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SUBSPECIALTY NEWS: Sustained-release drug, 12-week dosing, and more.

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Genentech Anti-VEGF Effective in Sustained Release

Most patients went 6 months without retreatment.

■ Much-awaited new data from Genentech’s 243-patient phase 2 LADDER trial demonstrates the promise of significantly reducing the current treatment burden for patients with neovascular macular degeneration. The data show that an implanted refillable reservoir, the Port Delivery System (PDS), can effectively deliver a special formulation of ranibizumab at therapeutic levels, with most patients going at least 6 months without the need for the reservoir to be refilled. The formulation of ranibizumab used in the trial is not FDA approved.

The results were presented at the recent ASRS meeting by investigator Carl Awh, MD, of Tennessee Retina in Nashville. The positive data led Genentech to announce that it is moving the PDS initiative into a phase 3 trial later this year.

Study patients implanted with the PDS were all responders to previous anti-VEGF treatment. They were randomized to monthly intravitreal injections of ranibizumab or to treatment using the PDS filled with 1 of 3 different concentrations of ranibizumab. For PDS patients receiving the 100 mg/mL dose (n=59), approximately 80% were able to go 6 months or longer until their first refill was required. Of the PDS patients receiving the 40 mg/mL (n=62) or the 10 mg/mL (n=58), 71.3% and 63.5%, respectively, were able to go 6 months or longer before their first required refill.

Dr. Awh said adverse events encountered during the trial included postoperative vitreous hemorrhages in the initial months of study enrollment, which were minimized by modifying the procedure to include laser coagulation of the choroid before incision. This step helped reduce the vitreous hemorrhage rate to about 5%. Most vitreous hemorrhages were mild and all cases were manageable. A very small number of the implant reservoirs were explanted during the trial. Some cases of conjunctival erosion were reported, but Genentech believes that an additional modification to the surgical technique can minimize that risk.

Regeneron, which developed Eylea (aflibercept), the only other FDA-approved anti-VEGF for retinal disease, also has a sustained-release initiative under way with partner Ocular Therapeutix.

Allergan DARPin Is Durable in Phase 3

12-week dosing is effective; inflammation a concern.

■ Allergan and Molecular Partners, partnering to develop a new class of drugs for retinal disease known as DARPin therapy (abicipar pegol), have released new data for 2 large-scale, phase 3 clinical trials, SEQUOIA and CEDAR, demonstrating that both the 8-week and 12-week treatment regimens met the prespecified primary endpoint of noninferiority to ranibizumab (Lucentis; Genentech).

SEQUOIA and CEDAR are identical global phase 3 studies designed to assess the efficacy and safety of abicipar compared with ranibizumab in treatment-naïve patients with wet AMD. The primary endpoint measured the proportion of treated patients with stable vision at week 52. In both studies, abicipar demonstrated similar efficacy after 6 or 8 injections, compared to 13 ranibizumab injections in the first year of this study. However, intraocular inflammation in both the SEQUOIA and CEDAR trials totaled 15% of trial participants compared to 0.6% inflammation in the ranibizumab cohort.

In the SEQUOIA study, the proportion of patients with stable vision in abicipar dosed every 8 weeks was 94.8%, stable vision with 12-week abicipar dosing was 91.3%, and ranibizumab dosed every 4 weeks achieved 96.0% stable vision. In CEDAR, the proportion of patients with stable vision receiving abicipar every 8 weeks was 91.7% and every 12 weeks was 91.2%, compared to ranibizumab dosed every 4 weeks achieving 95.5% stable vision.

In regard to the incidence of inflammation, Yehia Hashad, MD, Allergan’s vice president and global head of clinical development, ophthalmology, said, “The incidence of inflammation was broadly in line with our phase 2 studies, such as in PALM for DME. We are working to get the incidence down by optimizing our manufacturing process.”

Adverse events were similar across the 3 treatment arms. The SEQUOIA and CEDAR trials will continue on a masked basis for a second year. The filing for abicipar is planned for the first half of 2019.

New Tool Improves Screening for ROP

Six criteria used to obtain accurate predictions.

■ A cooperative research effort led by researchers at Children’s Hospital of Philadelphia (CHOP) has created a new set of criteria for more accurately determining which premature infants should be screened for retinopathy of prematurity (ROP). The recommendations have the potential to reduce the number of eye examinations being done, easing the burden of dealing with the many issues associated with premature birth. The findings were recently published in JAMA Ophthalmology.

