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SUBSPECIALTY NEWS

Genentech’s Promising Retina Pipeline

Top company researchers discuss major initiatives.

■ One need look no further than the past few months to the shocking failure of Opthotech’s anti-PDGF/anti-VEGF combination to see evidence that encouraging early-stage trials of investigational drugs do not easily translate into success in phase 3. With this sobering thought in mind, Genentech’s top drug researchers are cautiously optimistic as they discuss 3 promising investigational initiatives that involve potential next-generation treatments for retinal diseases. Retinal Physician spoke with Anthony P. Adamis, MD, Genentech’s Global Head of Ophthalmology, Immunology, Infectious Disease and Metabolism, Clinical Science, and Jason Ehrlich, MD, PhD, global head, Clinical Ophthalmology, about the progress of the company’s effort to deliver Lucentis (ranibizumab) in a sustained-release format; the potential of the bispecific anti-VEGF/Ang2 inhibitor RG7716, now in 3 phase 2 clinical trials, and the move into phase 3 trials for lampalizumab, a complement inhibitor with neuroprotective qualities aimed at combating geographic atrophy.

SUSTAINED RELEASE: RANIBIZUMAB REFILLABLE PORT DELIVERY SYSTEM

This sustained-release format for delivering a steady and appropriate dose of Lucentis is now in the phase 2, 220-patient LADDER study following a small phase 1 study that established proof-of-concept for the system.

The refillable implant with a drug reservoir lasting 4 months to 6 months offers the promise of a greatly reduced treatment burden for both physicians and patients. Currently, most patients receiving Lucentis require an intravitreal injection every 4 weeks to 6 weeks.

“We also see the implant as reducing the possibility of undertreatment, which has been identified in studies as a major reason for differences in real-world visual outcomes compared to those achieved in highly structured clinical trials,” says Dr. Ehrlich.

One hint that Genentech sees strong long-term potential in sustained release is that it recently purchased ForSight Vision4, the maker of the refillable implant.

“The technology of the implant is simple but elegant,” says Dr. Ehrlich. “We see it as a platform for delivering not only Lucentis, but also other ocular drugs.”

RG7716 ANG2 INHIBITING/ANTI-VEGF BISPECIFIC

Developed using its patented CrossMab technology that allows 1 antibody molecule to bind 2 different targets, Roche/Genentech’s RG7716 bispecific Ang2 inhibitor/anti-VEGF biologic is already in three phase 2 clinical studies. Roche/Genentech is now employing RG7716 in a 75-patient extended-dosing study for wet AMD called STAIRWAY. RG7716, which has attracted great interest in the retina community, is already being studied in the phase 2 BOULEVARD and AVENUE trials for DME and wet AMD, respectively.

Asked whether a small but encouraging phase 1 study in the United States helped “move the needle” in terms of building confidence in the future potential of RG7716, Dr. Ehrlich said, “It showed safety (that’s the goal for phase 1) and moved the needle for us to move into phase 2 studies, which will establish proof of concept for the mechanism.”

LAMPALIZUMAB FOR GEOGRAPHIC ATROPHY

Now in 2 fully recruited, 936-patient pivotal phase 3 trials (CHROMA and SPECTRI), lampalizumab is the furthest advanced of the company’s 3 investigational initiatives and is directed at the unmet medical need in geographic atrophy.

“MAHALO contained some interesting findings regarding genetic factors and subsets of patients but it was a smaller study and the findings have to be confirmed in the large-scale phase 3 studies,” said Dr. Adamis.

STRONG PROGRESS IN RETINAL RESEARCH

Asked to assess the progress in retinal research over the past decade, Dr. Adamis said, “It’s right up there compared to any other medical specialty.” He noted that the pace of research into potential therapies has advanced rapidly, with many new therapeutic targets, new companies, increased funding, and newly emerging areas of research such as gene therapy, gene editing, and neuroprotection.

