Article

SUBSPECIALTY NEWS: Prophylactic Eylea, combination therapy for wet AMD, plasma kallikrein inhibitors, bionic eye, and more.

Related

Prophylactic Eylea to Prevent Wet AMD

Two-year results show little benefit.

■ Can injections of an anti-VEGF agent act as a prophylactic to prevent eyes with dry AMD from converting to wet AMD? This is clearly an idea worth pursuing, but 2-year results from the 76-patient PRO-CON study reported recently at the American Society of Retina Specialists meeting by Jeffrey Heier, MD, proved inconclusive.

PRO-CON is a prospective, single-blind, randomized study investigating prophylactic quarterly intravitreal aflibercept (Eylea; Regeneron) injection to prevent conversion to wet AMD in 128 high-risk dry AMD eyes (defined as intermediate AMD in the study eye and wet AMD in the fellow eye).

At the 2-year mark, 9% of the patients in the aflibercept arm and 11% in the sham arm had converted to wet AMD. The majority of the conversions were in the first 12 months of the study, with more conversion in early disease of less than 2 years duration.

Conversion to wet was not statistically significant between the 2 groups, with no difference in BCVA change or mean change in GA between groups. No new safety signals were observed, consistent with previous studies of anti-VEGF. Dr. Heier concluded that quarterly aflibercept prophylaxis did not affect conversion using this approach. There may be potential for prophylaxis in longer-acting approaches.

Opthea Combination Therapy Combats Wet AMD

Phase 2b trial meets all endpoints.

■ Australia-based Opthea Limited said phase 2b results of a study of a “pan-VEGF” approach against VEGF A, C, and D using OPT-302 combined with ranibizumab (Lucentis; Genentech) showed that the combination met the primary endpoint of superiority in mean visual acuity gain at 24 weeks compared to ranibizumab alone in treatment-naïve patients with wet AMD. OPT-302 is a soluble form of VEGFR-3 or “trap” molecule that blocks the activity of 2 proteins (VEGF-C and VEGF-D) that cause blood vessels to grow and leak, processes that contribute to the pathophysiology of retinal diseases. Opthea is developing OPT-302 for use in combination with inhibitors of VEGF-A, such as ranibizumab and aflibercept (Eylea; Regeneron).

The randomized, double-masked, sham-controlled clinical trial recruited 366 wet AMD patients who were allocated to 2 intravitreal doses of OPT-302 (0.5 mg and 2.0 mg), administered monthly in combination with 0.5 mg ranibizumab over 24 weeks vs a control group that received standard of care 0.5 mg ranibizumab administered monthly.

Patients administered 2.0 mg OPT-302 combination therapy gained a mean of 14.2 letters of vision from baseline on the ETDRS standardized eye chart at 24 weeks, compared to 10.8 letters in the control group, a statistically significant benefit of 3-4 letters. The 0.5 mg lower-dose cohort receiving OPT-302 in combination had a similar outcome to the control group.

Secondary endpoint results were also supportive of the primary outcome. Of those in the 2.0 mg OPT-302 combination group, 45.0% gained 15 or more letters from baseline to week 24, compared to 40.5% of patients in the ranibizumab control group. The proportion of patients gaining 10 or more letters was 70% in the 2.0 mg OPT-302 combination group vs 57.8% in the control group. Stable vision was achieved in 99.2% with the 2.0 mg OPT-302 combination treatment, compared to 96.7% of the control group.

“To achieve this highly significant result and meaningful additional clinical efficacy with OPT-302 in a trial powered for superiority, against a Lucentis standard of care control arm that outperformed relative to prior published studies, is a great achievement,” said Pravin Dugel, MD, managing partner of Retinal Consultants of Arizona and clinical professor at the University of Southern California Roski Eye Institute, Keck School of Medicine, and study investigator on the trial. “OPT-302 has the potential to be a game changer in the treatment landscape, not just for wet AMD but also for other debilitating retinal vascular diseases where there remains a significant unmet medical need for more efficacious therapies. The phase 2b trial results demonstrate for the first time that clinically meaningful gains in visual acuity approaching 3 lines of vision (15 letters) may be possible with OPT-302 combination therapy targeting a novel mechanism of action.”

