Regenxbio Announces 2 Pivotal Trials for RGX-314

Wet AMD filing with FDA planned for 2024.

■ Regenxbio has announced that ATMOSPHERE, the first of 2 planned pivotal trials to evaluate RGX-314 for wet AMD, is active and patient screening is ongoing. RGX-314 is a potential one-time gene-derived anti-VEGF therapy for retinal disease.

The company completed an end-of-phase-2 meeting with the FDA to discuss details of a pivotal program to support a Biologics License Application (BLA). The company plans to conduct 2 randomized, well-controlled clinical trials to evaluate the efficacy and safety of RGX-314 in patients with wet AMD, enrolling approximately 700 patients total. In addition, Regenxbio and the FDA aligned on a clear path to support manufacturing plans in the pivotal program. The company expects to submit a BLA based on these trials in 2024.

“We have already begun site activation and patient screening for our first planned pivotal trial,” said Steve Pakola, MD, chief medical officer. “We have strengthened the key design elements for the planned trial based on the long-term data from our dose-escalation phase 1/2a trial of RGX-314 and believe that we are well positioned to execute on this pivotal program.”

The second pivotal trial is expected to be similar in design to ATMOSPHERE. The company plans to initiate the trial in the second half of 2021. In addition, Regenxbio said the first patient has been dosed in ALTITUDE, a phase 2 trial to evaluate the suprachoroidal delivery of RGX-314 using the SCS Microinjector for the treatment of diabetic retinopathy (DR).

“This is our second phase 2 trial using the in-office suprachoroidal delivery approach, which may allow physicians to treat patients with diseases like DR earlier in the disease course,” said Dr. Pakola. “We believe that one-time treatment with anti-VEGF gene therapy can have a meaningful impact for patients with DR, and we look forward to providing additional updates from this trial next year.”

“The SCS Microinjector is designed to provide targeted delivery of the gene therapy to the suprachoroidal space, with broad distribution to the back of the eye and into the retina through a one-time, in-office procedure, which could be an important alternative to current standard of care,” said Charles Wykoff, MD, PhD, trial investigator, retina specialist and director of research with Retina Consultants of Houston.

Faricimab Bispecific Durable in DME and Wet AMD

16-week dosing in phase 3 was effective in some patients.

■ Genentech announced positive top-line results from 2 identically designed large-scale global phase 3 studies in DME, YOSEMITE and RHINE, evaluating its investigational bispecific antibody faricimab. In addition, in the TENAYA and LUCERNE phase 3 trials for wet AMD, faricimab met the primary endpoint measuring the average change in BCVA score from baseline at 1 year compared to aflibercept (Regeneron).

Results in all studies showed that people receiving faricimab injections at intervals up to 16 weeks achieved noninferior visual acuity outcomes to that of aflibercept injections given every 8 weeks. Nearly half (45%) of people in TENAYA and LUCERNE and more than half in YOSEMITE and RHINE were treated with faricimab every 16 weeks during the first year. This is the first time this level of durability has been achieved in phase 3 studies of an injectable eye medicine for DME and wet AMD.

In all studies, faricimab was generally well-tolerated, with no new or unexpected safety signals identified. Both YOSEMITE and RHINE also met their primary endpoint and showed that faricimab given every 8 weeks and at personalized dosing intervals of up to 16 weeks demonstrated noninferior visual acuity gains compared to aflibercept given every 8 weeks.

Faricimab is the first investigational bispecific antibody designed for the eye. It targets 2 distinct pathways — angiopoietin-2 and VEGF-A — that drive a number of retinal conditions. YOSEMITE and RHINE are evaluating 1,891 people with DME (940 in YOSEMITE and 951 in RHINE).

Study Begins for Home-based OCT in Wet AMD

Patients will be trained in self-imaging.

