After Safety Review, FDA Grants Beovu Label Change
Warnings added regarding retinal vasculitis and retinal vascular occlusion.
■ Novartis has reported that the FDA approved a label update for Beovu (brolucizumab) to include additional safety information regarding retinal vasculitis and retinal vascular occlusion. This change follows the announcement by Novartis that it would pursue worldwide label updates after a review and further characterization of rare postmarketing safety events reported to Novartis.
The update to the US label includes the addition of a subsection dedicated to retinal vasculitis and/or retinal vascular occlusion under “Warnings and Precautions.” It also specifies that these adverse reactions are part of a spectrum of intraocular inflammation rates from the phase 3 HAWK and HARRIER trials. The company has also established an internal team collaborating with global experts to examine the root causes, risk factors, mitigation, and potential treatment protocols.
“This label update provides clinicians with important information to guide treatment decisions. We believe Beovu continues to represent an important treatment option for patients with wet AMD, with an overall favorable benefit-risk profile,” said Marcia Kayath, global head of medical affairs and chief medical officer, Novartis Pharmaceuticals, in a news release.
In an editorial published online in May in the American Journal of Ophthalmology, retina specialists Philip Rosenfeld, MD, PhD, of Bascom Palmer Eye Institute, and David J. Browning, MD, of Charlotte Eye, Ear, Nose, and Throat Associates, called on their colleagues to stop using the recently approved anti-VEGF for wet AMD until further studies could be conducted of the incidence of irreversible vision-robbing retinal vasculitis, retinal vascular occlusion, and combined retinal vasculitis and occlusion that has been reported in connection with the drug.1 The authors noted that the other approved anti-VEGF therapies for wet AMD do not pose such safety risks.
Twenty-six cases associated with 70,000 total injections had been reported to the American Society of Retina Specialists’ Research and Safety in Therapeutics (ReST) Committee by March 27. Incidence has been unpredictable and could develop weeks after the last brolucizumab injection despite the fact that previous injections had been well tolerated.
Novartis says that as of May 8, their numbers indicate a total incidence of 6.99 of the 3 adverse events for every 10,000 injections, with combined retinal vasculitis and occlusion being the most prevalent at 3.73 per 10,000 injections.
REFERENCE
- Rosenfeld PJ, Browning DJ. Is this a 737 Max moment for brolucizumab? Am J Ophthalmol. 2020. [In press] https://www.ajo.com/article/S0002-9394(20)30242-7/fulltext
AI Algorithms Can Detect AMD Progression
Groundbreaking study for either wet or dry macular degeneration.
■ A new deep-learning artificial intelligence (AI) algorithm developed by researchers at New York Eye and Ear Infirmary of Mount Sinai (NYEE) can rapidly and accurately detect AMD progression. The study, published in Translational Vision Science and Technology, is the first to show that AI technology may help doctors to predict the risk of AMD progression and severity, which can prompt patients to get earlier medical treatment and save their vision.
Researchers at NYEE developed deep-learning AI screening and prediction models using data from the Age-Related Eye Disease Study, a large study of AMD over 15 years sponsored by the National Institutes of Health. Patients between 55 and 80 years old were grouped into categories for normal, early, intermediate, and advanced or late AMD. For screening, the investigators took 116,875 color fundus photos from 4,139 participants and trained the algorithm to classify them as “no,” “early,” “intermediate,” or “advanced” AMD along a 12-level severity scale to match the findings of human experts. Overall, their algorithm achieved 98% accuracy when matching decisions of experts.
The researchers then took the severity scores and combined them with the patients’ sociodemographic clinical data and other imaging data in a second algorithm to predict AMD progression, specifically risk for progression to late AMD within 1 or 2 years. The AI model further refined the risk of progression to late AMD so that researchers were able to predict the exact type of progression of late AMD — either dry or wet. Testing has yielded favorable results.
New OpRegen Delivery, Formulation Effective Against GA
Data show evidence of improved vision and function.
■ Lineage Cell Therapeutics has updated patient data from its ongoing phase 1/2a clinical study of OpRegen, the company’s retinal pigment epithelium (RPE) cell transplant therapy, for the treatment of dry AMD. The first 2 cohort 4 patients treated using both a new subretinal delivery system and the company’s new thaw-and-inject formulation of OpRegen have shown significant improvements in vision, each having gained more than 10 letters 6 months following administration of OpRegen RPE cells, as assessed by the Early Treatment Diabetic Retinopathy Scale (ETDRS).