Oxurion PKal Inhibitor Shows Early Promise

Visual gains maintained at 3-month mark.

■ Oxurion NV reported positive top-line safety and efficacy data from a phase 1 study with THR-149, a novel plasma kallikrein (PKal) inhibitor for the treatment of diabetic macular edema (DME). THR-149 has been developed in partnership with Bicycle Therapeutics. Oxurion holds the exclusive license to the PKal-inhibitor portfolio originating from this partnership.

Plasma kallikrein, an enzyme, is an important component of the body’s inflammatory response and in excess can lead to increased vascular permeability, edema, and inflammation. The open-label, multicenter, nonrandomized Oxurion trial evaluated the safety of a single intravitreal injection of THR-149 at 3 ascending-dose levels in 12 subjects with visual impairment due to center-involved DME. Top-line data from the trial show that THR-149 is well tolerated and safe. No dose-limiting toxicities nor drug-related serious adverse events were reported.

The study also looked at efficacy, including changes to the patient’s best-corrected visual acuity (BCVA). A rapid onset of action was observed from day 1, with an increasing average improvement in BCVA of up to 7.5 letters at day 14. This activity was maintained with an average improvement in BCVA of 6.5 letters at day 90 following a single injection of THR-149.

In addition to Oxurion, several other companies are now studying PKal inhibition as a therapy for diabetic eye disease. These include KalVista, currently in clinical trials for the treatment of DME, Verseon, which is in the preclinical stage with oral dosing, and Rezolute, lso in a preclinical stage.

Australian “Bionic Eye” Progresses Through Clinical Trials

Retinal prosthesis targets end-stage RP.

■ Initiated in 2010 as an Australian government research project, the “bionic eye” retinal prosthesis has been making steady progress through clinical trials, with 4 patients having received the implant in 2018 now using the device unsupervised in their own environments (home, work place, shopping) to accomplish such tasks as sorting laundry, avoiding obstacles, and navigating their nearby neighborhoods. The patients have shown continued improvements on objective measures over time.

The “bionic eye” utilizes a camera on a pair of glasses that captures an image of the real world that is processed and then delivered to an array of electrodes implanted in the suprachoroidal space. The electrodes stimulate the retina and visual processing pathway. Prior to stimulating the electrodes, the image signal is processed by software using sophisticated algorithms to optimize functional outcomes.

Similar to the FDA-approved Argus II from Second Sight Medical, the bionic eye is intended to provide a level of functional “vision” for individuals with profound vision loss from end-stage retinitis pigmentosa. However, Bionic Vision Technologies believes its approach has several advantages in safety and efficacy. Among them are a less-invasive suprachoroidal surgical location within the eye wall that does not touch the retina. The bionic eye also does not interfere with any preoperative residual vision, and the surgery does not involve entering the globe.

Initial funding for the bionic eye was a $50 million (Australian) grant from the Australian Research Council to the research consortium, Bionic Vision Australia. This grant was matched by in-kind contributions of time and resources by consortium members, bringing the total funding between 2010 and early 2017 to more than $100 million Australian. Additional new funding has since been provided.

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Kodiak Sciences Drug Promising in Wet AMD, DME, and RVO

■ Kodiak Sciences announced positive interim results from the ongoing phase 1b study of KSI-301, its investigational intravitreal anti-VEGF antibody biopolymer conjugate in patients with anti-VEGF treatment-naïve wet AMD (n=17), DME (n=8), and macular edema due to RVO (n=10). The results were presented by Pravin U. Dugel, MD, an investigator in the study, at the recent American Society of Retina Specialists (ASRS) meeting. Across all 3 diseases, strong improvements in BCVA and central subfield thickness were observed over 12 weeks, particularly in RVO. The efficacy data presented at ASRS include outcomes from 35 patients in the study who had reached the week-12 visit. In the study, patients are being treated with 3 monthly doses of either 2.5 mg or 5 mg KSI-301 and followed for 7 months, with additional treatments according to protocol-specified retreatment criteria.