■ Notal Vision has initiated the first US-based study using its investigational home-based OCT platform. The study will evaluate the ability of subjects with wet AMD to perform sequential daily self-imaging of their eyes with the user-friendly, self-operated Notal Home OCT device in their homes. The Home OCT pipeline technology is designed to provide patient-initiated retinal OCT scans to support the management of patients with wet AMD, complementing existing standard-of-care treatments as well as emerging longer-acting drugs and drug-delivery systems.

“Remote OCT monitoring of wet AMD patients has the potential to personalize anti-VEGF treatment and improve outcomes while minimizing treatment burden by reducing the number of office visits,” said Jeffrey S. Heier, MD, one of the study’s principal investigators and co-president and medical director of Ophthalmic Consultants of Boston. “The importance and potential benefit of such an approach is even more important now in light of the COVID-19 pandemic.”

Led by Dr. Heier and Nancy Holekamp, MD, of the Pepose Vision Institute, the longitudinal study will remotely monitor 15 wet AMD patients receiving standard-of-care anti-VEGF therapy for 90 days to track the presence of retinal fluid, which may require a change in treatment regimen. Data from the Home OCT device will be automatically transmitted via a built-in cellular modem to the secure Notal Health Cloud, where the AI-based Notal OCT Analyzer will identify and quantify intraretinal and subretinal fluid from each daily OCT volume scan. Study investigators will have remote access to the Notal Home OCT images through a web viewer, an interactive interface that displays patient testing information. The Notal Vision Diagnostic Clinic, future provider of the Home OCT program, will monitor patient compliance with the self-imaging schedule and provide remote support as needed. The study is being partially funded by Genentech.

Medicated Drops Close Smaller Macular Holes

A nonsurgical approach shows promise.

■ A variety of medicated drops may help close small macular holes over a 2-week to 8-week period, allowing some patients to avoid surgery to fix the vision problem. This conclusion, based on a retrospective multicenter case series, was recently presented in Ophthalmology Retina.

“For certain patients, medicated drops may heal their macular hole by decreasing inflammation and increasing fluid absorption in the retina,” said ophthalmologist and retinal surgeon Dimitra Skondra, MD, PhD, senior author of the study. Skondra is an associate professor of ophthalmology and visual science and director of the J. Terry Ernest Ocular Imaging Center at the University of Chicago Medicine.

Between 4% and 11.5% of macular holes end up closing on their own, but for those that do not, the traditional treatment is a vitrectomy. Even then, a small percentage of holes do not close; others may reopen later or the patient may develop complications, such as a cataract, retinal detachment, scar tissue or peripheral vision loss.

All 14 of the study’s patients had some swelling around the hole, which is common, and half had previously undergone retinal surgery. As an alternative to surgery, the researchers prescribed a daily 3-drug regimen — medications that are FDA-approved and routinely used for other eye conditions — consisting of prednisolone or difluprenate, ketorolac, or bromfenac and brinzolamide or dorzolamide. The goal was to dehydrate patients’ retinas, decrease the swelling, and allow the edges of the macular holes to creep back together.

Using this topical medicated treatment, 12 of the 14 patients had holes that closed within 2 weeks to 8 weeks, which was 2 to 4 times faster than spontaneous closure rates of macular holes. The 2 patients that did not have closure within this time period had multiple missed follow-up appointments. The treatment was most effective for patients whose macular holes were less than 200 micrometers in diameter. The length of time the drops were administered then tapered off, ranged from 3.5 to 20 months.

“Adding a nonsurgical approach to even a small subset of patients is refreshing not only to retina surgeons, but especially for patients with small macular holes,” said Ronald Gentile, MD, a professor of ophthalmology at the Icahn School of Medicine at Mount Sinai in New York and contributing author of the study.

Gyroscope and University of Pennsylvania to Collaborate on Gene Therapies

Gyroscope Therapeutics Limited, a clinical-stage gene therapy company focused on diseases of the eye, announced that the company has entered a sponsored research agreement with the University of Pennsylvania and the Penn Center for Advanced Retinal and Ocular Therapeutics (CAROT) to develop gene therapies for serious eye diseases that can lead to permanent vision loss. Gyroscope has an exclusive option to the intellectual property associated with, and arising from, the research conducted under the agreement.