These 2 patients also demonstrated improved reading speed and slower progression of GA lesions than in the fellow eye. Investigators also found early evidence of cell durability, including the first reported incidence of RPE cell regeneration in 1 patient.
“Our team has independently reviewed these data as part of our ongoing collaborative efforts with Lineage and I think it is evidence of a partially restorative effect in this patient. We have observed apparent RPE regeneration on detailed review of imaging and will look forward to reviewing additional patient data from the OpRegen clinical trial to determine the reproducibility and durability of this unexpected finding,” said investigator Michael Ip, MD, in a news release.
“To our knowledge, this is the first time any experimental treatment for dry AMD has demonstrated a reduction, rather than expansion, of an area of atrophy over a clinically meaningful time period. If this finding is confirmed in additional patients, I believe it will create a new paradigm for how we and others approach the treatment of dry AMD and will help advance the incredibly promising area of cell therapy in which we enjoy a leadership position, the directed differentiation and transplant of specific cell types to treat severe diseases and conditions,” said Brian M. Culley, Lineage CEO, in a news release.
Both patients presented with asymptomatic small subretinal hemorrhage that self-resolved. Lineage is hopeful that the switch to thaw-and-inject and subretinal delivery will eliminate the epiretinal membrane side effect that was prevalent in cohorts 1 through 3.
“As a principal investigator on the OpRegen clinical study, I am excited to present this most recent update, where all Cohort 4 patients treated with OpRegen had improved best-corrected visual acuity up to 1 year or at their last visit, demonstrating a substantial treatment response,” said study investigator Christopher D. Riemann, MD, in a news release. “The pooled cohort 4 data demonstrate a significant, greater than 10-letter sustained visual acuity improvement over the entire followup period. Reading center assessments of GA also suggest a reduction in GA progression in the OpRegen treated eye when compared to fellow eye in cohort 4.
The data, except for the new report of RPE cell regeneration, were released online on the ARVOLearn website in conjunction with the 2020 ARVO virtual meeting.
PDS Effective in Initial Phase 3 Data
More complete data to come at a later date.
■ Genentech announced much-awaited but sparse positive top-line results from the 418-patient phase 3 Archway study, evaluating Port Delivery System with ranibizumab (PDS) in individuals with wet AMD. PDS is a permanent refillable eye implant, approximately the size of a grain of rice, that continuously delivers a customized formulation of ranibizumab over a period of months. The Archway trial met its primary endpoint, demonstrating that patients with PDS who received refills every 6 months achieved visual acuity outcomes equivalent to those receiving monthly ranibizumab 0.5 mg injections. In Archway, PDS was generally well tolerated with a favorable benefit–risk profile.
In addition to Archway, the Portal study is investigating the long-term safety and tolerability of PDS for the treatment of wet AMD. Furthermore, PDS is also being studied in the Pagoda trial for the treatment of DME. Full results from the Archway study will be presented at an upcoming medical meeting and submitted to health authorities around the world, including the FDA and European Medicines Agency, for consideration of regulatory approval for the treatment of nAMD.
IN BRIEF
Research and industry news in retina.
BY JERRY HELZNER, CONTRIBUTING EDITOR
Iveric bio Reports Continued Positive Data From Zimura in GA
■ Iveric bio has announced a continuation of positive results from the company’s first phase 3 clinical trial for Zimura (avacincaptad pegol), a novel complement C5 inhibitor, for the treatment of geographic atrophy (GA) secondary to AMD. The 18-month data from the 286-patient study were similar to the previously announced 12-month data from this trial, at which time point Zimura met the prespecified primary efficacy endpoint with statistical significance. The reduction in the mean rate of GA growth over 18 months was 28.11% for the Zimura 2 mg group as compared to the corresponding sham control group and 29.97% for the Zimura 4 mg group as compared to the corresponding sham control group.
In this trial, the treatment effect was observed as early as 6 months, with an increase in the absolute difference of the mean change in GA growth for treatment with either Zimura 2 mg or Zimura 4 mg, as compared to sham, at each subsequent time point, suggesting the progressive benefit of continuous treatment with Zimura. Zimura maintained its favorable safety profile at 18 months with no reported Zimura-related adverse events, no cases of endophthalmitis, and a lower rate of choroidal neovascularization than reported for C3 inhibition. The overall 18-month data may suggest a dose-response relationship.
