8-mg Aflibercept May Be Superior in Reducing Fluid
Phase 2 study called “encouraging.”
■ Regeneron announced that an ongoing phase 2 proof-of-concept trial evaluating an investigational 8-mg dose of aflibercept (Eylea) met its primary safety endpoint, with no new safety signals observed compared to the currently approved 2-mg dose of aflibercept injection in patients with wet AMD. In this small trial involving 106 patients, a higher proportion of patients in the aflibercept 8 mg group had no retinal fluid (43.4%, n=23/53) compared to patients treated with Eylea 2 mg (26.4%, n=14/53) at week 16, the primary efficacy endpoint. At this time point, patients had received 3 initial doses (administered at weeks 0, 4, and 8), after which dosing was extended. No comparisons for changes in BCVA were announced.
Aflibercept 8 mg is currently being evaluated in 2 large phase 3 trials in wet AMD and DME, which are expected to report results in the second half of 2022. The trials will assess the safety and efficacy of aflibercept 8 mg for up to 2 years, with visual acuity as the primary efficacy endpoint at 48 weeks, measured by the Early Treatment Diabetic Retinopathy Study BCVA. Both trials will assess aflibercept 8 mg compared to 2 mg, testing dosing intervals of every 12 weeks and every 16 weeks.
“We are cautiously optimistic that these early data suggest that a higher dose of aflibercept may potentially benefit patients with wet AMD, and we look forward to phase 3 data next year, which will be crucial to understand its overall efficacy and safety,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer of Regeneron. “Having worked for nearly 2 decades in retinal disease, we know that large, robust data sets are required to fully understand whether a medicine can achieve three critical things: improved visual and anatomic outcomes, convenient dosing, and a safety profile that is consistent with Eylea.”
During the initial 16 weeks of the phase 2 trial, adverse events (AEs) in the study eye occurred in 17.0% (9 of 53) of patients receiving aflibercept 8 mg and 22.6% (12 of 53) of patients receiving Eylea 2 mg. Serious ocular AEs occurred in 2 patients overall, 1 in the aflibercept 8 mg group (retinal tear), and 1 in the Eylea 2 mg group (visual acuity reduced).
Novartis Seeks FDA Approval for Beovu in DME
Durability is a key advantage.
■ Based on positive data from 2 pivotal phase 3 clinical trials (KITE and KINGFISHER), Novartis is seeking US Food and Drug Administration (FDA) approval for its anti-VEGF brolucizumab (Beovu) for the treatment of DME. A majority of patients who successfully completed an initial 12-week cycle following the loading phase in the 360-patient KITE trial were maintained on a 12-week or 16-week dosing interval through year 2. Both trials demonstrated an overall well-tolerated safety profile. Supported by previous findings from the KESTREL and KITE trials, Novartis has submitted its application for Beovu in DME to the FDA.
The KITE trial met its primary and key secondary endpoints, demonstrating noninferiority of brolucizumab 6 mg vs aflibercept 2 mg (Eylea; Regeneron) in mean change in BCVA. Brolucizumab also demonstrated superiority in improvement vs aflibercept in reduction of central subfield thickness. All aflibercept patients were on a 2-month dosing interval after the loading phase.
In addition, Novartis reported that the rate of intraocular infection (IOI) in KITE was 2.2% for Beovu vs 1.7% for aflibercept, and that there was no retinal vasculitis reported in either arm; also there were equivalent rates of retinal vascular occlusion for both treatments (0.6%).
KINGFISHER, a 1-year phase 3 study, demonstrated that Beovu was noninferior to aflibercept in mean change from baseline BCVA when dosed every 4 weeks. In KINGFISHER, the most common (≥5%) overall adverse events were COVID-19 and hypertension. Rates of IOI were 4.0% for Beovu (including 0.9% retinal vasculitis) and 2.9% for aflibercept (including 0.6% RV). The majority of IOI events were manageable and resolved without any clinical complications.
IN BRIEF
Research and industry news in retina.
BY JERRY HELZNER, CONTRIBUTING EDITOR
Abbvie and Regenxbio Announce Partnership for Gene Therapy
■ Abbvie and Regenxbio Inc. announced a partnership to develop and commercialize RGX-314, a potential one-time gene therapy for the treatment of wet age-related macular degeneration (wet AMD), diabetic retinopathy (DR), and other chronic retinal diseases. Under the collaboration, Regenxbio will be responsible for completion of the ongoing trials of RGX-314. Abbvie and Regenxbio will collaborate and share costs on additional trials of RGX-314, including the planned second pivotal trial evaluating subretinal delivery for the treatment of wet AMD and future trials.
