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SUBSPECIALTY NEWS: Results for combination therapy for DME, FDA asks for information on Xipere, Depo-Medrol retinal toxicity, and more.

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Oxurion Combo Has Mixed Results in DME

Anti-PIGF shows potential in 2 subsets.

■ Oxurion reported top-line data from a phase 2a study evaluating THR-317, a humanized antibody against placental growth factor (PlGF), in combination with ranibizumab for the treatment of diabetic macular edema (DME). The randomized, multicenter study evaluated the safety and efficacy of 3 monthly intravitreal injections of THR-317 and ranibizumab in subjects with center-involved DME. The combination of ranibizumab and sham was used as a control. Seventy patients were enrolled in the study.

At month 3, no improvement was observed in mean BCVA (the primary endpoint of the study) with the combination therapy when compared to ranibizumab monotherapy in the overall population. As measured by the Early Treatment of Diabetic Retinopathy Study standardized eye chart, the combination therapy achieved an increase of 8.71 letters vs an increase of 8.18 letters for the monotherapy arm.

The combination therapy did show a certain improvement at month 3 in mean BCVA in 2 prespecified patient subgroups. In patients with poor or no response to prior anti-VEGF, a mean increase of 8.08 letters was observed for the combination therapy vs 6.43 letters increase for ranibizumab monotherapy. In patients with baseline BCVA ≤65 letters, a mean increase of 11.14 letters was observed for the combination therapy vs 8.88 letters for ranibizumab monotherapy.

FDA Wants More Information on Clearside’s Xipere

Setback vacates possible October approval.

■ Clearside Biomedical experienced a setback on August 22 when the US Food and Drug Administration (FDA) requested information aimed at validating the enhanced manufacturing process for Xipere, the company’s corticosteroid therapy for macular edema associated with uveitis. The request will cause a delay to its original Prescription Drug User Fee Act (PDUFA) date of October 19 and may affect the company’s planned efforts to attract a partner for the drug.

The FDA’s Office of Pharmaceutical Quality (OPQ) requested that Clearside provide stability data for the triamcinolone acetonide (TA) suspension produced using an enhanced manufacturing process implemented by the company. The formulation of the TA suspension has not changed; however, OPQ requested the data to verify the comparability of the stability profiles of the batches made with the enhanced manufacturing process with that of the batches originally submitted as part of the NDA. The requested data do not relate to or affect the company’s suprachoroidal microinjector platform.

As a result of the request, Clearside expects to receive a Complete Response Letter from the FDA that vacates the original PDUFA date. The company plans to resubmit the NDA in the first quarter of 2020 with the requested stability data.

“After a productive meeting with the FDA, the agency has provided clear guidance on the Chemistry, Manufacturing, and Controls (CMC) data to be included in the NDA resubmission,” stated George Lasezkay, PharmD, JD, Clearside CEO. “We believe this is primarily a timing issue since our stability data from previously manufactured batches have been consistent and predictable, and we have every reason to believe this will continue to be the case. We will complete these efforts as quickly as possible as we work towards approval of Xipere as a potential treatment option for patients suffering from uveitic macular edema. Discussions with potential Xipere outlicensing partners remain ongoing. We continue to expect that we will have sufficient resources to fund operations into the third quarter of 2020, without relying on any partnership-related payments that we might gain through Xipere partnering or R&D collaboration agreements.”

Depo-Medrol Causes Toxicity to the Retina

Do not mistake it for another product.

■ Depo-Medrol (Pfizer) is a formulation of methylprednisolone acetate approved by the FDA for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions unresponsive to topical corticosteroids. However, it has been proven extremely toxic to the retina if injected into the vitreous.

Unfortunately, Depo-Medrol packaging and appearance is similar to Kenalog (Bristol-Myers Squibb) and Triesence (Alcon), which are commonly used for the treatment of inflammatory disorders, for macular edema, and to improve visualization during vitreoretinal surgery. These similarities can lead to Depo-Medrol being mistakenly or incidentally used with the potential for great harm.