“We are one step closer to potentially bringing a clinically meaningful therapy to patients with GA who currently do not have any FDA- or EMA-approved treatments available to them,” said Kourous A. Rezaei, MD, chief medical officer of Iveric bio, in a news release in June. “We believe the robust 18-month efficacy data further validates the potential role of complement C5 inhibition in GA secondary to AMD and has the potential to differentiate Zimura from other product candidates in development. We are poised to initiate our second pivotal trial, ISEE2008, comparing Zimura 2 mg with sham later this month.”
Genentech Moves GA Therapy to Phase 2 Trial
■ Following a successful 15-patient phase 1 safety study of intravitreal anti-high temperature requirement A1 (anti-HtrA1), a novel serine protease inhibitor in patients with GA, Genentech has moved on to the 285-patient GALLEGO phase 2 study evaluating the therapy’s efficacy at 4 and 8 weeks. Anti-HtraA1 is a fab of a humanized monoclonal antibody designed to inhibit HtrA1 activity. HtrA1 is associated with progression of macular degeneration from intermediate to advanced stage and increased lesion growth rates in GA.
The phase 1 safety study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of anti-HtrA1 following single and multiple doses in patients’ GA secondary to wet AMD, administered via intravitreal injection. Results were presented by Dante Pieramici, MD, at the 2020 ARVO virtual meeting.
Anti-HtrA1 treatment was well tolerated at single doses up to 20 mg and multiple doses of 20 mg every 4 weeks. No dose-limiting toxicities were observed and no ocular serious adverse events (AEs) or systemic or ocular AEs were reported related to anti-HtrA1. Furthermore, a sustained PD effect suggests a potential for at least 8 weeks of target inhibition.
Vasoptic Receives 510k Clearance for Retinal Imaging Device
■ Vasoptic Medical Inc. has announced that the company received 510(k) clearance from the FDA to market its XyCAM RI, a noninvasive retinal imager designed to capture and provide dynamic blood flow information for clinical use. The XyCAM RI enables ophthalmologists to rapidly and affordably assess the vascular status of the retina, which can improve disease detection and treatment.
“Today’s announcement represents an important milestone,” said Abhishek Rege, president and founder of Vasoptic. “After tremendous effort from a tremendous team of engineers, scientists, and clinicians, the FDA authorization will enable physicians to better understand the physiological status of their patients’ retina. Specifically, the XyCAM RI provides imaging of blood flow dynamics in the retina, the next frontier for ophthalmic imaging, and will allow physicians to make decisions about care that could dramatically impact the vision and quality of life for millions of Americans.”
Adverum Begins Gene-Derived Anti-VEGF trial in DME
■ Adverum Biotechnologies has announced the initiation of INFINITY, a phase 2, multicenter, randomized, double-masked, active comparator-controlled trial to assess a one-time intravitreal injection of gene-derived ADVM-022 in patients with diabetic macular edema (DME). The INFINITY trial will enroll approximately 33 patients and is designed to demonstrate superior control of disease activity following a single IVT injection of ADVM-022 compared to a single aflibercept injection, as measured by time to worsening of DME disease activity. Additional objectives include assessments of treatment burden, visual acuity, retinal anatomy, and safety outcomes.
Participants in this double-masked trial will be randomized to 1 of 3 arms for their study eye treatment. Arm 1 will receive the higher dose of ADVM-022 at 6x1011 vg. Arm 2 will receive the lower dose of ADVM-022 at 2x1011 vg. Arm 3 will receive aflibercept at a dose of 2 mg.
Aaron Osborne, MBBS, chief medical officer of Adverum, said, “DME affects approximately 5% of people with diabetes and is the most common cause of vision loss in people with diabetic retinopathy. We believe that the exciting data seen to date for ADVM-022 in the ongoing OPTIC trial in wet AMD highlight this therapy’s transformative potential to deliver long-term control of serious retinal vascular diseases, including DME.”
AAO Leveraging Twitter to Share Ophthalmic Articles
■ During the COVID-19 pandemic, the AAO has been using Twitter to good advantage to share links to peer-reviewed journal articles and other relevant ophthalmology-relate information. The (AAO) Ophthalmology journal Twitter account, @AAOjournal , shares recently published articles, and the AAO’s account, @aao_ophth , also posts regular updates for its members and the general public. By sharing recently published peer-reviewed articles online and alerting Twitter followers to these new updates, users can immediately access research and new information. As of May 1, 2020, the journal’s growing collection of COVID-19-related research articles and commentaries totaled over 58,059 impressions on Twitter (mean impressions per post was 6,451, ranging from 1,626 to 18,216).