Under the terms of the agreement, Abbvie will lead clinical development and commercialization of RGX-314 globally, and Regenxbio will participate in US commercialization efforts. Abbvie will pay Regenxbio a $370 million upfront payment with the potential for Regenxbio to receive up to $1.38 billion in additional development, regulatory, and commercial milestones. Regenxbio and Abbvie will share equally in profits from net sales of RGX-314 in the United States. Abbvie will pay Regenxbio tiered royalties on net sales of RGX-314 outside the United States. In addition, Regenxbio will lead the manufacturing of RGX-314 for clinical development and US commercial supply, and Abbvie will lead manufacturing of RGX-314 for commercial supply outside the United States.
RGX-314 consists of the NAV AAV8 vector, which encodes an antibody fragment designed to inhibit vascular endothelial growth factor (VEGF). RGX-314 is believed to inhibit the VEGF pathway by which new, leaky blood vessels grow and contribute to the accumulation of fluid in the retina. RGX-314 is currently being evaluated in patients with wet AMD in a pivotal trial with subretinal delivery and in patients with wet AMD and DR in 2 separate phase 2 clinical trials with in-office suprachoroidal delivery. Regenxbio has licensed certain exclusive rights to the SCS Microinjector from Clearside Biomedical, Inc. to deliver gene therapy treatments to the suprachoroidal space.
“We are committed to finding solutions for patients living with difficult-to-treat retinal diseases and to helping preserve and protect our patients from visual impairment and devastating vision loss,” said Tom Hudson, MD, senior vice president of research and development and chief scientific officer of Abbvie, in a news release. “In collaboration with Regenxbio, we aim to make a remarkable impact for the millions of patients suffering from vision loss associated with retinal diseases.”
“Abbvie is a strong, complementary partner for Regenxbio,” said Kenneth T. Mills, president and chief executive officer of Regenxbio, in a news release. “We expect to leverage Abbvie’s global developmental and commercial infrastructure within eye care with our expertise in AAV gene therapy clinical development and deep in-house knowledge of manufacturing and production to continue the development of RGX-314.”
Cell Implant for GA Shows Promise in Early Trial
■ Jane Lebkowski, PhD, president of Regenerative Patch Technologies, recently reported positive results from the company’s phase 1/2a clinical trial in geographic atrophy (GA). The CPCB-RPE1 implant, a bioengineered scaffold supporting a layer of stem cell-derived, retinal pigmented epithelial (RPE) cells, was delivered to the worst eye of 15 subjects with GA. All treated eyes were legally blind, having BCVA of 20/200 or worse. The implant was delivered safely to the area of GA in the outpatient setting and remained stable and in place throughout the trial. Refinements to the implantation procedure during the trial further improved its efficiency and safety profile.
Subjects in the trial were also assessed for visual function. At an average of 34 months after implantation (range 12-48 months), 27% (4/15) showed a greater than 5-letter improvement in BCVA and 33% (5/15) remained stable with a BCVA within 5 letters of baseline value. The improvements ranged from 7 letters to 15 letters or 1 to 3 lines on an eye chart. In contrast, BCVA in the fellow, untreated eye declined by more than 5 letters (range 8-21 letters or 1-4 lines on an eye chart) in 80% (12/15) of subjects. There was no improvement in BCVA in the untreated eye of any subject.
“The improvements in best corrected visual acuity observed in some eyes receiving the implant are very promising, especially considering the very late stage of their disease,” said Mark Humayun, MD, PhD, founder and co-owner of Regenerative Patch Technologies, director of the University of Southern California (USC) Ginsburg Institute for Biomedical Therapeutics, and co-director of the USC Roski Eye Institute, Keck Medicine of USC, in a news release. “Improvements in visual acuity are exceedingly rare in geographic atrophy as demonstrated by the large decline in vision in many of the untreated eyes which also had disease. There are currently no approved therapies for this level of advanced dry age-related macular degeneration.”
