ProQR Doses First Patients in Phase 2/3 Clinical Trials for its USH2A-Exon 13 RNA Therapy

ProQR, a developer of RNA therapies in the Netherlands, has dosed the first patients in its Phase 2/3 Sirius and Celeste trials for QR-421a, an RNA therapy for people with mutations in the exon 13 region of the USH2A gene. These mutations cause Usher syndrome type 2A (USH2A) or non-syndromic retinitis pigmentosa (RP). According to ProQR, more than 16,000 people in the Western world have USH2A or RP caused by these mutations.

“We are excited to see ProQR’s QR-421a RNA therapy move into Phase 2/3 trials, thanks to vision improvements observed in the Phase 1/2 trial,” says Benjamin Yerxa, PhD, chief executive officer, Foundation Fighting Blindness. “The Phase 2/3 trials, if successful, could lead to regulatory approval of QR-421a, potentially making it available to thousands of people affected by RP and Usher syndrome type 2A.”

The Foundation Fighting Blindness invested $7.5 million through its RD Fund to move QR-421a into and through the Phase 1/2 clinical trial. The RD Fund, a venture philanthropy fund, was established in 2018 to provide investments for promising retinal degenerative disease therapies that are in, or moving toward, early human studies.

QR-421a is an antisense oligonucleotide (AON) — a small piece of genetic material — designed to mask exon 13 mutations in the RNA derived from the USH2A gene. RNA are genetic messages that cells read to make proteins critical to their health and function. QR-421a enables retinal cells to skip over exon 13 (and any mutations inside it) when reading the USH2A RNA, enabling the cells to make functional protein that will hopefully halt or slow the disease process and vision loss.

Both Sirius and Celeste trials are for people 12 and older. In both studies, participants are randomly assigned to three parallel study arms. In the two treatment arms, participants receive intravitreal injections with QR-421a at different doses. In the third sham/control arm, the intravitreal injections are mimicked, but no injection or study medication is given.

The Sirius study will enroll 81 participants with advanced vision loss — those with baseline best corrected visual acuity (BCVA) of worse than 20/40 as measured using an eye chart. The primary endpoint in the study is mean change from baseline in BCVA at 18 months in the treated arms compared to the sham/control arm.

The Celeste study will enroll 120 participants with early to moderate vision loss (baseline BCVA equal to or better than 20/40). The primary endpoint in the study is the mean change from baseline in static perimetry at 12 months in the treated arms compared to the control arm. Static perimetry measures retinal sensitivity at different points in the patient’s visual field.

In the Phase 1/2 Stellar trial, QR-421a demonstrated benefits in BCVA, static perimetry, and retinal structure as measured by optical coherence tomography (OCT). Improvements in BCVA were greatest for the six treated patients with advanced disease. Improvements in perimetry were greatest for the eight treated patients with early-moderate disease. All 14 treated patients received one dose of QR-421a, and results were reported at 48 weeks after treatment.