An article available with open access full text in the journal Ophthalmology by Michael D. Ober, MD, and colleagues from the ophthalmology department at Henry Ford Hospital in Detroit, Michigan, cites 15 published case reports documenting accidental injection of Depo-Medrol into the vitreous, causing retinal damage. The authors also describe a case in which an ophthalmologist used Depo-Medrol during complicated cataract surgery to stain for vitreous in the anterior chamber following a torn posterior capsule. A retinal consultation 2 months after surgery confirmed a whitened atrophic macula. Spectral-domain OCT found central macular thinning with loss of all retinal layers in the central macula while fluorescein angiography confirmed infarction of the macula.

The toxicity is caused by the preservative myristyl-γ-picolinium chloride in Depo-Medrol. The authors advise that if Depo-Medrol is injected accidentally, prone positioning of the patient should be initiated immediately to limit contact of myristyl-γ-picolinium with the retina. Emergent pars plana vitrectomy has been advocated to remove Depo-Medrol after accidental injection to avoid retinal necrosis, but poor visual outcomes may still result. The authors believe that, at minimum, Depo-Medrol should carry a warning against intraocular use and different packaging to distinguish it from triamcinolone.

Retina Specialists Positively Impact AMD Patients

They score high on disease management.

■ A new survey from Health Union finds that people with macular degeneration who regularly see a retina or macular degeneration specialist for care have more satisfaction with their health care professional relationships, and treatment plan, and they have a better grasp of their condition than those who regularly see other health care providers. The survey, titled Macular Degeneration In America 2019, illuminates the perspectives and experiences of people living with macular degeneration.

Of the survey’s 461 respondents, 51% said they see a retina specialist or macular degeneration specialist most often for their condition. Three in 10 respondents said they typically see an ophthalmologist, 11% see an optometrist, and 6% don’t regularly see any health care provider for their macular degeneration.

Survey respondents who regularly see a retina or macular degeneration specialist were more likely than those who don’t to be diagnosed with wet AMD. Conversely, those who don’t see a specialist are more likely not to know what type of macular degeneration they have.

However, access to retina specialists — compared to nonspecialist ophthalmologists — can be difficult for some patients. Of survey respondents who regularly see a retina or macular degeneration specialist, 36% have traveled at least 30 miles, with 5% traveling more than 100 miles for an appointment. Unsurprisingly, respondents who regularly see a specialist were more likely to receive help with transportation to and from appointments.

Survey findings suggest that seeing a retina or macular degeneration specialist can also impact treatment. About 4 in 10 of all respondents said they feel their macular degeneration is well managed with their current treatment plan; those who regularly see a specialist were more likely than those who don’t to agree with this statement.

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Multifaceted Effort Needed to Beat Dry AMD

■ A blue-ribbon panel of the National Advisory Eye Council (NAEC) has recommended a large-scale, collective, multidisciplinary research effort to take on dry macular degeneration. The NAEC, a 12-member panel that helps guide the National Eye Institute, investigated the current state of research on this disease to guide the direction for future research. The article was published in the journal Nature Communications.

“There are a plethora of genetic and environmental factors interweaving and contributing to this disease in ways known and unknown,” explained co-corresponding author Lindsay Farrer, PhD, chief of the biomedical genetics division at Boston University School of Medicine. “Our article reflects on what we know thus far and calls for interdisciplinary research, with ideas on where to go next, toward answers that will bring about meaningful clinical results.”

Among the ideas mentioned in this “all hands on deck” approach are promoting “integrated collaboration of leading clinicians, imaging experts, a wide variety of basic scientists, bioinformaticians and biostaticians” as well as creating a large biorepository of eye tissue from donors with and without AMD, generating multiple types of data from disease and normal eye tissue, and designing computer models of the disease.

FDA and EMA Will Review Abicipar Pegol

■ Allergan and Molecular Partners, who are parntering in developing a new class of drugs known as DARPins, said the FDA has accepted a biologic license application for the DARPin abicipar pegol for the treatment of wet AMD and will review the application. In addition, the European Medicines Agency (EMA) has validated the marketing authorization application for abicipar pegol for the same indication.

If approved, abicipar pegol is expected to be the first anti-VEGF therapy to sustain vision gains on a true fixed 12-week dosing interval. Acceptance of these applications confirms that the submission is sufficiently complete to begin the formal review process.

