IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Editas Advances Gene-editing Program in Eye Disease

■ A widely hailed breakthrough in CRISPR “cut-and-paste” gene editing technology achieved in June by Intellia Therapeutics and partner Regeneron in a nonophthalmic indication bodes well for the future use of CRISPR in inherited retinal disease. Currently, Editas is pursuing a CRISPR initiative that seeks to treat patients with LCA10, Usher Syndrome, and retinitis pigmentosa. The phase 1/2 BRILLIANCE trial in LCA10 is already under way, with both adult and pediatric cohorts being dosed.

The BRILLIANCE trial of CRISPR-based EDIT-101 for the treatment of LCA10 is designed to assess the safety, tolerability, and efficacy of EDIT-101 in up to 18 patients with this disorder. Clinical trial sites are enrolling up to 5 cohorts, testing up to 3 dose levels in this open-label, multicenter study. Both adult and pediatric patients (3 to 17 years old) with a range of baseline visual acuity assessments are eligible for enrollment. Patients receive a single administration of EDIT-101 via subretinal injection in 1 eye.

The Editas CRISPR initiative was initially a partnership with Allergan, but Allergan was acquired for $63 billion earlier this year by Abbvie, which opted out of the deal. Editas now has full rights to the drugs originally included under that 2017 collaboration.

“We are currently focused on advancing EDIT-101 with dosing resumed in the phase 1/2 BRILLIANCE clinical trial,” said Cynthia Collins, CEO of Editas, in a news release. “We remain on track to complete dosing of the adult low-dose cohort and to dose at least one patient of the adult mid-dose cohort by the end of this year. We look forward to sharing additional updates from BRILLIANCE clinical trial and other medicines in development in our ocular program later this year.”

Mark Pennesi, MD, PhD, associate professor of ophthalmology, Kenneth C. Swan Endowed Professor, Division Chief, Paul H. Casey Ophthalmic Genetics, Casey Eye Institute, Oregon Health & Science University, and a principal investigator for the BRILLIANCE trial, said he was gratified that children were included in the trial. “If the trial’s investigational treatment is found to be safe and effective, it could enable children born with mutations in the CEP290 gene an opportunity for a lifetime of sight,” he said.

Allegro Drug Shows BCVA Gain in Dry AMD

■ Allegro Ophthalmics announced that positive results of the company’s 45-patient US phase 2a risuteganib dry AMD study were published in Ophthalmic Surgery, Lasers, and Imaging (OSLI) Retina, which describes the treatment effect of risuteganib 1.0 mg in patients with intermediate dry AMD. The primary endpoint—the proportion of subjects with ≥8 letters ETDRS BCVA gain from baseline — was met by 48% of patients in the risuteganib group at week 28 and 7% of patients in the sham group at week 12. Risuteganib was found to be safe with no reported drug related serious adverse events.

Risuteganib is a small peptide oxidative stress stabilizer that has been shown to protect human RPE cells against oxidative stress-associated cellular dysfunction. These clinical data suggest that risuteganib can reverse vision loss and restore functional vision in patients with intermediate dry AMD with treatment at a 12-week interval.

Vicken Karageozian, MD, president and CEO of Allegro Ophthalmics, said, “To our knowledge, this is the first study to use a functional endpoint and demonstrate reversal of vision loss in a study population with intermediate dry AMD, a sight-threatening disease for which there is currently no available therapeutic treatment. These clinical findings in dry AMD complement our extensive preclinical findings and earlier clinical studies that suggested risuteganib could restore visual function.”

Nanoscope Optogenetics Therapy Restores Vision in RP

■ Nanoscope Technologies said vision improvements for all evaluated advanced retinitis pigmentosa (RP) patients continued through year 1 following a single intravitreal injection in a phase 1/2a clinical study with multicharacteristic opsins (MCO). “We expect to begin the first randomized, placebo-controlled, double-masked phase 2b multicenter optogenetic trial in the United States this summer to further validate our gene therapy’s ability to improve clinically meaningful vision in RP patients. If successful, it will be the first-ever restorative drug for millions of RP patients worldwide,” Nanoscope CEO Sulagna Bhattacharya said in a news release. Three patients received low dose (1.75x10¹¹ vg per eye) and 8 received a high dose of 3.5x10¹¹ vg per eye. Fluorescence imaging of the retina revealed successful gene transduction. At completion, 6 high-dose MCO-therapy subjects gained an average of 15 letters of vision.

AAO Adopts New Prior Authorization Recommendations

■ The Special Meeting of the AMA House of Delegates has adopted new policies specifically targeting peer-to-peer (P2P) review of prior authorization decisions and the particular burden of prior authorization during a public health emergency. Specifically, P2P conversations refer to discussions between a physician and an insurance company physician employee that frequently take place, depending on the health plan, either during the initial prior authorization process or after an initial prior authorization denial. These conversations typically involve questions of medical necessity or treatment requests.