A team of researchers from CAROT and Gyroscope will work together to explore specific gene therapy targets for glaucoma, optic neuritis, and retinitis pigmentosa. The CAROT team is led by Jean Bennett, MD, PhD, the F.M. Kirby Professor of Ophthalmology, along with Ken Shindler, MD, PhD, an associate professor of ophthalmology, and Ahmara Ross, MD, PhD, an assistant professor of ophthalmology, of the Perelman School of Medicine.

Clearside Begins Enrollment in Wet AMD Trial

Clearside Biomedical said the first patients have been enrolled in its phase 1/2a clinical trial of CLS-AX (axitinib injectable suspension) in patients with wet AMD. Clinical sites, all based in the United States, are activated and currently screening wet AMD patients for this 15-patient trial, known as OASIS, involving a proprietary suspension of axitinib for suprachoroidal injection.

“The enrollment of the first patients for our OASIS trial is a key milestone for Clearside as we execute our strategy to expand our ophthalmology pipeline with innovative and relevant opportunities targeting critical medical needs through the suprachoroidal space,” said George Lasezkay, PharmD, president and CEO of Clearside. “We believe that axitinib, a small-molecule tyrosine kinase inhibitor (TKI), could provide safety and efficacy comparable to, or better than, current standard of care. And by delivering axitinib as a suspension into the suprachoroidal space using our in-office, nonsurgical SCS Microinjector, we may potentially extend the duration of therapeutic action and reduce or relieve the profound treatment burden for wet AMD patients. We expect data from our first cohort of patients in mid 2021.”

Optos Unveils Ultrawidefield Imaging Advances

Optos plc, part of Nikon Corporation, has introduced several advancements to its ultrawidefield (UWF) imaging devices. The Optos platform includes Daytona, California, Monaco, and Silverstone. Daytona, the most widely used true UWF device, will now offer improved optics for visualization across the entire optomap image and automatic laterality detection to improve image capture time. The new version also features an updated design and user interface, making the experience of using the device as fast and easy as possible for both the operator and the patient.

Silverstone, the only UWF retinal imaging device with optomap-guided swept-source OCT, now offers new functionality. The latest version includes a Repeat Scan tool, useful for precise monitoring of change over time. The new “explorer mode” displays OCT scan type and location on the optomap image, improving access to, and assessment of, OCT scans. Finally, auto contrast is now available for angiography capture.

In addition to the device-specific updates, the company has also applied optomap image enhancements across the entire Optos UWF platform. New processing technology yields clarity and detail across the entire 200° image, enabling eye care providers to detect pathology more efficiently centrally and in the periphery, where studies have linked the presence of pathology to a greater risk of disease progression.

Correlation Between BCVA and CST Changes After Anti-VEGF

In a large-scale post-hoc analysis of the VISTA and VIVID trials presented at the recent Macula Society meeting, researchers led by Susan Bressler, MD, of the Wilmer Eye Institute, assessed the correlation between change in BCVA and change in central subfield thickness (CST) for DME patients receiving fixed-dosing intravitreal aflibercept (Regeneron) injection over 100 weeks.

Post-hoc analysis of VISTA and VIVID were eyes randomized to 2 mg q4 weeks (2q4) or 2 mg q8 weeks after 5 initial monthly doses (2q8) with relationship between BCVA and anatomical CST outcomes at early (week 12) and later (week 52 and 100) visits determined using Pearson correlation.