Bausch+Lomb Licenses a Lucentis Biosimilar
■ Bausch + Lomb has entered into an exclusive licensing agreement with STADA Arzneimittel AG and its development partner, Xbrane Biopharma AB, a leading Nordic biosimilar developer, to develop and commercialize a biosimilar candidate to Lucentis (ranibizumab) in the United States and Canada. The companies aim to obtain all currently approved indications for Lucentis in both the United States and Canada.
Study: DR Associated With Anxiety, Depression
■ Researchers at the University of North Carolina Chapel Hill, led by Daniel Olson, MD, set out to determine whether patients with diabetic retinopathy (DR) were more likely to have anxiety and/or depression than the general population. Their hypothesis was that patients with a diagnosis of DR face lifestyle changes, loss of vision, and major treatments such as anti-VEGF injections and PRP.
The researchers analyzed the Carolina Data Warehouse and identified 4,315 patients over age 18 treated for DR between July 2008 and July 2018, 57% of whom were women. They found that of 95,575 patients in the total database, those without DR were diagnosed for anxiety at a rate of 18.7% and depression at a rate of 20.4%. Those with DR were diagnosed with anxiety at a rate of 21.5% and depression at a significantly higher rate of 33%. The rate of anxiety was found to be higher in younger patients who may have greater dread of the future course of their disease and the difficult treatments they may be facing.
The researchers concluded that the study, which was presented at the 2020 ARVO virtual meeting, demonstrates the importance of interdisciplinary coordination with primary care providers to manage diabetes, DR, and mental illness comorbidities.
Low-Dose Avastin Combats ROP
■ Infants born prematurely who require treatment to prevent blindness from retinopathy of prematurity (ROP) could be treated with a dose of bevacizumab (Avastin) that is a fraction of the dose commonly used for ROP currently. Results from the dose-finding study were published recently in JAMA Ophthalmology. The study was conducted by the Pediatric Eye Disease Investigator Group (PEDIG) and supported by the National Eye Institute (NEI), part of the National Institutes of Health.
“As a faster and easier treatment option, anti-VEGF eye injections were a welcomed alternative to laser therapy for treating severe ROP,” said the new study’s protocol chair, David Wallace, MD, MPH, chair of ophthalmology at the Indiana University School of Medicine. Laser therapy requires sedating the infant for as long as 90 minutes; an Avastin injection takes much less time and is generally less stressful to the patient.
“We know that anti-VEGF agents injected into the eye also get into the bloodstream, and doctors worry that inhibiting VEGF systemically could interfere with normal development of brain, lung, bone, and kidney tissues,” said Dr. Wallace. Evidence suggests that injections of anti-VEGF in the eye reduce levels of VEGF in the bloodstream.
In this study, Wallace and colleagues hoped to pinpoint the lowest possible therapeutic dose of bevacizumab by testing progressively lower doses in 10 to 14 infants per dose. “We didn’t want to start by testing an ineffective dose and risk a child going blind, so we started with 40% of the dose commonly used for ROP. When a dose was successful, we halved it and then tested that dose. Eventually we cut the dose in half 7 times,” he said.
“In the current study, we found that 0.004 mg of Avastin — a dose that’s merely 0.6% of the dose used in the 2011 study of Avastin for ROP — may be the lower limit to be effective for most infants with ROP,” said Wallace. The findings set the stage for a randomized controlled trial comparing long-term effects of low-dose Avastin with laser therapy for treating ROP,” he said.
BVI Launches Standalone Device for Cryosurgery
■ BVI announced the European launch of CryoTreq — the world’s first single-use, handheld cryosurgery device for ophthalmology. The product was developed in partnership with Prof. Stanislao Rizzo, a retinal surgeon and Professor at the University of Florence. This standalone device for cryosurgery functions without external connections to equipment, gas tanks, or power and does not require any service or maintenance.
During the last few years, CryoTreq has been developed to modernize a well-proven method for treating sight-threatening retinal tears and detachments. “Within a minute of opening the sterile blister, I am ready to treat retinal tears or detachment, whether I’m in my office or in the operating room. It’s never been this easy to perform a cryo procedure,” said Prof. Rizzo.