The new policies adopted call for:

• P2P prior authorizations to be made actionable within 24 hours of the discussion;
• The reviewing P2P physician to have clinical expertise to treat the medical condition or disease under review and to have knowledge of the current, evidence-based clinical guidelines and novel treatments;
• P2P reviewers to follow evidence-based guidelines consistent with national medical society guidelines where available and applicable;
• Temporary suspension of all prior authorization requirements and the extension of existing approvals during a declared public health emergency;
• And health plans must not require prior authorization on any medically necessary surgical or other invasive procedure related or incidental to the original procedure if it is finished during the course of an operation or procedure that was already approved or didn’t require prior authorization.

“Delayed and disruptive treatment due to unnecessary and bureaucratic prior authorization requirements can have life-or-death consequences for patients — something we know from data and surveys of physicians,” said AMA President Susan R. Bailey, MD. “P2P reviews are another burdensome layer insurers are increasingly using without justification, and the peer reviewers are often unqualified to assess the need for services for a patient for whom they have minimal information and to whom they have never spoken or evaluated. Particularly during a public health emergency like COVID-19, unnecessary prior authorizations should not stand between a patient and care they need.”

Faricimab Shows Extended Durability in DME

■ In announcing new 1-year data for its YOSEMTE and RHINE phase 3 trials for its bispecific (anti-VEGF/ANG 2) faricimab in DME, Genentech reported that the majority of patients on personalized dosing schedules were able to go at least 16 weeks without the need for retreatment. This is the highest level of durability ever shown by an investigational drug for DMI in a phase 3 trial.

FDA Accepts BLA for Genentech’s PDS

■ The FDA has accepted Genentech’s Biologics License Application (BLA) for its Port Delivery System with ranibizumab (PDS) for the treatment of wet AMD. If approved, PDS would be a first-of-its-kind therapeutic approach, offering people living with wet AMD an alternative to frequent eye injections of anti- VEGF, the current standard of care. The FDA is expected to make a decision on approval by Oct. 23.

“If approved, PDS would transform wet AMD treatment by providing up to 6 months of uninterrupted therapy that could potentially improve vision outcomes compared to what is currently achieved in the clinic,” Levi Garraway, MD, PhD, chief medical officer and head of global product development, said in a company news release.

PDS is a permanent refillable eye implant, approximately the size of a grain of rice, designed to continuously deliver a customized formulation of ranibizumab over a period of months, potentially reducing the treatment burden associated with frequent eye injections. The BLA submission is based on positive results from the phase 3 Archway study primary analysis, which showed that of those wet AMD patients being treated with PDS, more than 98% were able to go 6 months without needing additional treatment prior to the refill exchange. In addition, these patients achieved vision outcomes equivalent to patients receiving monthly ranibizumab eye injections. In the study, PDS was generally well tolerated, with a favorable benefit–risk profile.

In related news, the FDA has also accepted Genentech’s BLA, under Priority Review, for the bispecific (anti-VEGF and Ang2) faricimab for the treatment of wet AMD and DME. The FDA has also accepted the company’s faricimab submission for diabetic retinopathy.

Biogen Gene Therapy for Choroideremia Fails in Phase 3

■ Top-line results from Biogen’s phase 3 STAR study of timrepigene emparvovec (BIIB111/AAV2-REP1), an investigational gene therapy for the potential treatment of choroideremia, proved disappointing. The STAR study did not meet its primary endpoint of proportion of participants with a ≥15 letter improvement from baseline in BCVA at month 12 in the interventional group in comparison to the noninterventional control group, as measured by the ETDRS chart. In addition, the study did not demonstrate efficacy on key secondary endpoints. Safety results from the STAR study were consistent with previous studies.

Wide Gender Pay Gap in Year 1 of Clinical Practice

■ A study led by Jing Sasha Jia, BA, of Temple University, recently published in the journal Ophthalmology, reported that female ophthalmologists earn significantly less than their male colleagues in the first year of clinical practice. Salary differences persist after controlling for demographic, educational, and practice type variables. These income differences may lead to a substantial loss of accumulated earnings over an individual’s career.

Of 684 respondents from 68 programs, 384 were female (56% female, 44% male). Female ophthalmologists received a mean initial salary with bonus that was more than $22,000 to more than $33,000 less than their male counterparts received, depending on the type of analysis used. Although an association between gender and the attempt to negotiate was not detected, a greater portion of men subjectively reported success in negotiation.

