FDA-approvable Version of Bevacizumab in Pivotal Trials
Outlook Therapeutics sees key advantages.
■ The prospect of an FDA-approved formulation of ophthalmic bevacizumab, the most widely used anti-VEGF therapy for retinal disease, is moving closer to becoming a reality. Outlook Therapeutics is currently conducting 2 pivotal phase 3 clinical trials for its ONS-5010/LYTENAVA (bevacizumab-vikg) in wet AMD. NORSE TWO, a 228-patient pivotal registration clinical trial, is fully enrolled and will report top-line data during Q3 of 2021. NORSE THREE was recently completed and is an open-label 197-patient safety study encompassing a range of retinal diseases for which Outlook expects to report top-line data in the second quarter of 2021. Outlook says the patent and regulatory environments are now favorable for such an initiative.
If approved by the FDA, the drug could eliminate the risks and issues associated with the use of off-label repackaged bevacizumab, which currently are obtained from compounding pharmacies. These issues include inconsistent potency, lack of sterility or availability, syringe malfunctions, the rare but real possibility of tainted product that can lead to catastrophic vision loss, and the increased legal liability that comes with the use of any off-label therapy. Outlook has already released top-line results demonstrating anticipated safety and efficacy and positive proof-of-concept of ONS-5010/LYTENAVA for the treatment of wet AMD from its 61-patient NORSE ONE study.
“We are completely committed to development of ONS-5010 to treat wet AMD,” said Lawrence A. Kenyon, president, CEO, and CFO of Outlook Therapeutics. “Of the 3 clinical trials in our phase 3 program, NORSE ONE was successfully completed last year, NORSE THREE was just completed in February, and NORSE TWO is fully enrolled and ongoing. We look forward to reporting pivotal data in the third quarter of this year and our planned BLA filing with the FDA soon thereafter. If all goes as planned, we anticipate marketing approval in mid-2022. We expect that ONS-5010, if approved, will provide an approved and cGMP-manufactured ophthalmic bevacizumab that avoids the problems inherent in unapproved repackaged IV bevacizumab from compounding pharmacists.”
Gemini Begins Trial for Subset of Wet AMD Patients
The goal is to correct a complement H insufficiency.
■ Gemini Therapeutics, a clinical-stage precision medicine company developing innovative treatments for genetically defined AMD, has begun a 45-patient phase 2a trial advancing GEM103 as a potential intravitreal add-on therapy for patients with wet AMD who have, or may be at risk for, macular atrophy (MA) but require ongoing anti-VEGF treatment. The clinical trial will be a randomized, single-masked, and sham-controlled study of patients requiring ongoing VEGF inhibition for wet AMD. Top-line data related to safety, tolerability, effect on intraocular complement factor H (CFH) levels, and biomarkers are expected in the second half of 2021.
“Current anti-VEGF therapies have improved the quality of life for patients with wet AMD,” said Marc E. Uknis, MD, FACS, chief medical officer of Gemini Therapeutics. “However, there is no therapy for the MA that can develop in some patients. In these patients, ongoing anti-VEGF therapy has been associated with a compartmental insufficiency of CFH activity. In this setting, GEM103, a recombinant human CFH, has the potential to be a meaningful add-on therapy.”
“The addition of a clinical research program targeting a selected wet AMD population is a natural next step for Gemini, and builds on our existing focus in genetically defined dry AMD,” said Jason Meyenburg, CEO of Gemini Therapeutics. “GEM103 is uniquely suited to correct CFH insufficiency associated with VEGF inhibition. This study is an important next phase in our understanding of the potential role of GEM103 as an add-on therapy in a subset of patients with wet AMD who go on to have comorbid MA.”
RGX-314 Continues to Reduce Wet AMD Treatment Burden
Gene-derived anti-VEGF was effective out to 3 years.
■ In a recent update of its gene-derived RGX-314 anti-VEGF subretinal injection for wet AMD, RegenxBio reported that patients in cohorts 4 (n=12) and 5 (n=12) at 1.5 years after administration of RGX-314 demonstrated stable visual acuity and decreased central retinal thickness. A meaningful reduction in anti-VEGF treatment burden was observed in both cohorts 4 and 5 compared to the mean annualized injection rate during the 12 months before RGX-314 administration. Patients in cohort 4 and cohort 5 received a mean of 4.4 injections and 1.7 injections respectively over 1.5 years following administration of RGX-314, a 58.3% and 81.2% reduction in anti-VEGF treatment burden.
Following the phase 1/2a trial, patients can enroll in a long-term study to assess the safety and efficacy up to 5 years after RGX-314 administration. All 6 patients from cohort 3 of the trial enrolled in the long-term study and demonstrated a mean BCVA improvement of +12 letters from baseline at 3 years.
Patients also demonstrated long-term reductions in anti-VEGF treatment burden over 3 years, with a mean annualized rate of 2.4 anti-VEGF injections, a 66.7% reduction. RGX-314 continued to be generally well tolerated across all cohorts, with 20 serious adverse events (SAEs) reported in 13 patients, including 1 possibly drug-related SAE of a significant decrease in vision in cohort 5.
Adverum to Accelerate ADVM-022 Path to Approval
Two pivotal wet AMD trials will begin this year.
■ Based on the favorable safety and efficacy profiles observed to date from ADVM-022 in the phase 1 OPTIC trial as well as interactions with the FDA, Adverum is planning to accelerate the clinical development of its gene-derived anti-VEGF by conducting 2 global phase 3 trials targeted to initiate in parallel in the fourth quarter of 2021. Pending successful outcomes of these trials, Adverum anticipates being able to submit its Biologics License Application for ADVM-022 for wet AMD in 2024.
The most recent OPTIC data presented at the virtual meeting of Angiogenesis, Exudation, and Degeneration 2021 demonstrated that patients who received 2 x 1011 vg/eye of ADVM-022 experienced an 85% reduction in annualized anti-VEGF injections and two-thirds remained supplemental anti-VEGF injection free with median follow-up of 48 weeks. Patients completing 2 years in OPTIC are being enrolled into an extension trial to be followed for up to 5 years.
The 2 phase 3 trials will study the efficacy and safety of 2 doses of ADVM-022 straddling the 2 x 1011 vg/eye dose used in the OPTIC trial. In the phase 3 trials of approximately 450 patients each, patients newly diagnosed with wet AMD will be randomized to 1 of 3 arms, receiving a single IVT injection of either 3 x 1011 vg/eye or 1 x 1011 vg/eye of ADVM-022 compared to aflibercept IVT every 8 weeks. The primary endpoint will be noninferiority to aflibercept based on change from baseline in BCVA at 1 year.
“The remarkable durability and anatomical improvements seen with a single IVT injection of ADVM-022 in the OPTIC trial suggest that our therapy could provide clinically important benefits over currently marketed therapies and other late-stage programs in development for wet AMD,” said Aaron Osborne, MBBS, chief medical officer. “In our OPTIC trial, we enrolled difficult-to-treat wet AMD patients who required frequent anti-VEGF injections to maintain their vision. Our phase 3 clinical trials will enroll newly diagnosed wet AMD patients and will be comparable to the designs of previous intravitreal anti-VEGF agents’ phase 3 trials.”
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 21st 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