“Five years from now, I think anti-VEGF will still be at the core of treating retinal disease, but we should also have longer-acting options and some anti-VEGF/plus combinations that we can use. The move to more personalized treatment is a positive development — the right drug and the right dose for each patient — but today we still only have 1 major category of drugs (anti-VEGF) for retinal vascular diseases, so we need to see a greater range of approved therapies to get to a more personalized approach.”

Opthea Expands Program for “Pan-VEGF” Therapy

Will raise $45 million for wet AMD and DME trials.

■ Following the release of highly positive across-the–board data from its phase 1/2a trial for its OPT-302 “Trap” therapy in wet AMD, Opthea, based in Melbourne, Australia, said it intends to raise $45 million (Australian dollars) in an equity offering to move OPT-302 into 3 additional studies. The studies will encompass a phase 2b trial for treatment-naïve wet AMD patients, a phase 2a trial for previously treated wet AMD patients, and a phase 2a trial for patients with DME. The studies will employ a “pan-VEGF” approach to evaluate the efficacy of OPT-302, which combats VEGF C and D, in combination with Lucentis (ranibizumab), which is proven effective against VEGF A.

The 51-patient phase 1/2a study was deemed “very encouraging” by lead investigator Pravin U. Dugel, MD, of Retinal Consultants of Arizona, who noted in a conference call that the 2 mg dose (both in combination with Lucentis and as monotherapy) produced significant vision gains, plus reductions in both retinal thickness and subretinal fluid, with an excellent safety profile at 12 weeks. Positive results were consistent across all patient categories, including difficult-to-treat individuals who had previously had an average of 17 anti-VEGF injections. However, Dr. Dugel cautioned that the trial was early stage and that larger studies are needed to confirm the phase 1/2a findings.

“We recognize that we are reaching a ceiling for anti-VEGF monotherapy and that 33% of patients don’t achieve significant vision gains from these drugs,” said Dr. Dugel. “The time is ripe for combination treatment that benefits a larger percentage of our patients.”

Opthea CEO Megan Baldwin, PhD, said the decision to begin a 90-patient trial in DME later this year was based on the significant reduction of subretinal fluid achieved in the phase 1/2a study.

“We know that reducing fluid is a key to combating DME, which presents an opportunity for OPT-302 for that indication,” she said.

One of the key numbers to come out of the phase1/2a trial was that in 18 treatment-naïve patients who received the OPT-302/Lucentis combination monthly for 12 weeks (3 months), the mean change from baseline was +10.8 letters. That far exceeded the mean change of +5.9 letters achieved with Lucentis monotherapy at 3 months in the pivotal phase 3 MARINA study.

IN BRIEF

Lucentis approved for all forms of DR. The FDA has now approved Lucentis 0.3 mg (Genentech) as a monthly therapy for all forms of diabetic retinopathy (DR), including DR both with and without DME. This latest approval is for DR without DME and makes Lucentis the only FDA-approved medicine for all forms of DR.

The FDA had earlier granted Lucentis Priority Review for the treatment of DR without DME based on an analysis of the Diabetic Retinopathy Clinical Research Network’s (DRCR.net) Protocol S study. This NIH-funded study compared Lucentis treatment to panretinal laser treatment in diabetic retinopathy patients both with and without DME. In the analysis that supported this approval, patients with and without DME in the Lucentis group experienced improvements in the severity of their retinopathy. Adverse events were consistent with those seen in previous studies.

Eylea extension study data. Complete 212-week data from the VIEW 1 Extension study show that mean vision gains of more than 9 letters achieved in the first 2 years of Eylea (aflibercept; Regeneron) therapy for wet AMD were largely maintained in the second 2 years of treatment. In the 323-patient extension study, the mean vision loss in the second 2 years of treatment was 2.7 letters, resulting in a mean 212-week gain of 7.1 letters. The complete data was published online in Ophthalmology Retina.

Clarifications & corrections:

■ The May 2017 table of contents lists the incorrect author for “A Review of Treatment Trials for Dry AMD.” We regret the error. The authors are Sepehr Bahadorani, MD, PhD, and Michael Singer, MD.