Dr. Lebkowski added that the data position Regenerative Patch Technologies to proceed to a phase 2b clinical trial to advance development of the product. The CPCB-RPE1 implant uses unmatched, “allogeneic” RPE cells as one of its 2 main components. Subjects in the trial received a short course of immunosuppression shortly before and immediately after implantation. There were no clinical signs of rejection of the implant and subjects did not mount an antibody response to the implanted cells.
Avastin Biosimilars Not Suitable for Ophthalmic Use
■ The American Academy of Ophthalmology is warning ophthalmologists and insurance companies that 2 Avastin biosimilars, Mvasi (Pfizer) and Zirabev (Amgen), should not be used as anti-VEGF alternatives when Avastin is in short supply. These drugs have never been tested in the eye.
“Pfizer and Amgen have not recommended the use of their biosimilars in the eye,” said the Academy in a statement on its site. “The Academy does not oppose the use of biosimilars or the use of drugs off-label in general. We are against the use of drugs in the eye that have never been tested for ophthalmic diseases.”
The Academy has also advised the US Department of Health and Human Services HHS and Centers for Medicare and Medicaid Services that it is not appropriate to recommend or mandate use of these biosimilars for intravitreal injection without evidence from a clinical trial in eye disease as well as testing for retinal toxicity.
Alkeus Gets Breakthrough Status for Oral Stargardt Drug
■ Alkeus Pharmaceuticals said the FDA has granted Breakthrough Therapy Designation to ALK-001 for the treatment of Stargardt disease. ALK-001 (C20-D3-vitamin A) is a chemically modified form of vitamin A developed to treat multiple retinal degenerative diseases.
The investigational treatment is an oral drug taken once daily. Clinical data indicate that ALK-001 safely slows the progression of Stargardt while preserving the normal visual cycle. ALK-001 is the only drug to receive Breakthrough Therapy Designation for Stargardt disease. The company is also testing ALK-001 in a clinical trial for patients with dry AMD.
HtrA1 Augmentation May Ward Off AMD
■ Research conducted at the Sharon Eccles Steele Center for Translational Medicine (SCTM) at the University of Utah’s John A. Moran Eye Center explains why people with genetic variants strongly associated with the development of AMD may develop the disease, and identifies a potential therapeutic pathway for slowing or even reversing disease progression. Following more than 15 years of research that has employed an extensive repository of donated human ocular tissues, scientists found that HtrA1 protein normally increases with age in the eye at the retinal pigmented epithelium (RPE)–Bruch’s membrane interface, helping to maintain the normal function of this region.
These new data show this is not the case in individuals with AMD-associated risk variants located on chromosome 10. These variants were found to impair expression of the HTRA1 gene by the RPE, resulting in an approximately 50% reduction of HtrA1 protein levels at the RPE–Bruch’s membrane interface during aging. The failure to produce adequate levels of HtrA1 protein disrupts this key region of the eye and is associated with AMD-associated pathologies, including the deposition of abnormal deposits and the development of abnormal blood vessels.
These findings, coming from the laboratory of SCTM Executive Director Gregory S. Hageman, PhD, and reported in PNAS, represent the first explanation of the essential role of HtrA1 in maintaining ocular health and contradict literature previously published by others. They are anticipated to inform the development of novel therapies for chromosome 10-directed AMD.
BVI and Beyeonics Vision Team Up on Visualization System
■ BVI and Beyeonics Vision are have entered into a collaboration to streamline the US commercialization of Beyeonics-1, the first and only upgradable digital visualization system that replaces traditional microscopes. Beyeonics-1 is an open and upgradable digital visualization system, equipped with an ultra-high-resolution camera; processed and digitally enhanced images are transferred to high-resolution head-wearable displays, for an immersive and natural stereoscopic 3D viewing. Beyeonics-1 offers enhanced automation, programming autonomy, and more freedom for the surgeon to set up the operating room and adopt a more natural posture. The system supports a real-time decision-making process with customizable integration of accessible preoperative and intraoperative data and connectivity, as well as seamless integration with other devices.
Aldeyra Therapeutics Gets Orphan Status for RP Drug
■ Aldeyra Therapeutics said the FDA has granted orphan drug designation for ADX-2191 (methotrexate for intravitreal injection) for the treatment of retinitis pigmentosa. There are no approved drug treatments for patients with RP, a clinical group of rare genetic eye diseases characterized by retinal cell death and loss of vision.
