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SUBSPECIALTY NEWS: Lucentis effective for RVO, endophthalmitis after anti-VEGF injection, perfluorocarbon toxicity in vitreoretinal surgery, and more

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Lucentis Effective for RVO

Study focuses on treatment-naïve patients with BRVO and CRVO.

■ LUMINOUS was the largest prospective real-world observational study in retinal disease, encompassing 30,000 patients in 42 countries over a 5-year period through 2016 for all approved indications for Lucentis (ranibizumab; Genentech). Ian Pearce, MD, of the Royal Liverpool University Hospital, Liverpool, United Kingdom, led a team of researchers who presented positive results at the recent ARVO meeting for treatment-naïve BRVO and CRVO patients who received Lucentis therapy.

The patient cohort for RVO in LUMINOUS included both treatment-naïve and previously treated patients. However, this section of the overall study focuses only on treatment-naïve individuals. Of the 732 treatment-naïve RVO patients recruited worldwide, 405 had BRVO and 327 had CRVO. At baseline, the mean age of treatment-naïve BRVO/CRVO patients was 67.9/68.9 years, 42.5%/56.9% were male, and 71.9%/76.8% were Caucasian.

At 1 year, the researchers reported an average mean VA improvement of greater than 10 letters in 189 treatment-naïve BRVO patients (46%) and 144 treatment-naïve CRVO patients (44%). Mean VA gains were higher in RVO patients who received at least 2 Lucentis injections. Similar to year 1, VA gains at year 2 were greater in RVO patients (BRVO, n=67; CRVO, n=48) with lower baseline VA. The rate of ocular/nonocular adverse events and serious adverse events was 7.4%/9.1% and 0.3%/4.4% across all 405 treatment-naïve BRVO patients and 11.3%/8.6% and 1.2%/6.7% in across all 327 treatment-naïve CRVO patients, respectively.

The researchers concluded that Lucentis treatment for at least 1 year resulted in improved VA in treatment-naïve BRVO and CRVO patients, with greater improvement associated with increased injection frequency. No new safety signals were observed.

Endophthalmitis After Anti-VEGF Injection

Long-term study compares TAI to PPV treatment.

■ Kunyong Xu, MD, a current fellow in vitreoretinal surgery at Cornell Weill Medicine, New York City, led a long-term study that tracked the incidence and treatment of endophthalmitis following anti-VEGF injection. Study results were presented at the recent ARVO meeting.

A total of 258,357 injections were given over 10 years at a single institution, with 40 patients (0.016) developing endophthalmitis within 3 weeks of injection. Of these, 29 were treated with tap-and-inject intravitreal antibiotics (TAI) and 11 were treated with pars plana vitrectomy (PPV). Thirty-four of the 40 endophthalmitis patients had pain at initial examination and 25 presented with hypopyon. Of the 24 culture-positive cases, 16 were found to be caused by coagulase-negative Staphylococcus and 3 by Streptococcus. The Streptococcus cases had significantly worse final BCVA. Ninety percent of the patients treated with PPV were culture positive and 48% of the TAI-treated individuals were culture positive.

At initial presentation, the mean BCVA was count fingers to hand motion. At 6-month follow-up, the majority (32 patients; 80%) of patients achieved a BCVA of 20/400 or better, while 8 patients (20.0%) had a BCVA worse than 20/400.

Compared to the initial presentation, 32 patients (80%) had improved BCVA at 6-month follow-up, 5 patients (12.5%) had the same BCVA at 6-month follow-up, and 3 (7.5%) had worse BCVA at 6-month follow-up.

Researchers found no significant differences in final average BCVA between the TAI and PPV groups. Younger age and lower IOP upon presentation were the only variables that appeared to affect final outcomes. These factors were indicative of better outcomes of final BCVA of 20/400 or better.

“There are limited studies available describing visual outcomes among patients with endophthalmitis following anti-VEGF injection,” said Dr. Xu. “Prior to our study, it was unclear which initial treatment (ie, vitreous biopsy with intravitreal injection of antibiotics vs vitrectomy with antibiotics) offered optimal visual outcomes. Given no significant differences in final average BCVA between the TAI and PPV groups, initial tap and inject remains a viable treatment approach to patients who develop endophthalmitis after injection of anti-VEGF agents.”