Opthea Gets Fast Track Status for AMD Combo

■ Opthea said the FDA has granted Fast Track designation for the company’s VEGF-C/-D “trap” inhibitor, OPT-302, in combination with anti-VEGF-A therapy for the treatment of patients with wet age AMD. Opthea is currently recruiting patients into 2 concurrent global, multicenter, randomized, double-masked, sham-controlled phase 3 trials known as ShORe and COAST. The clinical studies 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, the ShORe trial) or 2.0 mg aflibercept (Eylea; Regeneron, the COAST trial), compared to anti-VEGF-A monotherapy.

“The Fast Track designation from the FDA for OPT-302 recognizes both the limited treatment options available to patients with wet AMD and the strong potential for our therapy to address this serious unmet medical need,” Opthea CEO Megan Baldwin, PhD, told Retinal Physician.

“The Fast Track status was based on the favorable safety profile in phase 1 and phase 2 clinical trials, as well as superiority in vision outcomes with OPT-302 combination therapy compared to standard of care in a large randomized controlled phase 2b trial. We look forward to continuing to advance OPT-302 as a truly differentiated treatment option that, when used in combination, may potentially offer patients improved outcomes over standard of care anti-VEGF-A monotherapy.”

Drug–Device Combination Studied for Eye Cancer

■ Delcath Systems reported promising preliminary data for its phase 3 FOCUS trial in liver-dominant metastastic ocular melanoma using its Hepzato drug–device combination. The company reported encouraging results compared to “best alternative care” (BAC) in such key metrics as time to progression, lesion growth, and maintaining stable vision.

Hepzato is designed to administer high-dose chemotherapy to the liver while controlling systemic exposure and associated side effects. In Europe, the product is a standalone medical device and is approved for sale under the trade name Chemosat Hepatic Delivery System for Melphalan, or Chemosat, where it has been used at major medical centers to treat a wide range of cancers of the liver.

The FOCUS trial achieved median progression-free survival of 9.0 months compared to 3.1 months for the BAC arm. In addition, a disease-control rate of 70.9% was reported vs 37.9% for patients in the BAC arm.

In the Hepzato safety population of 94 patients, 38 patients (40.4%) experienced a treatment-emergent serious adverse event. The most commonly reported treatment-emergent serious adverse events were thrombocytopenia (14.9% of patients), neutropenia (10.6% of patients), and leukopenia (4.2% of patients), which were manageable. Five percent of patients experienced treatment-emergent serious cardiac adverse events. In all cases, the events resolved with no ongoing complications. There were no treatment-related deaths in the trial.

Ocular Therapeutix and Mosaic to Collaborate on Dry AMD

■ Ocular Therapeutix entered into a discovery collaboration with Mosaic Biosciences to identify new targets and therapeutic agents aimed at the treatment of dry AMD. Under terms of the agreement, the collaboration between Ocular Therapeutix and Mosaic focuses on the discovery and development of novel complement inhibitors with extended duration of activity. The complement pathway represents a key component of innate immunity and maintains immune homeostasis throughout the body, including ocular tissues. Within the retina, the complement pathway has been associated with the development of age-related macular degeneration. The goal of complement inhibition is to block the pathway that can initiate and drive these diseases. RP

LETTER TO THE EDITOR

I am writing in response to Dr. Peter Kaiser’s Upfront editorial: “The New Career Landscape of Retina” in the July/August 2021 issue. All of Dr Kaiser’s assertions are untrue with regard to our experience at Retina Consultants of America (RCA). Although I can refute them one by one, they are simply too large in number with too little space available in a letter to the editor.

Suffice it to say that our clinical and practice management autonomy are durably enshrined in our legal agreements with RCA. Our physicians’ professional lives and clinical practices are unchanged by our affiliation. Our nonpartner physicians are on track to become partners in our practice faster than preaffiliation and, when partners, they will have the same influence over our practice as all other partners. The quality of our practice, along with the scale, resources, and growth levers that we have at RCA will assure us a successful and prosperous future.

Young retina specialists have multiple practice options to choose from, including academic medicine, managed care organizations, private equity-backed entities such as RCA, private multispecialty ophthalmology practices, and private retina-only practices. Each of these options have pros and cons. Dr. Kaiser suggests that small retina practices may be the best option for young retina specialists today. However, the future of medicine in the United States is uncertain and there is increasing risk that major disruptive systemic changes may occur that will disproportionately impact small independent private practices that lack the scale and resources to adequately respond. On the other hand, as a part of a large retina-only organization, I have over 100 of my retinal specialist friends and colleagues at my side to help navigate through the uncertain future of medicine. I can’t think of a better place to be than amongst this large, well aligned, cohesive group of the smartest and most talented physicians. Young retina specialists should carefully consider these factors.

Sincerely, David F. Williams, MD, MBA, VitreoRetinal Surgery, PLLC, Minneapolis/St. Cloud, Minnesota