“In addition to vision and anatomic improvements, we have observed encouraging signs of disease modification,” said Jason Ehrlich, MD, PhD, Kodiak’s chief medical officer and chief development officer. “Using OCT angiography we observed normalization of retinal vascular flow in an RVO patient seen as early as 1 week after the first dose and reduction in choroidal neovascularization size and vascular flow rate in a wet AMD patient. In a DME patient with proliferative retinopathy, we observed conversion to nonproliferative retinopathy and a 2-step improvement in diabetic retinopathy severity score at the 12-week assessment.”

FDA Approves Eylea Prefilled Syringe

■ The FDA has approved the Prior-Approval Supplement for the Eylea (aflibercept) injection prefilled syringe. The 2 mg, single-dose, sterilized prefilled syringe provides physicians with a new way to administer Eylea that requires fewer steps compared to using vials. Market supply of the prefilled syringe is expected to be available to physicians this year.

“With 8 pivotal phase 3 trials and millions of injections used around the world, Eylea sets a high bar for visual acuity and safety across multiple retinal diseases, including wet AMD and diabetic eye diseases,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer of Regeneron.

Aura Therapy Preserves Vision in Eye Cancer

■ Aura Biosciences presented 2-year data at the recent American Society of Retina Specialists meeting on its AU-011 light-activated therapy for uveal melanoma, showing good vision preservation and tumor control in a large majority of the study’s 36 subjects. Results have been superior to radiotherapy in early follow-up. The therapy has been well tolerated, with the most prevalent side effect being inflammation that was resolved with standard of care treatment. Two subjects experienced vision loss of greater than 15 letters.

Yutiq Reports Effectiveness in Phase 3 Trial

■ EyePoint Pharmaceuticals presented data at the recent American Society of Retina Specialists meeting supporting the efficacy of the company’s Yutiq (fluocinolone acetonide intravitreal implant) 0.18 mg 3-year microinsert for chronic, noninfectious uveitis affecting the posterior segment of the eye. Results at the 36-month follow-up of the phase 3, 129-patient trial of Yutiq demonstrated that visual acuity gains of 3 lines or more occurred in 33.3% of patients with Yutiq vs 14.7% with sham, and visual acuity losses were seen in 1.4% of patients with Yutiq and 8.8% with sham. Change in BCVA at 36 months showed an increase of 9.1±13.0 letters for Yutiq and an increase of 2.5±14.2 letters in sham-treated eyes.

In the subset of patients with greater central subfield foveal thickness at baseline, the proportion of eyes gaining 3 or more lines of vision was higher in Yutiq eyes than in sham eyes (46.3% vs 16.7%). Similarly, 3 or more lines of vision gains were seen in the subset of patients with macular edema at baseline (50.0% for Yutiq; 21.7% for sham) and patients with ≥1+ vitreous haze at baseline (55.9% for Yutiq; 26.7% for sham).

Port Delivery System Overcomes Major Hurdle in Trial

■ The Genentech Port Delivery System, a refillable implant for the 6-month, sustained-release delivery of a customized form of ranibizumab, is currently being studied in the 300-patient phase 3 ARCHWAY trial. However, before phase 3 could be initiated, a problem with vitreous hemorrhage from the insertion procedure in the phase 2 LADDER trial had to be overcome. A presentation by Mark Wieland, MD, at the recent American Society of Retina Specialists meeting described how Genentech addressed the problem.