Linear regression analysis, adjusted for relevant factors, showed CST changes accounted for 17% of variance in BCVA changes; with every 100 μm decrease in CST associated with a 1.2 letter increase in BCVA. Correlations between change in CST and change in BCVA were modest in this study. For any given change in CST from baseline, there was a broad range of change in BCVA from baseline at follow-up. These findings are consistent with a PRN regimen in the DRCR Retina Network, suggesting change in CST may be important in determining the need to withhold, continue, or resume anti-VEGF therapy, but is a poor surrogate for predicting visual acuity outcome, even with fixed-dosing treatment regimens.

HIV Drugs May Prevent Dry AMD

Inflammasome Therapeutics said data analyses published in the Proceedings of the National Academy of Sciences confirm that the company’s proprietary compounds hold promise in the prevention and treatment of dry AMD. The paper, authored by Jayakrishna Ambati, MD, at the University of Virginia School of Medicine, along with Salk Institute for Biological Studies’ Fred H. Gage, PhD, and collaborators from around the world, reveals that patients taking certain drugs to prevent HIV infection have a 40% lower risk of developing dry AMD compared to matched controls.

The drugs, nucleoside reverse transcriptase inhibitors (NRTIs), have been used for decades to fight HIV. In a 2014 publication in Science, Dr. Ambati found that NRTIs not only inhibit HIV replication but also inhibit part of the immune system — inflammasome activation — and that inflammasome inhibition by NRTIs prevented dry AMD in animal models. Nucleoside reverse transcriptase inhibitors have systemic toxicity that would limit their use in AMD, but Dr. Ambati also found that low toxicity derivatives of NRTIs (Kamuvudines) also block inflammasome activation and are at least as effective as NRTIs in dry AMD.

Oculogenex Takes “Winning Pitch” Competition With Gene Therapy for GA and Dry AMD

This year’s “Winning Pitch in Retina” challenge featured 3 final entrants with highly ambitious, possibly even transformative, presentations, 2 of which have preclinical initiatives already well under way and ready to take on major competitors with highly detailed plans for every aspect of the drug development process for retinal disease. The third finalist, Aditya Sudhalkar, MD, put forward a humanitarian effort to provide a very low-cost formulation of the steroid triamcinolone for diabetic eye disease in an easy-to-administer, sustained-release format to be targeted at India and other developing countries as an alternative to Ozurdex (Allergan).

The Winning Pitch competition helps accelerate the pace of innovation in ophthalmology by providing ophthalmologists with the tools and assistance they need to transform their novel ideas for improvements in patient care into functioning prototypes ready for early-stage studies.

In a close competition in which all 4 judges praised the finalists for their well-organized presentations and their passion, an Oculogenex gene therapy initiative targeting unmet needs in geographic atrophy and dry AMD with a one-time intravitreal injection was declared the winner of the $25,000 first prize. Oculogenex CEO Hema Ramkumar, MD, said extensive preclinical work on its regenerative ocular gene demonstrated potential efficacy to combat inflammation, prevent cell death, and repair and rejuvenate injured retinal cells. She also outlined a detailed plan for beginning dose-ranging clinical trials to establish safety and efficacy. She noted that the processes to deliver gene therapy for retinal diseases have already been proven and added that “We are not reinventing the wheel.”

A tie for second place was given to both Dr. Sudhalkar’s humanitarian effort as well as a presentation by Alan Franklin, MD, PhD, CEO and founder of ForwardVue Pharma, on a long-acting, patent-protected ORAI-1 inhibitor targeting neovascular retinal disease, with each receiving a $10,000 award. Dr. Franklin noted that the company’s small, synthetic molecule had already been proven safe with 900 cancer patients. The company says 1 or 2 injections per year would be sufficient to provide a durable response.

Regeneron is the primary sponsor of the competition. The event was moderated by John Pollack, MD, and David Williams, MD, MBA. Judges were Matt Chapin of Ora, Paul Hallen of Alcon, Angela Macfarlane of ForSight Labs, and Jim Mazzo, adviser to Carl Zeiss Meditec.

