ProQR Experimental RNA Therapeutic for Rare Eye Disease Misses Endpoints in Late-Stage Trial

ProQR Therapeutics reported that its pivotal phase 2/3 Illuminate trial of sepofarsen for the treatment of CEP290-mediated Leber congenital amaurosis 10 (LCA10) did not meet its primary endpoint of Best Corrected Visual Acuity (BCVA) at Month 12, and no benefit was observed in either treatment arm versus the sham group.

Photo: Daniel de Boer, founder and CEO of ProQR Therapeutics

For secondary endpoints full-field stimulus test (FST) and mobility, there was also no difference between the treated and sham groups in the top-line analysis. Sepofarsen was observed to be generally well-tolerated. Consistent with the findings observed in the phase 1/2 trial, cataracts, CME, and retinal thinning were observed.

ProQR’s trial result follows a string of setbacks for antisense technology that includes recent trial failures in Huntington’s disease from Roche and Ionis, and Ionis and Biogen in a genetically defined form of AML. The news sent ProQR’s stock plummeting 67 percent to $1.88 from $5.64.

“Given the results observed in earlier studies of sepofarsen, the Illuminate trial results are unexpected and disappointing, especially for people living with LCA10,” said Daniel de Boer, founder and CEO of ProQR Therapeutics. “ProQR was founded with the goal of developing RNA therapies for patients with high unmet medical need, and we will continue to advance our robust pipeline of therapies for genetic eye disease.”

Leber congenital amaurosis (LCA) is the most common cause of blindness due to genetic disease in children. It consists of a group of diseases of which LCA10 is the most frequent and one of the most severe forms. LCA10 is caused by mutations in the CEP290 gene on photoreceptor cells in which an extra base is inserted when DNA is transcribed into RNA. LCA10 leads to early loss of vision causing most people to lose their sight in the first few years of life. To date, there are no treatments approved that treat the underlying cause of the disease. Approximately 2,000 people in the Western world have LCA10 because of this mutation.

Sepofarsen (QR-110) is an experimental RNA therapy designed to restore vision in LCA10 due to the mutation in the CEP290 gene, which leads to aberrant splicing of the mRNA and non-functional CEP290 protein. Sepofarsen is designed to enable normal splicing, resulting in restoration of normal (wild type) CEP290 mRNA and subsequent production of functional CEP290 protein. Sepofarsen is intended to be administered through intravitreal injections in the eye and has been granted orphan drug designation in the United States and the European Union and received fast-track designation and rare pediatric disease designation from the FDA as well as access to the PRIME scheme by the EMA.

Illuminate, a randomized, sham-controlled trial, enrolled 36 participants aged eight years or older with genetically confirmed LCA10 due to the most common mutation in the CEP290 gene, at 14 study sites in nine countries. Participants were randomized to three equal groups (1:1:1) of the target registration dose sepofarsen (160 μg/80 μg loading dose/maintenance doses), a low dose of sepofarsen for masking (80 μg/40 μg loading dose/maintenance doses), or sham procedure, with sepofarsen administered via intravitreal injection and the sham procedure mimicking an injection with no drug or injection given.

“This was not the outcome we had hoped for, and we share in the disappointment many are feeling in the community,” said Benjamin Yerxa, CEO at the Foundation Fighting Blindness. “We will continue to work alongside ProQR to learn more from the ongoing analyses and as they work to advance RNA therapies to potentially help children, adults, and families who are affected by rare genetic eye diseases.”

ProQR did not say whether it will continue the sepofarsen program in CEP290-mediated LCA10, but it did reiterate that its cash position provides runway into mid- to late-2024.

Author: Rare Daily Staff