CryoTreq enables a minimally invasive ab-externo approach to treat retinal tears and detachments, providing an alternative to laser photocoagulation — especially for lesions located toward the anterior of the eye. It requires minimal time for preparation and is easy and intuitive to use, with a hand-controlled single button activation. Like existing cryo equipment, CryoTreq’s probe reaches temperatures as low as -88⁰C, and the tip reaches cryogenic temperatures within 4 to 6 seconds after activation. BVI is actively working on registrations in jurisdictions outside of Europe.
Free App Helps Guide Retinal Laser Treatments
■ To meet the fast-growing demand for interactive learning technology, OD-OS has developed the Navigate app, a tool for implementing the best approach to retinal laser treatment. Navigate is a free, interactive tool designed to support a team-learning approach to retinal laser treatment, both on site and online. The platform is already being used successfully in German university hospitals. Instructors and participants use Navigate to develop laser treatment strategies for different cases with various indications. A team can work with preloaded or custom examples based on a variety of diagnostic images. The goal of this app is to facilitate discussion and best practices for treatment on a case-by-case basis.
Vitreous Substitute Being Tested
■ A first-in-human feasibility clinical study of ABV-1701, or Vitargus (American BriVision), used as a biodegradable vitreous substitute in patients under vitrectomy surgery for retinal detachment or vitreous hemorrhage, was successfully completed at the Sydney Eye Hospital in Australia. The study showed Vitargus was generally well tolerated and effective as a vitreous substitute, and no apparent toxicity or serious adverse events directly caused by Vitargus were observed. Moreover, an exploratory analysis showed a statistically significant improvement in BCVA from the baseline. Given the encouraging study results, a multinational, multisite pivotal study for Vitargus is planned in 2020.
Dr. Humayun Wins Award for Innovation
■ Mark Humayun, MD, PhD, director of the USC Dr. Allen and Charlotte Ginsburg Institute for Biomedical Therapeutics and codirector of the USC Roski Eye Institute, was awarded the 2020 Medal for Innovations in Healthcare Technology by the Institute of Electrical and Electronics Engineers. Humayun was honored for his pioneering work in engineering and utilizing prosthetic devices to treat retinal neurodegenerative diseases.
NASA Awards Funding for Artificial Retina
■ LambdaVision, along with implementation partner Space Tango, has been selected by NASA for an award of $5 million. This new funding will support LambdaVision’s development of the first protein-based artificial retina to restore meaningful vision for patients who are blind or have lost significant sight due to advanced retinitis pigmentosa (RP), with follow-on applications in AMD. As part of this award, the company, together with Space Tango, will explore the benefits of microgravity for producing LambdaVision’s artificial retina on the International Space Station (ISS) US National Laboratory located in low-earth orbit. The contract will cover a series of flights to the ISS over 3 years to evaluate and improve on-orbit production processes and to produce artificial retinas that will then be evaluated on earth for the potential to restore vision to patients suffering from retinal degenerative diseases.
AGTC Enrolls High-Dose Cohorts in XLRP Trial
■ Applied Genetic Technologies Corporation (AGTC) announced it has completed enrollment in the 2 highest-dose groups of its phase 1/2 clinical trial evaluating the safety and efficacy of subretinal injection of AGTC-501 for the treatment of X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene. The patients in these additional groups received a higher or highest dose of AGTC’s XLRP candidate.
“We plan to report interim data from these 2 new dose groups and to report top-line 12-month data for the first 4 dose groups in the second half of 2020 and intend to initiate a pivotal trial by the end of the year,” said AGTC CEO Sue Washer in a news release. “Combined with the ongoing progress in our 2 achromatopsia clinical studies, we expect to have multiple data read-outs in 2020 that will build on the momentum we created in January.”
ProQR Drug Gets Rare Pediatric Disease Designation
■ ProQR Therapeutics has received rare pediatric disease designation from the FDA for QR-421a for the treatment of RP caused by mutations in exon 13 of the USH2A gene. The drug QR-421a is a first-in-class investigational RNA-based oligonucleotide designed to address the underlying cause of vision loss in Usher syndrome type 2 and nonsyndromic retinitis pigmentosa due to mutations in exon 13 of the USH2A gene.
The rare pediatric disease designation provides priority review by the FDA to encourage treatments for rare pediatric diseases. Under the rare pediatric disease program, a sponsor that receives an approval for a drug or biologic for a rare pediatric disease may qualify for a voucher that can be redeemed to receive a priority review by the FDA for any subsequent marketing application for a different product. Such a voucher is transferrable and may be sold. RP
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