Genentech quickly initiated a major animal study and found that the pars plana was the major source of the bleeding. After studying a number of possible “fixes,” company researchers determined that edge-to-edge laser ablation of the pars plana with a 5.32 nm laser to attain hemostasis was the most effective way to mitigate the problem. Other, smaller changes to the insertion procedure were also implemented, along with robust surgical training to promote procedural consistency in the phase 3 ARCHWAY trial. Once the implant insertion procedure was changed, the rate of vitreous hemorrhage dropped from 11 of 22 (50%) to 4 of 157 (4.5%).

CPT Code for Automated DR Screening

■ Artificial intelligence (AI) diagnostics company IDx said the AMA has accepted a new category 1 CPT code for automated point-of-care retinal imaging. This new code, submitted by the AAO with the support of IDx, facilitates correct billing of IDx-DR, an FDA-cleared autonomous AI system that detects diabetic retinopathy.

“This represents a significant milestone for autonomous AI in health care,” said Michael Abramoff, MD, PhD, founder and CEO of IDx, in a company news release. “By accepting this new CPT code, the AMA’s CPT Editorial panel has established a billing code for an AI-enabled system, which can help foster further adoption of autonomous AI technologies in health care.”

Portable OCT Developed at Duke

■ Biomedical engineers at Duke University have developed a low-cost, portable OCT scanner that has the potential to bring the vision-saving technology to underserved regions throughout the United States and abroad.

Thanks to a redesigned, 3D-printed spectrometer, the scanner is 15 times lighter and smaller than current commercial systems and is made from parts costing less than one-tenth the retail price of commercial systems — all without sacrificing imaging quality.

In its first clinical trial, the new OCT scanner produced images of 120 retinas that were 95% as sharp as those taken by current commercial systems, which was sufficient for accurate clinical diagnosis. The results appeared online in Translational Vision Science & Technology.

Glaukos to Acquire DOSE Medical

■ Glaukos Corporation has entered into an agreement to acquire DOSE Medical Corporation for $2.5 million in cash, plus performance-based consideration upon achievement of certain regulatory approvals and commercial milestones. Upon consummation of the acquisition, DOSE Medical will become a wholly owned subsidiary of Glaukos. DOSE Medical is developing multiple microinvasive, bioerodible, sustained-release drug-delivery platforms designed to be used in the treatment of various retinal diseases, including AMD and DME.

Dr. Shields Honored With Howe Medal

■ Jerry A. Shields, MD, director emeritus and founder of the Wills Eye Hospital Ocular Oncology Department, professor of ophthalmology, and recipient of The Brady Shields Endowed Chair, received the 2019 Lucien Howe Medal from the American Ophthalmological Society. Dr. Shields received the award for his distinguished service throughout his career to the fields of ocular oncology and ophthalmology.

Dr. Shields has been a leader for more than 50 years in the care and management of patients with ocular tumors and eye disease worldwide. Dr. Shields has diagnosed and treated countless patients with tumors of the eyelids, conjunctiva, intraocular structures, and orbit — helping them to become “cancer free.”

First awarded in 1922, the Howe Medal is international in scope and has recognized some of the most lauded and influential ophthalmologists in history.

Zeiss Gets Clearance for Clarus 700 Imaging System

■ Zeiss announced that it has received 510(K) clearance from the FDA for the Clarus 700 imaging system. Zeiss says the Clarus 700 is the first high-resolution, ultrawidefield imaging with true color and a complete range of fundus imaging modalities, including fluorescein angiography (FA). The high-resolution and high-contrast images of the FA from the Clarus 700 allow clinicians to capture the smallest details from the macula in early phase to the periphery in late phase of FA. Powered by Broadline Fundus Imaging, the ZEISS Clarus 700 captures images that closely resemble the natural coloration of the fundus as it appears under direct clinical observation.

Permanent J Codes Assigned for Yutiq and Dextenza

■ EyePoint Pharmaceuticals said that the Centers for Medicare and Medicaid Services (CMS) has assigned a specific and permanent reimbursement J-code, J7314, through the Healthcare Common Procedure Coding System (HCPCS) for Yutiq (fluocinolone acetonide intravitreal implant) 0.18 mg 3-year microinsert for chronic, noninfectious uveitis affecting the posterior segment of the eye. The code will become effective on October 1, 2019.

