IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Beovu Effective in Phase 3 DME Trial

■ Novartis reported initial results of the 360-patient phase 3 KITE study, assessing the efficacy and safety of brolucizumab (Beovu) 6 mg in diabetic macular edema. The trial met its primary and key secondary endpoints, demonstrating noninferiority of brolucizumab vs aflibercept 2 mg (Eylea; Regeneron) in mean change in BCVA at year 1. Brolucizumab demonstrated superiority in improvement vs aflibercept in change of central subfield thickness over the period of week 40 through week 52. More than half of patients in the brolucizumab arm were maintained on a 3-month dosing interval through year 1, following the loading phase. All aflibercept patients were on a 2-month dosing interval after the loading phase. Brolucizumab also demonstrated an overall well-tolerated safety profile comparable to aflibercept. In addition, the rate of intraocular inflammation was equivalent between brolucizumab and aflibercept.

Safety Issues Halt Trial for Oral Drug in Wet AMD

■ A phase 2 trial testing vorolanib (X-82; Tyrogenex) in patients with wet AMD was stopped due to concerns over toxicity. Tyrogenex had conducted phase 1 and phase 2 clinical trials for vorolanib as an oral therapy for wet AMD.

X-82 is a novel, potent, oral, multikinase VEGF-receptor and PlGF-receptor inhibitor. The phase 2 APEX trial was stopped because of elevated liver enzymes, despite some positive signs of efficacy, which were detailed at the American Society of Retina Specialists 2020 Virtual Sessions.

Lapses in Anti-VEGF Therapy Have Lasting Effects

■ A retrospective study of 3,304 patients with wet AMD who had treatment lapses of more than 3 months demonstrated poorer outcomes than a control group. Although macular thickness normalized on resumption of treatment, the decline in visual acuity did not recover, even after 12 months of follow-up. The study, published in the journal Retina, was led by Rishi Singh, MD, of the Cleveland Clinic. Another study, conducted by AMD Barometer and an international group of ophthalmologists called the Vision Academy, assessed the literature to determine the most-mentioned causes of lapses and discontinuation of anti-VEGF therapy. The study found that risk factors included worse vision at baseline, fear of injection, other illness, appointment-related issues, and lack of transportation. For discontinuing treatment, older age and poor visual response were additional risk factors. The research, which appeared in the journal Ophthalmology, can be used to identify at-risk patients earlier and improve real-world outcomes.

Two New Trials Use Clearside’s Suprachoroidal Delivery

■ Both Regenxbio and Aura Biosciences have recently begun new clinical trials that employ a suprachoroidal delivery approach developed by Clearside Biomedical. Both Aura, with a phase 2 study in choroidal melanoma, and Regenxbio, with a phase 2 study in wet AMD, are using the SCS Microinjector.

The SCS Microinjector provides targeted delivery to potentially improve efficacy and compartmentalization of medication to reduce or eliminate toxic effects on nondiseased cells. The SCS Microinjector is composed of a syringe and 2 30-gauge hollow microneedles of varying lengths, each less than 1.2 millimeters, within a custom-designed hub that optimizes insertion and suprachoroidal administration of drugs.

Multiple Nutrients Can Slow AMD Progression

■ A 10-year follow-up study of more than 8,000 participants (14,135 eyes) in the AREDS and AREDS2 studies conducted by the AREDS Research Group of the National Eye Institute found that dietary intake of multiple nutrients was a strong factor in slowing the progression of AMD and geographic atrophy (GA). None of the participants had late-stage AMD at baseline.

Higher dietary intake of multiple nutrients, including minerals, vitamins, and carotenoids, is associated with decreased risk of progression to late AMD. Both saturated and unsaturated fatty acids were associated with increased risk of progression. These associations are stronger for GA than for neovascular AMD. The same nutrients tend also to have protective associations against large drusen development.

More Stringent Guidelines for AI-Driven Studies

■ As evaluation of health interventions involving machine learning or other artificial intelligence (AI) systems moves into clinical trials, an international group has developed new, stricter guidelines aiming to improve the quality of these studies and ensure that they are reported transparently. Future clinical trials evaluating an AI intervention will be expected — and often required — to report their publications to the new standards. The guidelines also will help medical professionals, regulators, funders, and other decision-makers assess the quality of planned clinical trials and whether the algorithm is safe and likely to bring about patient benefit.

Researchers from the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust in the United Kingdom worked with leading institutions from across the world and have published their findings and the new guidelines in Nature Medicine, The BMJ, and The Lancet Digital Health.

“Before we introduce these technologies into everyday practice we need to know that they have been robustly evaluated and proven to be effective and safe,” said Prof. Alastair Denniston, lead for AI at Birmingham Health Partners Centre for Regulatory Science and Innovation, and consultant ophthalmologist at University Hospitals Birmingham, in a news release. “Our previous work showed just how big a problem this can be and that we needed a way to cut through the hype surrounding AI in health care.”

