am aware that there is already a treatment with good results for patients with hereditary RP. I would like to know if the Foundation is cooperating with scientists who are working on cases like mine to find out if there's any hope for non-hereditary RP patients regaining vision, or if you know of any advanced research in regard for these specific type of RP. I also want to know how the Foundation finds a procedure of removing cataracts for RP patients.

Okay, so we have a couple of different issues there. So I think when you say non-hereditary RP, I think what you mean is you don't we don't know the mutation. Yeah. Yeah, then the mutation in your particular case has not been identified.

49:21

So it's probably still hereditary, you just in that thirty percent where we don't know mutation yet and it is frustrating. You see all this work going on with RPGR or whatever it is and you wondering about you know, what about me? So there are non-genetic type approaches and the Foundation Fighting Blindness is supporting many of them.

49:50

One example is a program that's being sponsored by a company called Nicuity and they are looking at a potent cell stabilizer antioxidant that has been shown to be extremely helpful in animal models and it is not sensitive to the mutation at all. It doesn't matter which mutation you have. So the Nacuity is going to begin a trial next year, apparently, with patients that may or may not know their their mutation. So there there's a lot of work being done the stem cell approach again doesn't really require you to know the mutation.

50:39

I think like second part of the question was about removing cataracts, so you're asking whether there's any reason not to or if it's any particular problem and the answer almost everybody will give you is that it's not really any different from other patients.You know, you have a cataract you should have it removed unless it's felt that it's not going to benefit you.

51:11

You know, there's a there's can be a situation where you have very advanced RP, for example, where your vision is very low and it's probably not due to the cataract and in that situation it may not be of any benefit but there's really no no additional risk in removing cataracts in RP patients. That's really been identified.

51:37

Okay, thank you. The next question is long. So bear with me: I have RP and I would like to know: Do you have any news from jCyte for the phase 2B study. Hallucinations - are they commonly occurring in our patients? Do hallucination cause more impact on the retina? Some additional vitamins or supplements - are they recommended? And where can I go in the state of Louisiana for genetic testing?

Okay. So let's begin with jCyte. So jCyte has not released any information about the 2B study. jCyte, for those of you who aren't aware of it are doing a phase 1/2A

52:35

trial and they're using retinal progenitor cells - a type of stem cell - putting these cells into into the vitreous. Again, the gene doesn't really matter. It doesn't matter what is the genetic cause of your RP?

52:53

You can still get in this in this get this kind of treatment and these progenitor cells are thought to behave as a kind of super cells that produce lots of good things that help preserve the retina in RP and so they showed in their phase 1/2 study that, on the average, patients gained visually increased by almost by two lines basically in the study eye and that was in 28 patients.

53:29

So that was pretty encouraging. So their phase 2B study is now you is going to 85 patients and they're looking for 12 months. And I think I think they finished recruiting but I don't think they've finished the 12 months yet. So they presumably will be having some results coming out this coming year.

53:55

Okay, so - hallucinations. So this is presumably a question from a patient who has fairly advanced RP and low vision because halluciantions do become fairly common in patients with low vision, and there's actually a name for it. It's called the Charles Bonnet syndrome.

54:23

So Charles Bonnet was the person that really learned about this in great detail, and the thinking is, you know, you actually see with your brain, not with your eye. The brain is where all the images are put together and perception makes sense of everything with the digital part of your brain. It's all based on an input from the retina so that you're not getting enough.

54:52

You're not getting retinal input or not not getting what you used to getting. Your brain start guessing or making up things and trying to imagine what is going on out there in the in the periphery. So, you know, it's very common, I think, for patients to think they saw a deer or you know store sometimes very beautiful hallucinations can begin popping up. So I don't think it's any kind of sign of mental issues.

55:24

It's just a part of the condition.And let's see, the last part was where in state of Louisiana can you go. I know at the Retina Institute in New Orleans. They are part of My Retina Tracker. So Dr. Abraham in New Orleans -  that's probably the best place to go for getting to do functional testing.

56:04

Question: Dr. Birch, are you moving some papers around?

I was,  I'm sorry.

Okay, it's okay. We were just hearing the papers more than we were hearing you. Well, I think we have time for one more question: My wife was diagnosed as a carrier for x-linked RP. She had genetic testing and they did not find a known gene mutation.

56:33

We have two sons who have RP but have not been That what should be our next step.

56:44

So she does not have any disease herself, I take it. She's seeing normally but doesn't have the mutation. So that is tricky because about almost all the patients with x-linked RP have a detectable mutation.

57:15

So you know, I still think the next step would be to get the put the kids into My Retina Tracker and screen for genetic mutations. It may not turn out not to be x-linked, you know, it may turn out to be some other recessive condition.

57:35

Okay. Well, thank you. I think that's all the time we have for questions. I'm going to go ahead and close it out. First of all, I'd like to thank Dr. Birch and thank everyone for attending today's webinar. Once you leave today's webinar, you will receive a survey on the presentation and we would appreciate it if you would complete that and provide your feedback.

57:56

You will also receive a follow-up email by next week with the link to view a recording of today's webinar. Any questions, not addressed during today's presentation will be answered via email within the next two weeks on behalf of the Foundation Fighting Blindness and our presenter. Thank you for joining us today and have a great rest of your day.