Novartis Takes Option on Anti-Tissue-Factor Drug

■ Iconic Therapeutics said the company has signed an agreement with Novartis in which Novartis will have an option on Iconic’s ophthalmology program, now in preclinical development. Novartis made an upfront payment and an equity investment in Iconic. Iconic is evaluating its anti-tissue factor monoclonal antibody ICON-4 as a potential therapeutic for AMD, aiming to begin clinical trials in 2020.

“Iconic Therapeutics is pursuing an innovative approach to targeting tissue factor, a promising target with early clinical validation and potential applicability in a broad range of diseases, including retinal disease and cancer,” said Dr. William Greene, Iconic CEO. “While current AMD therapies have improved visual acuity for patients, they do not stop the inexorable progression of the disease. We believe that addressing tissue factor overexpression in macular degeneration may modify the course of AMD, improving both durability and efficacy.”

Eyenuk AI System Detects DR in Major Study

■ Eyenuk, Inc., a global artificial intelligence (AI) medical technology and services company, said the journal Diabetes Technology and Therapeutics has published a study of more than 100,000 consecutive diabetic patient visits analyzed using the EyeArt AI Eye Screening System. The largest study of AI in health care reported that the EyeArt AI System achieved greater than 91% in both sensitivity and specificity for detection of referable diabetic retinopathy. The study found the EyeArt AI System to be a safe and effective, fully automated tool to advance the worldwide need for diabetic retinopathy screening.

ASRS Award Winners

■ Winners of major awards at this summer’s American Society of Retina Specialists meeting included, in alphabetical order: Sophie J. Bakri, MD, of the Mayo Clinic, the Young Investigator Award; Seenu M. Hariprasad, MD, of the University of Chicago, the Crystal Apple Award for excellence in teaching and mentorship; Joan M. O’Brien, MD, of the University of Pennsylvania School of Medicine, the Pyron Award for contributing to the knowledge of vitreoretinal disease; and Lawrence A. Yannuzzi, MD, of Columbia University School of Medicine, the Founders Award.

Aerie Initiates Study of Sustained-Release Implant

■ Aerie Pharmaceuticals has begun patient dosing in a first-in-human clinical trial of its AR-13503 sustained-release implant in patients with wet AMD or DME. This multiarm, 24-week study is being conducted in 2 sequential stages. The first phase is a multicenter, open-label, dose-escalation study of the safety and tolerability of a single intravitreal injection of the AR-13503 implant, using 2 doses, in up to 12 patients. The second phase, enrolling up to 90 patients, is a multicenter, single-masked, randomized, parallel group study of the safety and preliminary efficacy of low- or high-dose AR-13503 implant, dosed as monotherapy and in combination with aflibercept (Eylea; Regeneron), compared to aflibercept alone.

“This study is designed to confirm our preclinical observations that AR-13503 could be useful as either monotherapy or in combination with VEGF inhibitors, and to help us select an appropriate dose for later-stage trials. It will also provide the first clinical data for our polyesteramide bioerodible polymer implant technology, which allows us to deliver small-molecule drugs to the back of the eye while extending treatment duration,” said Vicente Anido, Jr., PhD, Aerie Chairman and CEO.

Regenxbio to Update Gene Trial in Wet AMD

■ Regenxbio said that an interim trial update from the RGX-314 gene-based phase 1/2a clinical trial for wet AMD will be reported during a presentation at the Retina Subspecialty Day program of the American Academy of Ophthalmology 2019 Annual Meeting in San Francisco. The results will be presented by Jeffrey S. Heier, MD, co-president and director of retina research at Ophthalmic Consultants of Boston and primary investigator for the trial. Dr. Heier will present the interim results that include data for all 5 dose cohorts. The company has previously reported some positive interim data from this trial and remains confident it can begin a phase 2b study late this year.

DORC Brilliant Blue Accepted for FDA Review

■ DORC said it has received notification from the FDA that its New Drug Application for Brilliant Blue G Ophthalmic Solution has been accepted for review. The proposed indication for Brilliant Blue G Ophthalmic Solution is to selectively stain the internal limiting membrane (ILM) which forms the inner layer of the retina. Cellular proliferation on the ILM can lead to the formation of vision-impairing epiretinal membranes (ERM) and macular holes. While the removal of the ILM can relieve symptomatic macular distortion caused by ERMs and macular holes, the transparent nature of the ILM makes it difficult to visualize and peel.