To reduce blindness from ROP, about 70,000 babies have repeated diagnostic eye examinations in the United States each year, but only about 6% actually require laser surgery to try to prevent loss of vision. These babies are identified based upon birth weight and gestational age screening criteria. While several hospitals, including CHOP, had tried to develop new models for screening for ROP, the models were based on relatively small numbers of patients and therefore did not consistently perform well enough to replace existing screening guidelines and reduce the number of examinations performed each year.

“We knew we had to use as large a cohort as possible so that we could develop a new model that is easy to use and more accurately identifies all premature infants who are at high risk for developing severe ROP,” said Gil Binenbaum, MD, MSCE, an attending surgeon in the Division of Ophthalmology at CHOP and senior author of the study, in a news release.

The researchers analyzed 7,483 premature infants at risk for developing ROP. They identified 6 key criteria that could be used to determine whether a child should receive examinations for ROP: birthweight below 1,051 grams (about 2.3 pounds), gestational age younger than 28 weeks, and hydrocephalus, or slow weight gain during 3 time periods between ages 10 and 40 days.

Using these 6 criteria, the researchers were able to correctly predict 100% of infants with type 1 ROP, which requires treatment, while reducing the number of premature infants who would require examinations by 30.3% because they met none of the 6 criteria.

The criteria were highly sensitive and more accurate than the current guidelines, Dr. Binenbaum said. He added that the next step is to validate the results in a second large clinical study before using the criteria in practice.

Clearside Plans NDA for Suprachoroidal CLS-TA

Visual gains achieved in macular edema due to uveitis.

■ Based on highly positive phase 3 trial data, Clearside Biomedical plans to file a New Drug Application for suprachoroidal CLS-TA in patients with macular edema associated with noninfectious uveitis. CLS-TA is Clearside’s proprietary suspension of the corticosteroid triamcinolone acetonide formulated for administration to the back of the eye via the suprachoroidal space.

Of the 160 patients enrolled in the phase 3 PEACHTREE trial, 96 were randomized to receive two 4.0-mg doses of suprachoroidal CLS-TA 12 weeks apart, and 64 were randomized to undergo sham procedures at the same 12-week interval. Patients were evaluated every 4 weeks for a total of 24 weeks and 97% of those enrolled completed the full evaluation period of the trial. In the PEACHTREE trial, 47% of patients who received CLS-TA every 12 weeks gained at least 15 letters in BCVA from baseline to week 24, compared to 16% of patients who underwent a sham procedure. The mean improvement from baseline was maintained throughout the evaluation period, with 9.6 letters gained at week 4 and 13.7 letters at week 24 in the active arm, compared to 1.3 letters at week 4 and 3.0 letters at week 24 in the control arm, respectively.

In a key secondary endpoint, suprachoroidal CLS-TA resulted in a mean reduction from baseline of 153 microns in central subfield thickness at week 24 in the active arm compared to 18 micron mean reduction in the sham arm. Additional data showed resolution of macular edema in at least 50% of patients at every visit in the trial and that approximately 50% or more patients were able to read at least 70 Early Treatment of Diabetic Retinopathy Study letters (20/40 or better) in the CLS-TA arm. The vast majority (85%) of patients in the CLS-TA arm did not require rescue therapy during the study.

Acucela Drug Has Positive Data in Clinical Trial

Significant reduction in retinal thickness.

■ Acucela has announced positive clinical data on the effect of emixustat hydrochloride on retinal thickness in diabetic retinopathy (DR), a key secondary endpoint in a phase 2 study. The announcement did not address the primary endpoint, which is the change in aqueous humor concentration in 8 specific biomarkers. However, in response to a question regarding findings relating to the primary endpoint, Acucela provided the following response: “Following 3 months of once-daily treatment, there were numerical differences favoring emixustat over placebo in the change-from-baseline aqueous humor concentrations of vascular endothelial growth factor. However, these changes were not statistically significant.”

The study is a randomized, placebo-controlled trial exploring the effect of oral emixustat hydrochloride in a proliferative DR population with and without macular edema. Twenty-four subjects were enrolled in the study, in which subjects in the emixustat group were titrated to their maximum tolerated dose of up to 40 mg per day. Beyond the initial assessment of the primary endpoint, a key secondary objective was to evaluate the effects of emixustat on the change in central subfield thickness as assessed by spectral domain optical coherence tomography from baseline to day 85.