Perfluorocarbon Toxicity in Vitreoretinal Surgery

Better ISO-approved test methods are needed.

BY J. CARLOS PASTOR, MD, PHD

■ Since the introduction of perfluorocarbon liquids in vitreoretinal surgery by Stanley Chang, MD, in the 1990s, questions have been raised concerning their intraocular tolerance. Now, it appears widely accepted that they are capable of inducing inflammation if left in the eye for prolonged periods, and their use is only recommended as surgical manipulators that should be removed before surgery is finished.

Since 2013, Spanish healthcare authorities have been notified of at least 3 episodes caused by different commercial products from different companies in Turkey, Germany, and India of acute toxicity implicating perfluoro-octane and perfluoro-hexyl-octane compounds causing cases of complete retinal atrophy and amaurosis after contact times of less than 60 minutes. Clinical pictures and the identification of possible toxic substances have been published in Retina (2017) and British Journal of Ophthalmology (2018).

These products had CE marks, having passed cytotoxicity tests before their commercialization in the European Union. After several months of research, the IOBA (Eye Institute) of the University of Valladolid in Spain has shown that several types of cytotoxicity tests complying with ISO standards, and used by companies worldwide, have failed to detect toxic batches.

Indirect or extraction methods, in which endotamponators do not directly contact the testing cells, do not guarantee the safety of the products. IOBA has developed a direct method capable of identifying possible toxic lots, which has just been published in Scientific Reports.

In collaboration with the Spanish Agency for Medicines and Medical Devices and with the ISO Standards Committee, the IOBA is working to modify ISO guidelines for biological evaluation of ophthalmic surgical devices (ISO 16672 and ISO 10993) according to the current safety needs of the market to prevent the recurrence of dramatic cases of blindness due to the use of these manipulators, which are very useful in intraocular surgery.

Safer cytotoxicity tests, proof from distribution companies that their products are supported by valid biological tests, and testing the chemical purity of raw materials will ensure patient safety.

Dr. Pastor is the founder of IOBA (Eye Institute) of the University of Valladolid in Valladolid, Spain.

Complication Rates After Argus II Implantation

The large majority of retinal prostheses performed well

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ Researchers led by Laura Cinelli, MD, of Azienda Ospedaliero-Universitaria Careggi in Florence, Italy, conducted a retrospective observational study of the postoperative complication rates from implantation of Argus II retinal prostheses (Second Sight) and how these complications were managed with a follow-up of longer than 1 year. Results were presented at the recent ARVO meeting. The Argus II has been approved for blindness caused by end-stage retinitis pigmentosa.

Thirty-six eyes of 36 patients who received the Argus II from October 2011 to November 2017 were initially evaluated. Only 29 eyes were included in this study as they had follow-up longer than 12 months. At each follow-up visit (1 day, 1 week, and 1, 3, 6, 12, 24, and 36 months), a complete ophthalmologic examination was performed, including OCT, retinal fundus photography, and B-scan ultrasonography.

Five patients were reported to have left the study for personal reasons. Out of a total of 24 remaining patients, 4 experienced postoperative serious adverse events requiring surgery. One eye had severe hypotony associated with choroidal detachment that did not resolve with medical treatment, and 3 eyes had an irreparable retinal detachment. Nine eyes had adverse events that were not serious, such as development of macular schisis, between 6 and 36 months without deterioration in visual performance. The other 11 eyes remained uncomplicated.

None of the eyes required explantation of the device or enucleation within the follow-up period. In these patients, the device resulted well tolerated and functional. The researchers concluded that serious adverse events were relatively uncommon and the safety profile of the device and the complications were managed according to their severity.

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

DME Study Shows Safety of Anti-PlGF

■ ThromboGenics has reported encouraging topline results from a phase 1/2, single-masked, multicenter study to evaluate the safety and efficacy of 2 dose levels (4 mg and 8 mg) of THR-317 for the treatment of DME.

THR-317 is a recombinant humanized monoclonal antibody directed against the receptor-binding site of human placental growth factor (PlGF). In preclinical models, anti-PlGF has been shown, in addition to antiangiogenic and anti-edema properties, to be anti-inflammatory. The THR-001 study enrolled a total of 49 patients, including anti-VEGF naïve patients as well as suboptimal anti-VEGF responders.