Brilliant Blue G Ophthalmic Solution is intended to be injected onto the inner retinal surface, enabling the ILM to be clearly stained and distinguished from unstained retina, thereby facilitating removal. If approved, Brilliant Blue G Ophthalmic Solution will be the first FDA-approved product for this orphan indication.

Adverum Reports Data on Its Gene Therapy for Wet AMD

■ Adverum Biotechnologies has announced 24-week clinical data from the first cohort of 6 patients treated with a one-time intravitreal dose of gene-derived aflibercept (ADVM-022) in the OPTIC phase 1 clinical trial for wet AMD. Patients treated in this cohort, who averaged 35 previous anti-VEGF injections, achieved an acceptable level of vision maintenance (average loss of 2 letters) and improvements in retinal anatomy, with no anti-VEGF rescue injections required. These patients previously required frequent anti-VEGF injections to control their wet AMD and to maintain functional vision. ADVM-022 was safe and well tolerated.

Adverum’s gene therapy candidate uses a proprietary vector capsid (AAV.7m8) carrying an aflibercept coding sequence under the control of a proprietary expression cassette. ADVM-022 is a one-time intravitreal injection designed to deliver long-term efficacy by significantly reducing the treatment burden of frequent anti-VEGF injections and improving real-world vision outcomes for patients with wet AMD and diabetic retinopathy.

Patient Registry Started for Uveal Melanoma

■ Immunocore Limited, a T-cell receptor biotechnology company, and Pulse Infoframe, a data aggregation and analytics company, announced plans to support the first global patient registry in uveal melanoma, which typically has a poor prognosis and for which there is no currently accepted optimal management or treatment. The insights gained through the academic registry will provide a more comprehensive understanding of the disease and may help to shape future research. The registry will initially include institutions from across the United States, United Kingdom, and Australia.

“The rarity of uveal melanoma makes it difficult to collect the data needed to better understand how the disease manifests and evolves, and who is likely to respond to treatment and why,” said Richard Carvajal, MD, of Columbia University School of Medicine. “For the first time we’ll have the opportunity to prospectively collect and analyze global real-world data, including patient-reported outcomes. This will help to guide medical research, innovative trial design and recruitment, potentially paving the way for accelerated treatment advances.”

Research generated from the registry will examine risk factors, genetics, epidemiology, treatment cost effectiveness and real-world outcomes from a database of patients with uveal melanoma. The goal is to create a benchmark framework, or ecosystem, for collecting and assessing clinical outcomes, as well as providing necessary data for future genetic, subphenotype, and biomarker research.

Children’s Hospital Treats 14th Luxturna Patient

■ Children’s Hospital Los Angeles (CHLA) has emerged as a national leader in using the gene replacement therapy Luxturna (Spark Therapeutics) to treat inherited retinal degeneration in children and adults, having recently treated its 14th patient.

“We have found that using gene therapy to treat this condition can be life changing for children under the age of 10,” explains CHLA surgeon Aaron Nagiel, MD, PhD. “While they are not going to have normal vision, we can improve it to a degree that they can do activities they couldn’t do before, like playing outside at night. They gain greater visual clarity of edges on objects, so they can draw and enjoy picture books, and play with toys.”

The breakthrough one-time treatment replaces a defective gene called RPE65 located in the retina with a healthy copy made from artificial DNA, the equivalent of human DNA. RPE65 produces a protein that makes light receptors work in the eye.

Of the 7 hospitals nationwide originally approved to deliver this therapy to patients, CHLA was the only program with 2 full-time, dedicated pediatric retinal surgeons on site —Nagiel and Thomas C. Lee, MD, director of The Vision Center at CHLA and associate professor of ophthalmology at the USC Roski Eye Institute.

CHLA has performed the procedure on 9 children, as young as age 3, and a handful of adults. Results have been less dramatic with adult patients because eyesight improvement is largely contingent on how far the condition has advanced.

