Leber Congenital Amaurosis CRISPR Therapy Paused for Disappointing Efficacy


Editas has paused enrollment in the BRILLIANCE trial after efficacy was only seen in a very small subset of patients.

Editas Medicine has shelved development of its lead clinical program, EDIT-101, a CRISPR/Cas9 therapy, after efficacy was mainly seen in only patients with Leber congenital amaurosis 10 (LCA10) homozygous for IVS26 mutation, which represents a very small population of the disease.1

“The results from the BRILLIANCE trial provide a proof of concept and important learnings for our inherited retinal disease programs. We’ve demonstrated that we can safely deliver a CRISPR-based gene editing therapeutic to the retina and have clinically meaningful outcomes,” Gilmore O’Neill, MB, MMSc, president and chief executive officer, Editas Medicine, said in the statement.1 “While we will not progress EDIT-101 on our own and have made the decision to pause enrollment, we have the patient community top of mind and are looking for a collaboration partner to advance this program.”

EDIT-101 was being evaluated in the phase 1/2 BRILLIANCE trial (NCT03872479). The trial has treated 14 participants to date, 12 adults and 2 pediatric patients. The trial is assessing the safety, tolerability, and efficacy of 3 dose levels of EDIT-101 in up to 34 participants in up to 5 cohorts in multiple clinical trial sites. Participants receive a single subretinal injection of EDIT-101 in 1 eye and are monitored every 3 months for a year after treatment and then less frequently for 2 more years.

EDIT-101 is designed to treat LCA10 by deleting the IVS26 mutant allele in vivo directly in photoreceptor cells. The therapy has been granted rare pediatric disease and orphan drug designations from the FDA and orphan medicinal product designation from the EMA.

READ MORE: Gene Therapy Restores Night Vision in 2 Patients With Leber Congenital Amaurosis

The CRISPR therapy was well-tolerated, and investigators did not observe any ocular serious adverse events (AEs) or dose-limiting toxicities. AEs were mostly mild and expected with subretinal delivery. Investigators found that no other baseline characteristics besides homozygous IVS26 CEP290 mutations could predict responders in the trial, with only 3 of 14 participants experiences clinically meaningful improvements in best corrected visual acuity (LogMAR > 0.3). Two of these 3 participants had homozygous mutations. These participants had some additional improvements in full field sensitivity test, visual function navigation course, and/or visual function quality of life.

While approximately 1,500 LCA10 patients in the US have LCA10 with the IVS26 CEP290 mutant allele, only 300 of these patients have a homozygous mutation. Given the small population with the potential to benefit from EDIT-101, Editas has decided to pause development of the therapy and enrollment in the trial. The company will be seeking a partner to advance the program.

“I think the original rationale was that that was actually a reasonable population, a commercially viable patient population,” Gilmore said in a conference call.1 “Nevertheless, when you actually look at the data...that patient population is obviously substantially reduced.”

Editas licenses the use of CRIPSR/Cas9 technology, used in multiple programs, from the Broad Institute, which won a hard-fought patent battle for use of the technology in eurkaryotic cells in March 2022.2 The US Patent and Trademark Office Patent Trial Appeal Board ruled that the Broad Institute of Harvard University and the Massachusetts Institute of Technology were the first to invent CRISPR/Cas9 editing in eukaryotic cells not the group known collectively as CVC, which includes the University of California (UC), University of Vienna, and Emmanuelle Charpentier, PhD.

1. Editas Medicine announces clinical data demonstrating proof of concept of EDIT-101 from phase 1/2 BRILLIANCE trial. News release. Editas Medicines. November 17, 2022. https://finance.yahoo.com/news/editas-medicine-announces-clinical-data-121500871.html
2. Patent Interference No. 106,115 (DK): Decision on Priority 37 C.F.R. § 41.125(a). USPTO. February 28, 2022. Accessed March 3, 2022. https://drive.google.com/file/d/1-NxaE-FqWz1spjckk-Q6I_-LuKSzvMg3/view
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