The results indicate that the emixustat group experienced a reduction in central subfield thickness when compared to placebo at a statistical significant level (difference in means of 48.1 microns), favoring emixustat. Additionally, the emixustat group experienced a reduction in total macular volume in the study eye compared to placebo that also met statistical significance (difference in means of 0.361 mm3), favoring emixustat. Both prespecified analyses included 9 patients in the emixustat group and 11 patients in the placebo group.

Acucela said these results illustrate the potential for emixustat to decrease retinal thickness in patients with DR. From these phase 2 findings, Acucela is preparing to advance the clinical program and is actively discussing research partnerships prior to the planned regulatory approval studies.

“This proof of concept is exciting as it not only addresses an important unmet need but does so through oral administration, a first for the industry,” Ryo Kubota, MD, PhD, chairman, president and CEO of Acucela, said in a company news release.

LETTER TO THE EDITOR

The relationship between genetics and AREDS supplements is highlighted in the July Retinal Physician article, “The Age-Related Eye Disease Study (AREDS) and AREDS 2 Supplements in 2018,” by Emily Y. Chew, MD, but there are few points that were not highlighted. The AREDS study (https://nei.nih.gov/amd ) has been one of the most debated studies in ophthalmology.1 It is the single randomized trial of high-dose vitamin and mineral supplements for AMD in the field. Before filing a marketing application, the FDA requires a drug developer to have adequate data from 2 large, controlled clinical trials.

Moreover, adjustments during its execution and concerns noted following the completion of the AREDS study has led to misconceptions. Many believe that AREDS supplements affected the progress of dry AMD, whereas it only showed statistical significant reduction in conversion to neovascular AMD (Table 8 and Figure 8 of AREDS Report 8). Progression of dry AMD to geographic atrophy (GA) was not affected, and the noncentral GA even showed a trend for worsening (AREDS report 8, Figure 8).1 A finding further supported by the work by Chew et al. that noted that AREDS supplements do not delay or prevent central GA.2

Furthermore, in contrast to what was printed in the July 2018 Retinal Physician article, Klein et al3 and AREDS Report 384 did not show that all genetic risk groups benefit from the AREDS supplement. Of individuals with 2 complement factor H (CFH) risk alleles, 27 progressed while on placebo and 35 did not progress. For those on AREDS, 26 progressed and 40 did not progress. These ratios are indistinguishable with a P value of 0.63 (Chi2).3 In AREDS Report #38, due to the many subgroup examined, none of the groups showed benefit or harm in a statistically significant way, although they showed trends for benefits in some genetic groups and trends for worsening in others (AREDS Report 38, Figure 1).4

Other studies that were not cited show a relationship between genetics and supplementation in determining outcomes.5,6 The study by Vavvas et al6 used a large cohort of patients to examine a specific genetics–treatment interaction identified by multiple independent researchers5,7 and showed in a multi-iterative bootstrap validation analysis with a validation group that there is likely an interaction between the CFH and age-related maculopathy susceptibility 2 (ARMS2) genotypes and the conversion to neovascular AMD (but not the progression to GA). This study included the largest assembled cohort of patients with these genotypes treated with the AREDS supplements and included a small, independent validation group to support their analysis. A key feature of their analysis that contrasts with the conclusion of Assel et al8 hinges on taking into account that AREDS Report 8 only showed conversion to neovascular AMD to be affected while atrophy was not (central and noncentral GA showing opposing trends). Although there is little doubt that high-risk participants particularly benefited from the AREDS supplements, a genetics–treatment interaction cannot be ignored.

There may be millions of people taking AREDS-based formulations. Many of these patients may see no significant benefit and some may even be experiencing an increased risk. We are entering an era where genetic profiling will be used to tailor therapy for eye disease. We have to pause and decide how to proceed in the era of increasingly personalized medicine.

- David J. Ramsey, MD, PhD, MPH, assistant professor of ophthalmology, Tufts University School of Medicine, Peabody, Massachusetts. Dr. Ramsey reports no related disclosures.