Initial data reported are for the anti-VEGF treatment naïve group (n=40) up to day 90; 30 days after the last intravitreal anti-PlGF administration. The primary focus of this study was safety outcomes. THR-317 was safe and well tolerated. No dose-limiting toxicities or relevant safety events were reported at either dose level.

Thirty percent of the anti-VEGF treatment-naïve study subjects treated with THR-317 in the 8-mg group showed a greater or equal to 15 letter gain from baseline at day 90, compared to 5.3% in the 4 mg group. These data support initiation of a next study evaluating THR-317 in combination with an anti-VEGF. The clinical trial is targeted to be initiated in 2018.

Leber Study Endpoint Not Met

■ GenSight Biologics said a phase 3 study of GS010 gene therapy in patients with Leber hereditary optic neuropathy (LHON) failed to meet its primary endpoint, with sham-treated eyes demonstrating similar improvements in vision compared to the gene therapy.

The topline results from the REVERSE clinical trial evaluated the safety and efficacy of a single intravitreal injection of GS010 in 37 subjects whose visual loss due to 11778-ND4 LHON commenced between 6 and 12 months prior to study treatment.

According to GenSight, topline results highlight the favorable safety and tolerability profile of GS010, and demonstrate a clinically meaningful improvement of +11 ETDRS letters in treated eyes at 48 weeks as compared to baseline in all 37 patients. Untreated contralateral eyes (treated with a sham injection) show a similar improvement of +11 ETDRS letters. Due to this improvement in untreated eyes, the trial did not meet its primary endpoint, defined as a difference of improvement in visual acuity in GS010-treated eyes compared to sham-treated eyes at 48 weeks.

The improvement of visual acuity in sham-treated eyes was unexpected based on the natural history of LHON, for which partial spontaneous recovery is reported in only 8% to 22% of patients with the G11778 ND4 mutation. “This meaningful improvement of untreated eyes observed at week 48 was totally unexpected given what is known and has been published about the natural history of this devastating disease. We will continue to analyze the data to better understand our results, but they suggest that GS010 benefits both eyes in a way that is still to be understood,” said Bernard Gilly, CEO of GenSight, in a company news release.

Eylea Effective Against NPDR

■ Regeneron Pharmaceuticals said the phase 3, 402-patient PANORAMA trial evaluating Eylea (aflibercept) in moderately severe to severe nonproliferative diabetic retinopathy (NPDR) met its 24-week primary endpoint. In the trial, 58% of Eylea-treated patients experienced a 2-step or greater improvement from baseline on the Diabetic Retinopathy Severity Scale (DRSS) at week 24, compared to 6% of patients receiving sham injection.

“This is the first time a therapy has demonstrated it can reverse disease progression in patients with moderately severe to severe nonproliferative diabetic retinopathy without diabetic macular edema, in a trial specifically designed to study this population,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer of Regeneron. “Patients in the trial continue to be evaluated to determine if Eylea can prevent progression to neovascular vision-threatening complications or diabetic macular edema. We look forward to sharing one-year results later this year.”

Patients in the active treatment groups received, on average, 4.4 Eylea injections during the first 24 weeks. There were no new safety signals in the trial. There was 1 case of mild intraocular inflammation (IOI) in a patient treated with Eylea (0.085% rate per injection), which is consistent with the rate of IOI seen in previous clinical trials. PANORAMA will form the basis of a supplemental Biologics License Application (sBLA) to the FDA later this year.

Researchers Study Aspirin as AMD Therapy

■ Australian researchers are conducting the ASPREE-AMD (Aspirin in Reducing Events in the Elderly) study to determine whether long-term, low-dose aspirin therapy can affect the incidence and progression of AMD in participants 70 years of age and older who have no significant baseline physical disabilities. Several previous studies of aspirin therapy for AMD have produced inconclusive results. ASPREE-AMD is a substudy in the larger, 19,000-person ASPREE (Aspirin in Reducing Events in the Elderly) study. The larger ASPREE study is designed to determine whether low-dose aspirin can produce overall or specific health benefits in an aging population.

