An RNA therapy from ProQR Therapeutics has failed a crucial test in an inherited eye disorder, an unexpected setback for the biotech company’s most advanced program. According to preliminary results, patients who received the experimental treatment, sepofarsen, showed almost no difference compared to the control group.
The Phase 2/3 study in patients with Leber congenital amaurosis also missed secondary endpoints assessing other measures of vision. ProQR, based in Leiden, the Netherlands, said it would continue to analyze the data and present more details at a future medical meeting. Speaking on a conference call Friday, CEO Daniel de Boer expressed surprise and disappointment at early data from the trial, named ILLUMINATE.
“We will find out what happened with the sepofarsen ILLUMINATE trial, where we will leave no stone unturned,” de Boer said.
Leber congenital amaurosis (ACL) is a disease in which photoreceptors in the retina degenerate or do not function properly. The disease arises from genetic mutations; defects in the CEP290 gene lead to the most common and severe form, called LCA10. People born with LCA10 typically lose vision within the first few years of life. There is no treatment for the underlying cause of the disease.
ProQR aims to treat ACL10 by correcting the genetic defect that causes it. Sepofarsen is an RNA therapy designed to restore the ability of the CEP290 gene to produce functional CEP290 protein. The treatment comes from a ProQR platform technology that has produced five programs, all inherited retinal diseases that biotechnology aims to treat with RNA therapies delivered as injections into the eye.
The pivotal Phase 2/3 trial of sepofarsen enrolled 36 patients aged 8 years or older who were genetically confirmed to have LCA10 due to a CEP290 mutation. These patients were randomly assigned to three groups: either a low or high dose of sepofarsen, or a third group receiving a sham procedure mimicking an injection.
The primary objective of the study was to measure best corrective visual acuity according to a widely used vision assessment in which a negative score indicates improvement in vision and a positive score indicates deterioration in vision. ProQR said that after 12 months, the mean change in best visual acuity from baseline was -0.11 in the high dose group and -0.13 in the low dose arm. In the group of patients who underwent a sham procedure, the mean change in score was -0.12.
The study’s secondary endpoints included a full-field stimulation test, which is a measure of the faintest flash of light that elicits visual stimulation, as well as performance on a mobility course. On these measures, ProQR also reported no difference between the treatment groups and the sham arm.
No serious adverse events were reported in the study and RNA therapy was well tolerated by patients. Chief Medical Officer Aniz Girach said cataracts, cystoid macular edema and retinal thinning were seen; these results are consistent with what was reported in sepofarsen phase 1/2 trials. In this study, which included five children and six adults, ProQR reported “rapid and sustained improvement in vision” in the majority of patients, paving the way for the pivotal Phase 2/3 study. The 12-month data reported on Friday is the first results of this three-year study, which will continue, de Boer said. In response to an analyst’s question about whether another Sepofarsen study is needed, de Boer said ProQR won’t know until the company better understands the results of the current study.
“It’s all on the table,” de Boer said. “We can come back to you once we have done this analysis.”
Through the end of the third quarter of 2021, ProQR reported its cash position was €156.1 million, which the company says is sufficient to sustain operations through mid to late 2024. Until then, ProQR will continue with its other RNA therapies. Last year, ProQR reported positive Phase 1/2 data for ultevursen, an RNA therapy for Usher syndrome and retinitis pigmentosa. This therapy is now in phase 2/3 testing. Another ProQR program, QR-504a, is in early clinical development for Fuchs endothelial corneal dystrophy type 3. Both studies are expected to report data later this year.
ProQR is also continuing to develop its Axiomer technology platform, which enables RNA editing. Although ProQR will use this technology to develop treatments for genetic eye diseases, the company is open to partnerships with companies interested in applying the technology to other therapeutic areas. Through a partnership with Eli Lilly, ProQR is using Axiomer to develop drugs for up to five targets in the liver and central nervous system.
De Boer rejected suggestions that early sepofarsen Phase 2/3 results in LCA10 would affect the company’s other programs. He said ProQR has obtained consistent results leading to clinical trials and extension studies with several molecules produced by his technology.
“In our opinion, the outlier here is the ILLUMINATE results that we represent today,” he said. “Therefore, we remain confident in the platform as such.”
Investors did not share de Boer’s optimism. Shares of ProQR fell more than 75% on Friday to around $1.37 per share.
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