Regenxbio to Test Suprachoroidal Delivery

■ Regenxbio and Clearside Biomedical have concluded an option and license agreement for exclusive worldwide rights to Clearside’s proprietary in-office SCS Microinjector for the delivery of gene-based RGX-314 to the suprachoroidal space to treat wet AMD, diabetic retinopathy, and other conditions for which anti-VEGF treatment is currently the standard of care. RegenxBio plans to evaluate RGX-314 using Clearside’s SCS Microinjector for in-office, nonsurgical delivery into the suprachoroidal space, while continuing to advance its RGX-314 subretinal delivery program currently in development for wet AMD and DR.

Delivery of NAV AAV8-based gene therapy through the suprachoroidal space can potentially provide a targeted, in-office, nonsurgical approach to widespread transgene expression in the retina without exposing the vitreous and the anterior segment of the eye to the injected drug. Clearside’s patented SCS Microinjector is specifically designed to allow for consistent injection into the suprachoroidal space and has been tested in more than 1,000 injections in clinical trials to date. In early clinical trials, RGX-314 has expressed a molecule similar to ranibizumab over many months without retreatment needed.

Phase 3b Trial Announced for Brolucizumab

■ Novartis has announced it is initiating the 692-patient, 64-week, phase 3b TALON trial for brolucizumab in wet AMD, matching its investigational drug against aflibercept (Eylea; Regeneron). Brolucizumab is currently under review by the FDA for possible approval based on positive data from the phase 3 HAWK and HARRIER trials.

TALON will match a 6 mg dose of brolucizumab against a 2 mg dose of aflibercept, with the primary endpoints being average change in BCVA and “distribution of the last interval with no disease activity” (durability).

Cigna to Fully Cover Gene Therapies

■ Health insurer Cigna Corp has introduced a plan to fully cover costs for expensive gene therapies, eliminating any out-of-pocket payments for patients. While there are currently only 2 approved gene therapies in the United States, drug makers have been spending millions of dollars on the development of these treatments that could offer a potential one-time cure to rare and life-threatening disorders. The first 2 gene therapies to be included in the Cigna program are Spark Therapeutics’ Luxturna for inherited retinal disease, and Novartis’s $2.1 million spinal muscular atrophy treatment, Zolgensma, the insurer said.

Lucentis Approved in Europe for ROP

■ Novartis has announced European approval of Lucentis (Genentech) for preterm infants with retinopathy of prematurity (ROP), making it the first and only licensed pharmacologic treatment for this indication. The approval is based on the landmark RAINBOW study, showing Lucentis is an efficacious and safe treatment for infants with ROP.

Early Data on Ribomic Aptamer for Wet AMD

■ Ribomic has announced initial top-line results from its SUSHI study, a phase 1/2a single ascending-dose clinical study of RBM-007, anti-FGF2 aptamer, in 9 subjects with wet AMD. The SUSHI study achieved its primary endpoint of safety and tolerability, and also demonstrated efficacy trends in favor of RBM-007.

Subjects recruited for the SUSHI study had wet AMD poorly responsive to previous anti-VEGF therapy. Through the 56-day exit visit, a single dose of RBM-007 demonstrated no dose-limiting toxicities and no systemic or ocular serious adverse events.

Secondary outcomes at the primary study endpoint of 28 days showed evidence of bioactivity of RBM-007. Seven out of 9 subjects responded to RBM-007 with gain in BCVA or ≥50 µm improvement in central retinal thickness on OCT. Overall, a single intravitreal injection of RBM-007 was well tolerated and indicated bioactivity in a majority of these wet AMD subjects, who had been poorly responsive to prior anti-VEGF therapy.

Gene-Editing Clinical Trial for LCA10

■ Allergan and Editas Medicine, Inc. have initiated the Brilliance phase 1/2 clinical trial of AGN-151587 for patient enrollment. AGN-151587 is an experimental medicine for the treatment of Leber congenital amaurosis 10 (LCA10), an inherited form of blindness caused by mutations in the CEP290 gene. The clinical trial will be the world’s first in vivo study of a CRISPR-based genome editing medicine, where the editing takes place inside the human body. The study will assess safety, tolerability, and efficacy in approximately 18 patients. Up to 5 cohorts across 3 dose levels will be enrolled in this open-label clinical trial in multiple centers. Patients will receive a single dose of AGN-151587 administered via subretinal injection in 1 eye following vitrectomy. RP