IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Gyroscope Gene Therapy Is Promising in Early-stage GA Trial

■ Gyroscope Therapeutics Limited announced positive interim safety, protein expression, and biomarker data from the ongoing open-label phase 1/2 FOCUS clinical trial of its investigational gene therapy, GT005, in patients with geographic atrophy (GA) secondary to AMD. Interim results showed GT005 was well tolerated and resulted in sustained increases in vitreous complement factor I (CFI) levels in the majority of patients, as well as decreases in the downstream complement proteins associated with overactivation of the complement system. These results were observed both in GA patients who had rare variants in their CFI gene as well as those who did not.

“There is strong evidence that an overactive complement system is a key driver of dry AMD,” said Arshad Khanani, MD, MA, director of clinical research at Sierra Eye Associates and an investigator in the FOCUS trial. “The recently released data from the FOCUS trial suggest the potential of a one-time gene therapy with GT005 to regulate an overactive complement system. It is encouraging that GT005 generated sustained increases in CFI in a majority of the patients, even in some patients treated more than a year ago. We continue to look forward to learning more about GT005 as a potential treatment for GA in the ongoing phase 2 clinical trial program.”

DORC Gets Health Canada Approval for Staining Dye

■ INTERNATIONAL NEWS – DORC has received notification from Health Canada that the application for Tissueblue (Brilliant Blue G Ophthalmic Solution) 0.025% has been approved and will be available later in 2021 via INNOVAMED, DORC’s local distributor partner. This news follows almost exactly 1 year after Tissueblue received FDA approval. Since FDA approval, DORC estimates Tissueblue has been used in more 15,000 retina procedures in the United States. Tissueblue is the first dye approved by Health Canada for use as an aid in ophthalmic surgery by selectively staining the internal limiting membrane.

Commenting on the launch, David Chow, MD, assistant professor at St. Michael’s Hospital, said, “Health Canada approval of Tissueblue is an important milestone for retina surgeons in Canada. Retina specialists will welcome the opportunity to use an approved ILM dye that combines consistent, high-quality staining performance with a long track record of safe use worldwide in over 350,000 surgeries since launch. A further benefit is the convenience and added security of its packaging in a sterile, prefilled syringe, avoiding the need for mixing the dye prior to use.”

Sustained-release Axitinib Shows Signs of Strong Durability

■ In a presentation at the recent Angiogenesis, Exudation, and Degeneration meeting, Andrew A. Moshfeghi, MD, of the University of Southern California Roski Eye Institute, reported that the OTX-TKI axitinib intravitreal implant, currently in a phase 1 trial for Ocular Therapeutix, has shown anecdotal signs of long-term durability in several patients receiving the 400-μm dose of the drug.

In the 7-patient cohort 2 (400-μm dose), several subjects demonstrated durability of therapy for up to 10 months, and 1 subject demonstrated durability to 13.5 months. In the 6-patient cohort 1 (200-μm dose), three patients have gone 9 months without requiring rescue. There have been no reports of serious ocular adverse events thus far in the study.

In another development relating to axitinib, Aerie Pharmaceuticals announced a new pipeline candidate, AR-14034, a preclinical sustained-release retinal implant for the potential treatment of wet AMD and DME for up to 1 year durability. AR-14034 contains the pan-VEGF inhibitor axitinib formulated in a unique bioerodible polymer blend using Aerie’s exclusive PRINT technology.

The 21st Annual Fellows Forum Goes Virtual

■ The 21^st Retina Fellows Forum format was dramatically changed, with no in-person academic and social activities in Chicago, no distinguished guest speaker, and no hotly contested Retina Fellows Forum bowling tournament. Instead, the Virtual Retina Fellows Forum took place online over 3 nights in late January and the audience was expanded from the usual group of senior North American vitreoretinal fellows to include a global audience of fellows, residents, and practicing retina specialists. Each night began with a virtual “meet and greet” for fellows, faculty, and industry attendees, followed by energetic panel discussions covering a broad spectrum of medical and surgical retina issues. Lectures and panel discussions were punctuated by questions and comments from the audience and the format was designed to highlight differences in the way the faculty approach clinical challenges.