AGTC Reports Promising Data in Achromatopsia

Applied Genetic Technologies Corporation reported encouraging interim 6-month data from the dose-escalation cohorts of its ongoing phase 1/2 clinical programs in patients with achromatopsia due to mutation in the ACHM CNGB3 or ACHM CNGA3 genes. The interim results from both studies demonstrate encouraging signs of biologic activity and a favorable safety profile. The company plans to report data from additional dose groups, age groups, and time-points in the second half of 2020.

“We are pleased that both of our achromatopsia clinical candidates are demonstrating preliminary signs of biologic activity for patients who have no current treatment options for a disease that significantly compromises their vision and quality of life. We are further encouraged by many patients’ real-world positive anecdotes. We are continuing dose escalation in order to determine the highest safe dose with the potential to provide maximal benefit,” said Sue Washer, president and CEO of AGTC.

The data reported are from 22 patients who have been dosed in the initial groups of the trials, comprising 13 patients in the ACHM CNGB3 trial and 9 patients in the ACHM CNGA3 trial.

The company is currently dosing 2 higher-dose groups in adults and 3 groups of pediatric patients at the 3 highest-dose groups in both trials. The company will use the additional data, which is expected to be available in the second half of 2020, to inform decision-making regarding readiness to move the product candidates to pivotal trials.

In another achromatopsia initiative, MeiraGTx Holdings Plc announced that the FDA has granted Fast Track designation to its AAV-CNGA3 gene therapy product candidate for the treatment of achromatopsia caused by mutations in the CNGA3 gene. MeiraGTx and Janssen are jointly developing AAV-CNGA3 as part of a broader collaboration to develop and commercialize gene therapies for the treatment of inherited retinal diseases.

CE Mark for Norlase LION Green Laser System

INTERNATIONAL NEWS — Norlase said it has been granted the European CE Mark for the LION green laser system. LION combines the Keeler Vantage Plus diagnostic indirect with Norlase’s advanced compact laser technology into one device. With LION’s untethered and portable design, physicians can move freely between treatment rooms, treating patients anywhere, anytime.

“We are excited to greet 2021 with this important milestone,” said Oliver Hvidt, Norlase president and CEO. “With CE Mark approval for LION, following the recent establishment of our strategic distribution partnerships, we have expanded our reach and will arm even more ophthalmologists with innovative laser solutions to optimize practice efficiency and workflow.”

Clearside Demonstrates Benefits of Suprachoroidal Drug Delivery

At the recent Macula Society meeting, Clearside Biomedical offered multiple data presentations supporting the benefits of its proprietary suprachoroidal drug delivery as a safer, more targeted and compartmentalized method of administration, with applicability across a range of retinal disorders.

“With well over 1,000 injections performed to date, the mounting evidence points to the potential reliability and consistency of our suprachoroidal injection delivery approach,” said Thomas A. Ciulla, MD, MBA, chief medical officer and chief development officer. “Our SCS Microinjector has now been used to deliver small molecules, gene therapy, and viral nanoparticle conjugates in eye diseases, including macular edema associated with uveitis, wet AMD, diabetic retinopathy, and choroidal melanoma. With its broad applicability and in-office delivery method, our suprachoroidal injection platform could facilitate novel targeted treatment options for patients suffering from retinal diseases.”

In a safety study presented at the Macula Society meeting, data from the day of the procedure were compiled from 8 clinical trials where suprachoroidal injections were performed across 3 disease states, including noninfectious uveitis, DME, and RVO.

Analysis included a total of 621 patients who received 1 or more suprachoroidal injections. Rare but serious adverse events (SAEs) that are known to occur with intraocular injection were assessed, and there were no SAEs involving lens injury, suprachoroidal hemorrhage, or endophthalmitis in any patient receiving one or more suprachoroidal injections. In these 8 clinical trials, the safety profile of suprachoroidal injections was comparable to intravitreal injections alone for events occurring during or on the same day as the injection procedure. The results from the retrospective analysis demonstrated the robustness of the suprachoroidal injection regardless of indication.