The lead candidate of Editas Medicine, EDIT-101, an in vivo CRISPR gene editing treatment for Leber congenital amaurosis-10 (LCA10), showed positive initial clinical data showing it to be safe, and to have generated “signals” of efficacy in two of three patients in the study’s adult mid-dose cohort according to information released by the company at the XIXth International Symposium on Retinal Degeneration (RD2021).

One of the trial’s principal investigators reported that researchers saw a positive safety profile for EDIT-101 through up to 15 months, with mostly mild adverse events primarily related to the procedure of retinal injection.

The safety profile has allowed researchers to continue enrolling and treating patients in the high-dose adult cohort (3×10¹² vg/ml)—while beginning to enroll and treat patients in the mid-dose pediatric cohort (1.1 x 10¹² vg/ml)—of the Phase I/II BRILLIANCE clinical trial (NCT03872479). The ongoing study is designed to assess the safety, tolerability, and efficacy of EDIT-101 in up to 18 patients with LCA10, divided into five cohorts—three different dosages among adults, two among children. The first patient was dosed last year.

“I am encouraged by these initial results, which indicate this investigational gene editing treatment has been well-tolerated in this trial’s participants thus far and may also help improve sight for people with mutations in the CEP290 gene,” stated Mark Pennesi, MD, PhD, of Oregon Health & Science University, where he is a Professor of Molecular and Medical Genetics, Kenneth C. Swan Endowed Professor of Ophthalmology, and Paul H. Casey Ophthalmic Genetics Division Chief for OHSU’s Casey Eye Institute.

Lisa Michaels, MD, Editas’ executive vice president and chief medical officer, stated that the preliminary results “support our belief that EDIT-101 has the potential to provide meaningful benefits to people living with CEP290-related retinal degeneration or LCA10.”

“These encouraging results provide a proof of concept on our in vivo gene editing platform and increase Editas’ confidence in the broad potential of our gene editing technology to address additional serious diseases,” Michaels added.

“Savor the moment!”

Echoing the positive assessments of Michaels and Pennesi is Fyodor Urnov, PhD, director for technology and translation at the Innovative Genomics Institute at University of California, Berkeley, who was not connected to the study.

“@editasmed, and the field, are on the right track,” Urnov tweeted today, soon after congratulating the clinical trial team: “Take a moment to savor the moment! This is a TOUGH target, the road ahead is long, but the early data are promising.”

Brad Loncar, CEO of Loncar Investments, took a more cautious view on Twitter: “Hints that it could work but not enough to give you confidence that it will work. In other words, a borderline non-event that won’t make anyone happy.”

Urnov replied: “I strongly (and respectfully) disagree: 1. No immune response (so far) 2. AAV-Cas9 in eye is safe (to date) 3. Modest response in mid-dose 4. Advancing to peds [pediatric patients].”

Investors appeared to share Loncar’s caution rather than Urnov, however, sending Editas shares down 19% in trading today, to a closing price of $42.50 from yesterday’s close of $52.45. Over the past year, shares of Editas have traded between a low of $27.01 and a high of $99.95.

EDIT-101 is being evaluated as a potential treatment for LCA10 caused by a homozygous or compound heterozygous mutation involving c.2991 + 1655A>G in intron 26 of the CEP290 gene (LCA10-IVS26). EDIT-101 is designed to eliminate the mutation by using CRISPR to cut out that nucleotide and surrounding DNA, thus restoring normal protein expression and function of remaining photoreceptor cells.

Editas reasons that therapeutic approaches aimed at restoring function of remaining photoreceptor cells could arrest further loss of vision for patients with LCA10, the most common cause of inherited childhood blindness, for which no treatment options now exist.

EDIT-101 was one of up to five Editas early-stage CRISPR genome-editing programs targeting eye diseases for which Allergan held a licensing option when the companies launched their R&D partnership in March 2017, with Allergan paying Editas $90 million upfront. A year later, Allergan agreed to develop and commercialize EDIT-101, in return committing up to $40 million to Editas. Allergan was acquired in a $63 billion deal completed last year by AbbVie, which ended the partnership with Editas.

In the BRILLIANCE trial, patients received a single administration of EDIT-101 directly to photoreceptor cells via subretinal injection in one eye. The trial’s estimated primary completion date is March 22, 2024.

Pennesi and Editas presented preliminary safety and efficacy results from the trial’s first two cohorts totaling six patients—the four-patient adult mid-dose cohort (1.1 x 10¹² vg/ml), as well as the two-patient adult low-dose cohort (6 x 10¹¹ vg/ml).

Within both cohorts, most adverse events (AEs) were mild and primarily resulting from the surgical procedure and subretinal injection, Editas said.

Researchers saw no dose limiting toxicities, but did see mild anterior chamber inflammation, which according to Editas was “adequately” controlled with oral steroids. No Cas9-specific antibody or T-cell response was detected, and no treatment-related cataracts, edema, or retinal thinning have been seen to date, according to the company.

Two patients show improvement

Pennesi and Editas also presented efficacy data from both adult low-dose patients, and three of four adult mid-dose patients, as all of which had at least three months of post treatment follow-up. The follow-up focused on measures shown to be consistent and reproducible in subjects with CEP290 retinal degeneration, including BCVA, FST, and Visual Function Navigation (VNC™, developed by Ora).

Two of the three adult mid-dose patients followed for up to six months showed efficacy signals suggesting productive editing and providing initial support for clinical benefits, including improvements in BCVA, FST, and/or mobility navigation, Editas said.

The company highlighted improvement in two of the three adult mid-dose patients:

• A 54-year-old white woman showed improvement in BCVA of approximately 0.7 logMAR at Month 1.5 which was sustained at Month 6 follow-up. Editas also reported a “positive trend” toward improved retinal sensitivity by FST in the study eye relative to the untreated eye in the patient, who also showed a 5-level improvement in mobility at month 6, as assessed via VNC.
• A 20-year-old Hispanic man showed improvement by month 3 with a stable BCVA and a notable improvement in retinal sensitivity in the study eye relative to the untreated eye by FST, detectable at month 1.5 that continued to improve through month 3.

In a presentation to investors, Editas acknowledged that the third adult mid-dose patient, a 19-year-old white woman, showed “indeterminant” clinical improvement up to three months following treatment. The fourth adult mid-dose patient, a 63-year-old white woman, had only been in the trial for two months.

In June, the trial’s Independent Data Monitoring Committee (IDMC) endorsed proceeding with the mid-dose pediatric cohort based on a review of clinical safety data from the adult low-dose and adult mid-dose cohorts.

The trial’s fifth cohort will consist of up to four pediatric high-dose patients (3.0 x 10¹² vg/ml).

BCVA eligibility criteria for the adult low-dose cohort were light perception (LP), black-white discrimination, and white field projection. For the adult mid-dose and all other cohorts, the first subject is required to have light perception to BCVA of 1.6 logMAR (20/800 Snellen). BCVA criteria for all subsequent patients is LP to 0.4 logMAR (20/50 Snellen).