The final “Real World” panel discussion addressed challenges facing young retina specialists as they begin practice: maintaining and improving surgical skills, interacting with patients and staff, work-life balance, and time management. The faculty of 12 leading retina specialists was led by course director Tarek Hassan, MD, and co-directors Carl Awh, MD, and David Chow, MD. Other faculty members were Thomas Albini, MD; Caroline Baumal, MD; Dean Eliott, MD; Sunir Garg, MD; Aleksandra Rachitskaya, MD; Alan Ruby, MD; David Sarraf, MD; Amy Schefler, MD; and Rishi Singh, MD.

Ranibizumab “Nonresponders” May Be Brief Responders

■ Researchers from the University of Crete and Mass Eye and Ear set out to determine whether some patients classified as nonresponders to ranibizumab (Lucentis; Genentech) may actually reach their maximum reduction in central retinal thickness (CRT) prior to week 4. A total of 48 eyes of 48 patients (52% treatment naive) were assessed weekly by SD-OCT. Two-thirds (64.6%) reached maximal CRT reduction earlier than the standard 4-week interval: 6.3% at 1 week post-injection, 22.9% at 2 weeks post-injection, and 35.4% at 3 weeks post-injection. Only 35.4% of patients had maximal CRT reduction at 4 weeks. Twenty percent of treatment-naive and 34.8% of non-naive patients had a week-4 CRT that was >35 μm thicker than the earlier occurring lowest CRT value. The time to maximal CRT reduction was not related to axial length, age, lens status, or history of injections.

The researchers concluded that the optimal dosing interval for maximal CRT reduction may be less than 4 weeks for a significant proportion of patients. Disease load rather than eye size appears to be the driver of anti-VEGF treatment duration and, therefore, the dosing interval needs to be optimized in the cohort of short-term responders.

Researchers Identify Causes of Severe Vision Loss in Wet AMD

■ Researchers who conducted the AREDS2 study set out to determine why some study participants were experiencing catastrophic vision loss (mean 20/500; 56 of 594 eyes) even after 2 years of anti-VEGF therapy. Of the 55 poor BVCA eyes with fundus photography available at 2 years, 33 (60.0%) had central macular atrophy and 22 (40.0%) had central subretinal fibrosis assessed as the principal cause for poor vision. The group with poor BCVA had lower BCVA 2 years earlier, with a mean baseline of 20/160. They also had a higher proportion of baseline macular atrophy 2 years earlier (26.8% vs 12.3%), a higher proportion with macular hemorrhage (25.5% vs 13.2%), and fewer anti-VEGF injections (7.6 vs 10.2).

The researchers, who reported their findings in Ophthalmology Retina, found that at 2 years after starting anti-VEGF therapy, almost 1 in 10 eyes showed BCVA at the level of legal blindness. From fundus photography grading, the cause of poor vision appeared to be macular atrophy in 60% and subretinal fibrosis in 40%. These data may be useful in understanding the long-term limits to good vision in wet AMD.

Immunocore Uveal Melanoma Drug Gets Breakthrough Status

■ Immunocore, a late-stage biotechnology company leading the development of a novel class of T cell receptor (TCR) bispecific immunotherapies, said the FDA has granted breakthrough therapy designation to tebentafusp for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

Bahija Jallal, CEO of Immunocore, said, “We are delighted that the FDA has granted breakthrough therapy designation for tebentafusp based on the survival benefit from our phase 3 clinical trial. There is an urgent need for an approved treatment for this rare and aggressive form of melanoma and we look forward to continuing to work with regulators to bring tebentafusp to patients as quickly as possible.”

In an initial preplanned interim analysis of a randomized phase 3 clinical trial in previously untreated metastatic uveal melanoma, a cancer that has historically proven to be insensitive to other immunotherapies, tebentafusp demonstrated superior overall survival benefit as a monotherapy.

Kodiak Sciences Provides Positive Update on KSI-301

■ As part of its year-end review, Kodiak Sciences said its phase 1b KSI-301 clinical trial was producing positive results in wet AMD, DME, and RVO as the company advanced the drug into pivotal trials.