Also, Ocular Therapeutix said that CMS has assigned a permanent reimbursement J-code for Dextenza (dexamethasone ophthalmic insert) 0.4 mg for the treatment of ocular inflammation and pain following ophthalmic surgery. The code is J1096, and will also become effective on October 1, 2019.

Clearside Licenses Suprachoroidal Injector to Aura

■ Clearside Biomedical, which has pioneered the concept of drug administration via the suprachoroidal space, has entered into a worldwide licensing agreement with Aura Biosciences for the use of Clearside’s Suprachoroidal Space (SCS) Microinjector to deliver Aura’s proprietary drug candidates into the suprachoroidal space for the potential treatment of certain ocular cancers, including choroidal melanoma. Clearside is using suprachoroidal administration for its own investigational drug Xipere for macular edema associated with uveitis, for which it has completed a phase 3 clinical trial.

Aura is developing a novel class of therapies, viral nanoparticle conjugates, designed to selectively bind and eliminate cancer cells without damaging surrounding normal tissues. Aura is licensing Clearside’s proprietary SCS Microinjector as a potential nonsurgical alternative to intravitreal delivery of Aura’s proprietary anticancer drug candidates, which may enable the delivery of higher concentrations using a lower dose to the choroid and adjacent areas.

B+L Introduces Infusion System for Retina Surgery

■ Bausch + Lomb has launched the FreeFlow infusion system for retina surgery. The company says the new offering allows for higher level of infusion flow compared to previous generation infusion lines to support the efficient vitreous removal provided by the company’s Bi-Blade dual-port vitrectomy cutters and Vitesse hypersonic vitrectomy system, both designed exclusively for use with the Stellaris Elite vision enhancement system. In the FreeFlow system, the infusion line goes over the top of the trocar cannula rather than inside of it, significantly increasing the size of the inner lumen and allowing surgeons to increase inflow by 40%. Unlike a traditional infusion line that extends vertically off the top of the cannula, this line extends at a 30-degree angle to the cannula, providing the surgeon better access to the eye with less torqueing to direct infusion more centrally.

Oral Drug Shows Promise in Refractory Wet AMD

■ Alkahest, Inc. said its 25-patient phase 2a trial of AKST4290, an orally administered small-molecule CCR3 inhibitor, met the primary endpoint of achieving an increase in BCVA in patients with refractory wet AMD, or disease no longer responding to treatment with anti-VEGF injections. AKST4290 was also found to be safe and well tolerated, meeting the secondary endpoint of the trial. The results were presented at the recent ASRS meeting.

Twice-daily administration of AKST4290 for 6 weeks was safe and well tolerated, with 72% of patients showing maintenance or improvement in BCVA. The mean change across 6 weeks of treatment in this refractory population was an increase of +2.0 letters gained according to the ETDRS system. Eight percent of subjects gained 10 or more letters. AKST4290 was administered as a monotherapy without concomitant use of anti-VEGF therapy. There were no serious adverse events or adverse events leading to discontinuation of treatment.

Registry Initiated for Yutiq Use

■ EyePoint Pharmaceuticals is initiating a registry study to collect real-world data on Yutiq (fluocinolone acetonide intravitreal implant) in partnership with the Center for Ophthalmic Bioinformatics at the Cleveland Clinic Cole Eye Institute under Rishi P. Singh, MD. Participating clinicians will report cases via a HIPAA-compliant, web-based form, which will also allow for pooling of data into a large patient cohort. This will allow investigators to generate ideas for analyses to elucidate disease mechanisms and their indices for optimal treatment outcomes with Yutiq. The results will be presented at meetings and published in the medical literature with the aim of better understanding the real-world, long-term use of Yutiq and to help with treatment decision-making in noninfectious uveitis affecting the posterior segment. RP