REFERENCES

  1. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436.
  2. Chew EY, Clemons TE, Agrón E, et al; Age-Related Eye Disease Study Research Group. Long-term effects of vitamins C and E, β-carotene, and zinc on age-related macular degeneration: AREDS report no. 35. Ophthalmology. 2013;120(8):1604-1611.
  3. Klein ML, Francis PJ, Rosner B, et al. CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology. 2008;115(6):1019-1025.
  4. Chew EY, Klein ML, Clemons TE, et al; Age-Related Eye Disease Study Research Group. No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology. 2014;121(11):2173-2180.
  5. Seddon JM, Silver RE, Rosner B. Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis. Br J Ophthalmol. 2016;100(12):1731-1737.
  6. Vavvas DG, Small KW, Awh CC, Zanke BW, Tibshirani RJ, Kustra R. CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation. Proc Natl Acad Sci U S A. 2018;115(4):E696-E704.
  7. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study. Ophthalmology. 2015;122(1):162-169.
  8. Assel MJ, Li F, Wang Y, Allen AS, Baggerly KA, Vickers AJ. Genetic polymorphisms of CFH and ARMS2 do not predict response to antioxidants and zinc in patients with age-related macular degeneration. Independent statistical evaluations of data from the Age-Related Eye Disease Study. Ophthalmology. 2018;125(3):391-397.

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Aura Early Data Promising in Ocular Cancer

■ Aura Biosciences has presented encouraging interim data from an open-label phase 1b/2 study of its lead program, light-activated AU-011 for the treatment of primary choroidal melanoma. The findings were presented by Amy Schefler, MD, clinical assistant professor at Weill Cornell Medical College/Methodist Hospital.

Dr. Schefler provided an update on the multicenter trial, which has been designed to evaluate the safety and efficacy of single and multiple ascending doses in 30 adult subjects with clinically diagnosed small-to-medium primary choroidal melanoma. Interim data show that in an expanded set of subjects, AU-011 continues to be well tolerated, with no related serious adverse events, no severe adverse events, and no dose-limiting toxicities observed, including the cohorts in the multiple-ascending-dose phase of the study. Adverse events were manageable with standard-of-care treatments and there have been no long-term clinical sequelae. Pretreatment visual acuity was maintained in all subjects that have been followed for 6 to 12 months.

Early efficacy results continue to be promising, with several subjects in the multiple-ascending-dose cohorts showing evidence of reduction in tumor height and 100% of the patients meeting the endpoint of stable disease at 3 months.

“A treatment that is office-based, minimally invasive, and has a low risk of side effects would be a dramatic improvement in the therapeutic landscape for this deadly disease, ” said Dr. Schefler.

EIDON FA Color Confocal Scanner Gets FDA Clearance

■ Centervue Inc. said its EIDON FA fluorescein angiography system has received FDA approval. The company says the EIDON FA combines ultra-high resolution and widefield imaging in a fully automated system that is a first in ophthalmology.

Centervue says the Eidon FA with fluorescein angiography capability obtains multiple types of high-value information from multiple imaging modalities in a simple and efficient examination, requiring minimal operator involvement.

Alcon Launches 3D Visualization System

■ Alcon introduced the new Ngenuity 3D Visualization System with Datafusion at the 2018 ASRS meeting. Alcon says the high-definition screen of the Ngenuity system will continue to provide retinal surgeons 3D visualization of the back of the eye with greater depth and detail during surgery than traditional microscopes. With the addition of the Datafusion software, Ngenuity now also offers integration with the Constellation Vision System, a leading technology platform for vitreoretinal surgery.

Apellis GA Drug Gets FDA Fast Track

■ Apellis Pharmaceuticals announced that the FDA has granted fast track designation to the company’s APL-2, a novel inhibitor of complement factor C3, as a next-generation monotherapy for the treatment of patients with geographic atrophy (GA). The FDA’s fast track program facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need, allowing important new drugs to reach the patient earlier.

Apellis plans to initiate its phase 3 program for patients with GA later this year. The phase 3 study will consist of 2 identical, prospective, multicenter, randomized, double-masked, sham-injection controlled studies to assess the efficacy and safety of multiple intravitreal injections of APL-2 in patients with GA.

Elsalys Retina Drug Shows Preclinical Efficacy

■ Elsalys Biotech announced the publication of 2 studies in Investigative Ophthalmology & Visual Science that validate the potential of its first-in-class anti-CD160 antibodies for the treatment of neovascular diseases of the eye. In view of the positive data, the company plans to begin an initial clinical trial of its anti-CD 160 antibodies in the near future.