“Our phase 1b data show 2 in every 3 patients are on a 6-month or longer treatment-free interval at year 1 in each of the 3 major retinal vascular diseases after only 3 loading doses,” said Victor Perlroth, MD, CEO of Kodiak. “Importantly, the durability profile of KSI-301 is tied to strong efficacy improvements in all three diseases at year 1. The treatment-naïve wet AMD patients in our study achieved 20/40 vision on average at year 1, and DME and RVO patients achieved 20/32 vision on average. We also are pleased with the retinal anatomic effects of KSI-301 observed through 1 year of treatment, with robust retinal drying seen across all 3 diseases being studied. The safety profile of KSI-301 continues to be very encouraging. The initiation of our phase 3 studies in DME (GLEAM and GLIMMER) and RVO (BEACON) and the timely completion of patient recruitment into our pivotal wet AMD study (DAZZLE) are meaningful operational milestones on our path toward multiple top-line clinical study readouts planned for 2022.”

Kodiak also said it intends to initiate a pivotal phase 3 randomized study of KSI-301 in nonproliferative diabetic retinopathy patients (GLOW). KSI-301 is an investigational anti-VEGF therapy built on the Kodiak’s antibody biopolymer conjugate (ABC) platform and is designed to maintain potent and effective drug levels in ocular tissues for longer than existing agents.

Asclepix Begins DME Trial That Integrates At-home OCT

■ Asclepix Therapeutics has begun the phase1/2a, 12-patient, dose-ranging CONGO study (n=12) in DME employing AXT107, an intravitreal self-forming gel depot peptide regulator that the company believes could be dosed once a year. Study subjects who participate in CONGO will perform sequential daily self-imaging of their eyes with the self-operated Notal Home OCT device to provide interim data between scheduled office visits. The Notal Vision Diagnostic Clinic will monitor patient compliance of the self-imaging and provide remote support as needed. The AI-based Notal OCT Analyzer will identify and quantify intraretinal and subretinal fluid from each daily OCT volume scan.

“Remote OCT monitoring of patients with exudative retinal diseases in a regulatory clinical trial allows Asclepix Therapeutics to capture critical data points while potentially reducing the burden of frequent office visits” said Arshad M. Khanani, MD, MA, one of the study’s investigators and director of clinical research at Sierra Eye Associates in Reno, Nevada.

Opthea Finalizes Protocols for Pivotal Wet AMD Trials

■ Australia-based Opthea Limited has finalized the protocol study designs and key startup activities in readiness for the initiation of the phase 3 ShORe and COAST pivotal clinical trials of “pan-VEGF” therapy OPT-302 in wet AMD. The global multicenter, double-masked, sham-controlled pivotal clinical trials will each enroll 990 treatment-naive patients and assess the efficacy and safety of intravitreal 2.0 mg OPT-302 in combination with 0.5 mg ranibizumab (Lucentis; Genentech) (ShORe trial) or 2.0 mg aflibercept (Eylea; Regeneron) (COAST trial), compared to ranibizumab or aflibercept monotherapy, respectively.

In addition, extended durability of the OPT-302 treatment effect on clinical outcomes with less frequent every-8-week dosing will be compared with OPT-302 administered on an every-4-week dosing regimen, in combination with each VEGF-A inhibitor. If effective in these phase 3 studies, OPT-302 could be adopted for administration with either Eylea or Lucentis.

The primary endpoint for both trials is the mean change in BCVA from baseline to week 52 for OPT-302 combination therapy compared to anti-VEGF-A monotherapy. Each patient will continue to be treated for a further year to evaluate extended safety and tolerability over a 2-year period.

Opthea remains on track to initiate the trials in the first quarter of calendar year 2021 and to report top-line data in the second half of 2023. Opthea’s lead product candidate, pan-VEGF therapy OPT-302, is being developed for use in combination with anti-VEGF-A monotherapies to achieve broader inhibition of the VEGF family, with the goal of improving overall efficacy and demonstrating superior vision gains over that which can be achieved by inhibiting VEGF-A alone. RP