ASPREE-AMD participants are randomized to receive either 100 mg of aspirin daily or placebo. Participants in the government-funded study will be followed up for 5 years, with initial results expected this year. Early study parameters were presented at the recent ARVO meeting.

FDA to Review Sustained-Release Implant

■ pSivida said its new drug application (NDA) for Durasert 3-year treatment for posterior-segment uveitis has been accepted by the FDA for filing. The acceptance of the NDA reflects the FDA’s determination that the application is sufficiently complete to permit a substantive review. The application will be subject to a standard review and will have a Prescription Drug User Fee Act (PDUFA) date of November 5, 2018.

The NDA includes data from 2 phase 3 studies that each successfully achieved the primary efficacy endpoint at 6 months with a P value of <.001. In addition, the safety profile in patients treated with Durasert 3-year for posterior segment uveitis was consistent with the safety profile of steroid treatments that are currently considered standard of care for this disease.

FDA Approves Lucentis for DR in Prefilled Format

■ The FDA has approved the Lucentis (ranibizumab) 0.3 mg prefilled syringe (PFS) as a new method of administering the medicine to treat all forms of diabetic retinopathy. In April 2017, Lucentis 0.3 mg became the first and only FDA-approved medicine to treat all forms of diabetic retinopathy in people with or without DME.

The Lucentis 0.3 mg PFS, made of borosilicate glass and packaged in a single-use sterile, sealed tray, allows physicians to eliminate several steps in the preparation and administration process. With the Lucentis PFS, physicians snap off the syringe cap, attach the injection needle to the syringe and adjust the dose prior to administration. The Lucentis 0.3 mg PFS is expected to be available in the second quarter of 2018.

Prognostic Test Added to Melanoma Guidelines

■ Castle Biosciences said the National Comprehensive Cancer Network (NCCN) has included the DecisionDx-UM gene expression profile (GEP) test class results in their new clinical practice guidelines for uveal melanoma. These recommendations are the first-ever NCCN guidelines for uveal melanoma, and their publication is an important milestone in the care of patients with this rare eye cancer.

The new guidelines recognize the important role of genetic testing in determining risk of distant metastasis. Information from this testing is important to guide risk-appropriate surveillance imaging and follow-up, as well as clinical trial eligibility.

As many as 50% of patients with uveal melanoma will experience distant metastasis, usually to the liver. Therefore, the accurate identification of patients at low risk of metastasis who can be safely followed with a less intensive surveillance regimen, and those with a high risk of progression who can benefit from a more intensive surveillance plan to identify early disease progression, is critical to improve health outcomes.

pSivida Acquires Icon Bioscience

■ pSivida announced the acquisition of Icon Bioscience, a specialty biopharmaceutical company whose lead product Dexycu (dexamethasone intraocular suspension) 9% was recently FDA approved for postoperative inflammation and is administered as a single dose at the end of ocular surgery. Dexycu is the first long-acting intraocular product approved by the FDA for the treatment of postoperative inflammation. Dexycu utilizes Icon’s proprietary Verisome drug-delivery platform, which allows for a single injection that releases over time. Icon also has investigational drugs for retinal disease and ocular cancer in its early-stage pipeline.

pSivida, now known as EyePoint Pharmaceuticals, has also entered into a financial agreement with EW Healthcare Partners, which, with a third-party investor will make equity investments in EyePoint Pharmaceuticals for a total of up to approximately $60.5 million. In addition, SWK Holdings Corporation has agreed to provide EyePoint Pharmaceuticals with up to $20 million in a debt facility. The company will use these resources to finance the Icon acquisition and prepare for the commercial launches of Dexycu and, if approved by FDA, Durasert microinsert for the treatment of noninfectious uveitis affecting the posterior segment of the eye.

Stem-Cell–Based Implant Developed for Dry AMD

■ Physicians and researchers at the USC Roski Eye Institute have collaborated with other California institutions to show that a first-in-kind stem-cell–based retinal implant is feasible for use in people with advanced dry age-related macular degeneration. The results of the phase 1/2a study, which was funded in part by the California Institute for Regenerative Medicine, were published in Science Translational Medicine.