The first study, by Henry et al, reveals that CD160 endothelial expression in retinal vessels is higher and correlates with a wide range of ocular neovascular diseases, while the second, by Menguy et al, reports the safety of the antibody and demonstrates, in relevant animal models, its therapeutic benefit alone and in combination with anti-VEGF agents, the current standards of care for retinal vascular pathologies.

The results of these two studies confirm Elsalys Biotech’s preclinical data in ophthalmology: CD160 antibodies could be used (1) for its additive or synergistic effect with the current standard of care, or (2) as alternative therapies in patients with anti-VEGF-resistant or refractory neovascular diseases.

Rare Genetic Variants Make Anti-VEGF Ineffective

■ Researchers have long known that individuals with wet AMD respond differently to anti-VEGF therapy, with approximately 10% of patients actually losing vision following anti-VEGF treatment. In an effort to determine whether genetic variability could be one key factor in individual response to treatment, researchers led by Laura Lores-Motta of Radboud University Medical Center in the Netherlands genotyped 2,058 patients for selected common variants. These individuals then received 3 monthly loading doses of bevacizumab, with the mean average vision gain of 5.1 letters after 3 months.

However, as recently reported in JAMA Ophthalmology, a very small number of patients with rare protein-altering variants in the C10ORF88 and UNC93B1 genes were associated with worse visual acuity response to anti-VEGF therapy. The effect of these rare variants was remarkably large, as patients who were shown to have variants in the C10ORF88 and UNC93B1 genes lost a mean 6 and 5 lines, respectively, on the Early Treatment of Diabetic Retinopathy Study letter chart after treatment.

The researchers concluded that identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in wet AMD.

Lombart Acquires Distributor of Preowned Instruments

Atlantic Street Capital, a private equity firm targeting entrepreneurial businesses poised for growth, said its portfolio company Lombart Instrument, a leading US distributor of ophthalmic instruments to ophthalmologists and optometrists, has acquired Enhanced Medical Services (EMS), a leading distributor of preowned ophthalmic instruments in the United States.

Optovue Gets FDA Clearance on AngioAnalytics

■ Optovue announced FDA 510(k) clearance of AngioAnalytics, the first optical coherence tomography angiography (OCTA) blood vessel measurement technology to help clinicians manage diseases that cause progressive blindness. The company also received clearance for its 3-dimensional projection artifact removal (3D PAR) software, which improves OCTA image quality and enables accurate measurement and interpretation of OCTA images. AngioAnalytics and 3D PAR are now available for purchase in the United States.

“AngioAnalytics and 3D PAR are game changers because they ‘erase’ overlying inner retinal blood vessel artifacts, allowing for better visualization and more accurate measurement of the outer retina and choroidal structures, essential in treating the abnormal blood vessel growth that leads to blindness for patients with wet age-related macular degeneration,” said Paul E. Tornambe, MD, FACS, with Retinal Consultants of San Diego.

FDA Clears Software for Self-Monitoring of AMD

■ Oculocare Medical said the FDA has granted 510(k) clearance of its Alleye mobile medical software application for the detection and monitoring of AMD. Alleye is designed to detect and characterize central and paracentral visual distortion in patients with macular conditions, including AMD and diabetic retinopathy. After medical diagnosis by an eye care practitioner, Alleye enables patients to regularly perform simple self-tests to monitor their eyesight and/or assess disease progression.

The Alleye technology has 2 components. Patients perform measurements using an app on smartphones or tablets, and doctors assess the results on a web application in their practice or clinic. Alleye has been studied in 5 scientific studies in which several hundred subjects made more than 25,000 measurements. Clinical findings have been presented at conferences and in scientific journals.

New Initiative for Sustained-Release Lucentis

■ Genentech is participating in a very early-stage collaboration with Denmark-based Ascendis Pharma to determine if Ascendis’ TransCon technology can be successfully applied in a sustained-release format for Lucentis. Genentech already has its own internal initiative to develop a sustained-release format for Lucentis. This program is currently in the phase 2 LADDER trial and employs a refillable reservoir originally developed by ForSight4 Vision. A sustained-release version of Lucentis would allow a greater interval between retreatments, which could represent an advantage over the more durable therapies for retinal disease now advancing through the investigational pipeline. RP