Researchers developed the additional guidance to tackle concerns that studies of AI are of insufficient quality and are not transparent. This was highlighted by recent research, led by several of the same researchers, which highlighted that less than 1% of 20,500 analyzed studies relating to health AI were of sufficient quality that independent viewers could have confidence in their results. Discrepancies uncovered include using data samples that are not comparable and reporting results that could not be validated by external criteria.

Haag-Streit Introduces New Surgical Chair Design

■ Haag-Streit USA is seeking to reinvent the surgical chair to provide ideal ergonomics for the ophthalmologist in the surgical suite. To understand the unique issues ophthalmic surgeons face, Haag-Streit USA collaborated with Michael E. Snyder, MD, of the Cincinnati Eye Institute and other ophthalmologists across the country.

“As an ophthalmologist, there’s nothing more important than ergonomics, especially if you develop neck and spine disease,” said Dr. Snyder in a news release. “I’ve been proactive on this approach for more than 20 years. By improving ergonomics in your practice, you do a better job and your patients benefit from better care.”

“The new CO:RE Surgical Chair is a concrete example of the visionary ideas we’re developing to maximize comfort and prolong the careers of surgeons,” said Mike Luley, Haag-Streit USA Surgical Division director of sales. “Historically, equipment design has not focused on the comfort and well-being of the surgeon. Shifting our focus to encompass the surgeon’s joints and spine will improve not only their health in the operating room, but also their overall quality of life as well.”

FDA Approves Treatment for Rare Eye Disease

■ The FDA has approved Enspryng (satralizumab-mwge) for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with a particular antibody — patients who are anti-aquaporin-4 antibody-positive. NMOSD is a rare autoimmune disease of the central nervous system that mainly affects the optic nerves and spinal cord. Enspryng is the third approved treatment for the disorder.

In patients with NMOSD, the body’s immune system mistakenly attacks healthy cells and proteins, most often those in the optic nerves and spinal cord. Individuals with NMOSD typically have attacks of optic neuritis, which causes eye pain and vision loss. Approximately 50% of patients with NMOSD have permanent visual impairment and paralysis caused by NMOSD attacks. Estimates vary, but NMOSD is thought to impact approximately 4,000 to 8,000 Americans.

New Nomenclature for PCV

■ As part of the Asia-Pacific Ocular Imaging Society (APOIS), an international group of experts surveyed and discussed the published literature regarding the current nomenclature and lesion components for polypoidal choroidal vasculopathy (PCV) and proposed an updated consensus nomenclature, which reflects the latest understanding based on imaging and histology reports.

The group evaluated a set of diagnostic features based on OCT and color fundus photographs for PCV that may distinguish it from typical wet AMD and assessed the performance of individual and combinations of these non-ICGA features, aiming to propose a new set of diagnostic criteria that does not require the use of ICGA. The final recommendation was validated in 80 eyes from 2 cohorts.

The group recommended the terms “polypoidal lesion” and “branching neovascular network” for the 2 key lesion components in PCV. For the diagnosis of PCV, the combination of 3 OCT-based “major criteria” (sub-retinal pigment epithelium [RPE] ring-like lesion, en face OCT complex RPE elevation, and sharp-peaked pigment epithelial detachment) achieved an area under the receiver operating characteristic curve of 0.90. Validation of this new scheme in a separate subset of 110 eyes achieved an accuracy of 82%.

Kubota Stargardt Therapy Gets Orphan Status

■ Kubota Vision said the FDA Office of Orphan Products Development has awarded an orphan products clinical trial grant to support the ongoing phase 3 study of emixustat in Stargardt disease. The total fund Kubota Vision receives in 3 years will be up to $1.6 million. The study is a multicenter, randomized, double-masked, placebo-controlled trial in which subjects are randomly assigned to emixustat 10 mg or placebo (2:1 ratio) once daily for 24 months.

Regenxbio Set to Begin Single-Injection DR Trial

■ Regenxbio announced the clearance of the Investigational New Drug (IND) application by the FDA to evaluate the suprachoroidal delivery of the gene-derived anti-VEGF RGX-314 in patients with diabetic retinopathy (DR). Regenxbio plans to begin dosing patients in the phase 2 ALTITUDE trial before the end of 2020.

“We believe one-time treatment with RGX-314 can provide sustainable, long-term anti-VEGF delivery to the eye, potentially reducing the severity of DR and preventing vision threatening complications,” said Steve Pakola, MD, chief medical officer of Regenxbio, in a news release. “We are pleased to advance this program, and look forward to initiating our second clinical trial utilizing suprachoroidal delivery, building upon clinical and preclinical data from the RGX-314 program.”