Zimura Pivotal Trial for GA Fully Enrolled
■ Iveric Bio announced the early completion of enrollment of the 448-patient GATHER2 phase 3 clinical trial, the company’s second pivotal trial of Zimura (avacincaptad pegol), a complement C5 inhibitor for the treatment of geographic atrophy (GA) secondary to AMD.
The company expects topline GATHER2 data to be become available during the second half of 2022, approximately one year after the enrollment of the last patient, plus the time needed for database lock and analysis.
“The time to complete enrollment in the Zimura GATHER2 clinical trial was four months ahead of our original timeline. That we were able to accomplish this during the unprecedented challenges stemming from the global COVID-19 pandemic, we believe highlights the unmet need of patients and physicians for a treatment of GA secondary to AMD,” stated Glenn P. Sblendorio, CEO of Iveric Bio.
In GATHER2, 448 patients were randomized to receive either monthly administration of Zimura 2 mg or sham during the first 12 months of the trial, at which time the primary efficacy analysis of the mean rate of change of GA growth at 12 months will be performed. If the 12-month results are positive, the Company plans to file an application with the US Food and Drug Administration and the European Medicines Agency for marketing approval of Zimura for GA following receipt of that data. At month 12, the company plans to re-randomize patients in the Zimura 2 mg arm to receive either monthly or every other month administration of Zimura 2 mg. The final evaluation will take place at month 24.
Second Sight Gets Significant New Funding
■ Second Sight Medical, a leading developer of implantable visual prosthetics that are intended to create an artificial form of useful vision for blind individuals, has received almost $59 million in new funding, including an annual installment of a 5-year NIH grant and proceeds from a corporate stock offering.
The company said it has received notice from the National Institutes of Health (NIH) of the release of year three funding for its Early Feasibility Clinical Trial of a Visual Cortical Prosthesis (the Orion Trial), The NIH released $1.4 million of the $6.4 million planned 5-year grant. The company uses the funds primarily to pay UCLA and Baylor College of Medicine to conduct the Orion Trial. This NIH notice of grant award follows the reporting by the company of promising 2-year data from the Orion Trial,
In addition, the company reported gross proceeds from the stock offering, including the exercise of the over-allotment option, were $57,500,000, before deducting underwriting discounts, commissions and other offering expenses.
The company intends to use the net proceeds from the offering primarily for development of the Orion device and general corporate purposes.
Joint Venture Seeks Approval of Lucentis Biosimilar
■ Polpharma Biologics Group said its joint venture Bioeq has submitted a Biologics License Application (BLA) for a biosimilar ranibizumab (Lucentis; Genentech) to the FDA. The reference product is a monoclonal anti-angiogenic antibody fragment (Fab) used to treat various types of macular-degenerative diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, macular edemas, and myopic choroidal neovascularization.
“This announcement carries a tangible promise of treatment choice and improved access to those who suffer from debilitating vision loss, including age-related macular degeneration,” said Joerg Windisch, CEO of Polpharma Biologics Group, in a news release. If the BLA is approved, the product will be commercialized by Coherus Biosciences in the United States.
A Safer Method to Deliver Anti-VEGF Injections
■ Researchers at the University of British Columbia, reporting in the Canadian Journal of Ophthalmology, documented a safer way to deliver anti-VEGF injections that largely decreases the risk of ocular hypertension (OHT). A retrospective review of consecutive treatment-naive patients receiving intravitreal anti-VEGF injections in a group practice was performed. Data from the cohort receiving nonfiltered anti-VEGF in insulin syringes (IS group) was collected from June 2015. Data from the cohort receiving filtered anti-VEGF in silicone-free syringes (SFS group) was collected from June 2019. Follow up data were collected at 1 year.
In this study, the authors compared the incidence of ocular hypertension in 100 patients receiving nonfiltered anti-VEGF in insulin syringes with 100 patients receiving filtered anti-VEGF in silicone-free syringes. The latter group had less ocular hypertension and the need to treat it. Specifically, the incidence of IOP ≥21 mmHg was 34% in the IS group and 15% in the SFS group.
The researchers concluded that incidence of OHT and treatment with IOP-lowering therapy significantly decreased after the introduction of filtered anti-VEGF medication and silicone-free syringes. RP
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