The treatment, which consists of a layer of human embryonic stem-cell–derived retinal pigment epithelium cells on an ultrathin supportive structure, was implanted in the retina of 4 patients by a USC Roski Eye Institute surgeon. The patients were followed for up to 1 year to assess safety. There were no severe adverse events related to the implant or the surgical procedure, indicating that it was well tolerated. There was also evidence that the implant integrated with the patients’ retinal tissue, which is essential for the treatment to be able to improve visual function.

In preliminary assessment of the therapy’s efficacy, 1 patient had improvement in visual acuity, and two patients had gains in visual function. None of the patients showed evidence of progression in vision loss.

“This is the first human trial of this novel stem-cell–based implant, which is designed to replace a single-cell layer that degenerates in patients with dry age-related macular degeneration,” says lead author and surgeon for the study Amir H. Kashani, MD, PhD, assistant professor of clinical ophthalmology at the Keck School of Medicine of USC, in a news release. “This implant has the potential to stop the progression of the disease or even improve patients’ vision. Proving its safety in humans is the first step in accomplishing that goal.”

Diopsys Launches New Electroretinography Products

■ Diopsys unveiled 2 new additions to its portfolio at the American Society of Cataract and Refractive Surgery (ASCRS) meeting: the Retina Plus, a flicker electroretinography (ERG) system, scalable to create a complete visual electrophysiology suite, and a multifocal electroretinography (mfERG) module for use with the company’s Nova, Argos, or Retina Plus platforms. These tools are designed to help eye care specialists gather objective, quantifiable information about the function of the retina.

Retina Plus is a carry-case sized device that offers clinicians a more convenient way to conduct flicker ERG testing, with the added ability to scale the system to a full visual electrophysiology suite, including multifocal, flash, and pattern ERG, as well as visual evoked potential (VEP). The new device complements existing cart-based (Nova) and tabletop (Argos) systems in a portfolio of testing platforms intended to provide clinics of all sizes access to visual electrophysiology testing.

Diopsys mfERG is a test of localized retinal function, which measures the electrophysiological activity of individual regions within the retina that span the central 42 degrees of the retina. According to the company, the test records responses primarily from bipolar cells combined with contributions from photoreceptor cells. The American Academy of Ophthalmology (AAO) recommends the use of mfERG for chloroquine and hydroxychloroquine retinopathy screening.

Telemedicine Effective for ROP Detection

■ A newly published study of 281 infants indicates that ophthalmologists studying wide-angle telemedicine images remotely can achieve the accuracy of in-person examinations in diagnosing retinopathy of prematurity (ROP). The study, believed to be the first of its kind, was recently published in JAMA Ophthalmology.

“A lack of access to trained ophthalmologists with experience diagnosing ROP sadly prevents many premature infants from receiving much-needed screening,” said lead researcher Michael F. Chiang, MD, of Oregon Health Sciences University School of Medicine.

The researchers concluded that there was no difference in the overall accuracy between the two evaluation methods. In-person examiners were found to be slightly better at accurately diagnosing the condition’s later-stage development, but the research team concluded telemedicine could be used to diagnose clinically significant ROP.

Oral Zeaxanthin Studied With Triple Therapy

■ Oral zeaxanthin supplementation of triple combination therapy for the treatment of neovascular AMD is comparatively effective and cost-effective to triple therapy alone according to a study published in the Journal of Clinical and Experimental Ophthalmology. Findings from the randomized, 24-month clinical trial also suggest that the addition of oral zeaxanthin further improves vision and reduces the incidence of subsequent neovascular AMD in fellow eyes, as well as the number of treatment cycles required.

Spending on AMD Drugs to Grow Sharply

■ Pharmaceutical sales in age-related macular degeneration (AMD) were estimated to be $4.9 billion across the 7 major markets in 2016. This is expected to reach $11.5 billion in 2026, at an impressive compound annual growth rate of 8.9%, according to GlobalData, a data and analytics company.

The company’s report, “PharmaPoint: Age-Related Macular Degeneration,” states that this growth will be driven by new therapies entering the market and aging of the global population, which will lead to increasing numbers of elderly people developing AMD.

GlobalData predicts the launches of 3 drugs for the treatment of geographic atrophy (GA), the late stage of dry AMD, and 3 late-stage pipeline drugs for wet AMD. In particular, the launch of drugs into the AMD market to treat dry AMD will be a large driver of growth, as there are currently no prescription medications available for these patients. RP