ALTITUDE is a multicenter, open label, randomized, controlled dose-escalation study that will evaluate the efficacy, safety, and tolerability of suprachoroidal RGX-314. The trial is expected to enroll 40 patients with DR across 2 cohorts. Patients will be randomized to receive RGX-314 vs observational control at a 3:1 ratio, and 2 dose levels of RGX-314 will be evaluated: 2.5x10¹¹ GC/eye and 5.0x10¹¹ GC/eye. Patients will not receive prophylactic immune suppressive corticosteroid therapy before or after administration of RGX-314. The primary endpoint of the study is the proportion of patients who improve in DR severity, based on the Early Treatment Diabetic Retinopathy Study-Diabetic Retinopathy Severity Scale (ETDRS-DRSS) at 48 weeks. Other endpoints include safety and development of DR-related ocular complications.

Seven-Year Results for MUST Trial

■ The Multicenter Uveitis Steroid Treatment Trial (MUST) and Follow-up Study enrolled 248 eyes of 177 participants with uveitic macular edema. Among 227 eyes with macular edema followed ≥1 year, the cumulative percentage of eyes with macular edema resolving at any point during 7 years was 94%. Epiretinal membranes on OCT were associated with a lower likelihood of macular edema resolution. Among 177 eyes with resolved macular edema, the cumulative percentage with relapse within 7 years was 43%. Eyes in which macular edema resolved gained a mean of 6.24 letters compared to eyes that remained free from macular edema during the 1-year follow-up intervals, whereas eyes in which macular edema did not resolve experienced no gain in vision and eyes that developed macular edema during the year (either incident or relapsed) experienced a mean change of -8.65 letters of visual acuity.

The researchers reported in the journal Ophthalmology that given sufficient time and treatment, nearly all uveitic macular edema resolves, but episodes of relapse were common. Visual acuity results were better among eyes with resolved macular edema, suggesting that control of inflammation and resolution of macular edema might be visually relevant treatment targets.

A Roundup of Presentations From the Virtual ASRS Meeting

Early Results for Prima Retinal Prosthesis in GA

■ Joseph Martel, MD, of the University of Pittsburgh Eye Center, led a prospective study in patients with visual acuity ≤20/400 due to geographic atrophy (GA) of at least 3 optic disc diameters and with central absolute scotoma in the study eye. The 2-mm wide, 30-μm thick wireless photovoltaic prosthesis (Prima; Pixium Vision), invented by Daniel Palanker, PhD, of Stanford University, and containing 378 pixels (each 100-μm in diameter), was implanted subretinally within the area of GA in the worse eye. The subretinal prosthesis functions in tandem with augmented-reality glasses containing a camera and near-infrared projector. Pixels convert light projected on the retina into electric current to stimulate the inner retinal neurons. Anatomic outcomes were assessed with fundus photography and OCT imaging.

Two subjects have thus far been implanted with the Prima. In both patients, the prosthesis remained within the GA after implantation and patients perceived visual sensitivity and bar orientation recognition in the former central scotoma without loss of residual natural acuity. No study-related serious adverse events have been observed at 3-month follow-up. Three more implantations and further testing of prosthetic vision is planned, including bar orientation, letter recognition, and acuity.

Gene Therapy Effective in Choroideremia

■ Results from the phase 2 GEMINI gene therapy clinical trial sponsored by Biogen were reported. The trial consists of 6 males aged 32-72 years with advanced choroideremia who received subfoveal injection of AAV2-REP1 in the worse-sighted eye. Four of the same 6 patients also were treated in the better-sighted fellow eye at month 24 as part of the same trial. The primary measure was BCVA improvement. Secondary endpoints included change from baseline in microperimetry, fundus autofluorescence, and OCT. Safety evaluations included adverse events, viral shedding in body fluids, and vector antibody responses. Baseline mean BCVA ranged from 20/32 to 20/80 in the treated eyes and 20/32 to 20/40 in the untreated eyes.

At month 36, mean BCVA in the treated eye was 20/25 to 20/40, with the best outcome of +12 letters and worst outcome of -1 letter. Of the 4 initially untreated eyes that received treatment at month 24; best outcome at month 36 was +3 letters and worst outcome was -2 letters. No serious adverse event occurred. The researchers concluded that sustained improvement or maintenance of BCVA is achievable in advanced choroideremia with high-dose AAV2-REP1. Bilateral sequential high-dose AAV2-REP1 treatment delivered with intraoperative OCT has a good safety profile. The multicenter bilateral sequential phase 2 and the randomized phase 3 clinical trials are ongoing.

No Safety Signal With Eylea for Occlusive Retinal Vasculitis

■ After Novartis reported incidence of occlusive retinal vasculitis (ORV) associated with its newly FDA-approved anti-VEGF brolucizumab for wet AMD, Regeneron conducted a review of all of its phase 3 and postmarketing studies for aflibercept (Eylea) and found no ORV-connected safety issues. RP