In the July 2016 Retinal Physician article, “Treatment of Retinal Vein Occlusion,” a portion of the text, while cited appropriately, was a direct quotation and not identified as such. The authors regret this error. This portion of the text has been set off in quotation marks in the online version of this article.

ONL Therapeutics Gets New Funding

Company has neuroprotective for RD.

■ ONL Therapeutics, a biopharmaceutical company developing novel neuroprotective therapies for preserving sight in a range of retinal diseases, said it has been awarded a commercialization readiness pilot (CRP) grant of approximately $1.0 million from the National Eye Institute to continue advancement of ONL1204, the company’s lead therapeutic candidate, into human clinical trials. In addition, the company has received new funding of more than $1 million from other investors, including Novartis and Invest Michigan.

ONL1204 is a novel, first-in-class small molecule peptide (Fas inhibitor) designed to protect key retinal cells, including photoreceptors, from cell death that occurs in a range of retinal diseases and conditions. Death of these retinal cells, both direct and via inflammatory signaling, is the root cause of vision loss and the leading cause of blindness.

ONL intends to use the funding to support the remaining ONL1204 preclinical development activities required for submission of an investigational new drug application. The company is initially developing ONL1204 for the treatment of retinal detachment, a condition for which the compound has been granted orphan drug designation by the FDA. While initial development efforts are focused on retinal detachment, ONL says preclinical in vivo data along with a growing body of literature support potential application in several additional ocular diseases, including AMD.

“The area of retinal cell protection represents a critical unmet medical need that we believe can have an important impact on the preservation of vision for patients with a range of ocular diseases and conditions,” said John Freshley, CEO of ONL Therapeutics, in a press release. “The NEI is playing a key role in research that may one day make a difference in the lives of ocular disease patients.”

ONL has assembled a blue-ribbon scientific advisory board, including highly respected members of the retina community such as Joan Miller, MD, of Harvard; Allen Ho, MD, of Wills Eye Hospital; and Peter Kaiser, MD, of the Cleveland Clinic.

IN BRIEF

First Argus II implanted in Asia. Second Sight Medical Products, a developer, manufacturer, and marketer of implantable visual prosthetics intended to provide useful vision to blind patients, said the Argus II Retinal Prosthesis System has been implanted in the first patient in Asia through an exclusive distribution partnership with Orient Europharma Co., Ltd. and with charitable support from the Hong-Lu Foundation in Taiwan. The Argus II was provided under special import permits authorized by the Taiwan Food and Drug Administration. The procedure was performed by Dr. Yih-Shiou Hwang and his team at Chang Gung Memorial Hospital in Linkou, Taiwan in a 40-year-old patient who suffers from blindness caused by retinal degeneration.

Long-term anti-VEGF and GA development. Recognizing the ongoing and unresolved debate over whether long-term treatment of wet AMD with anti-VEGF drugs plays a role in the development of geographic atrophy (GA), researchers at the Cole Eye Clinic in Lakewood, Ohio, set out to determine the incidence of GA in Cole patients who had been receiving anti-VEGF therapy for at least 4 years. No prior study of this type had gone beyond 2 years.

In this retrospective study, the researchers identified 22 eyes that were free of GA at baseline, with an average of almost 20 anti-VEGF injections. By the end of 4 years, 8 of the 22 eyes (36.4%) had developed GA.

The researchers, who presented their findings at ARVO 2017, concluded that the incidence of GA in these patients was higher than in previous shorter-term studies and also higher than in patients who had not been treated for wet AMD.

Dr. William Tasman dies. William Tasman, MD, who served as ophthalmologist-in-chief at Wills Eye Hospital from 1985 until 2009, has died. He was 87. Dr. Tasman, who developed a widely used technique to treat retinopathy of prematurity that has saved the sight of countless infants around the world, was also the founding physician of Mid-Atlantic Retina in Philadelphia. Recipient of numerous honors and awards, he was also a past president of the AAO and the Retina Society.

IN BRIEF

Study: Avoid antibiotic prophylaxis for anti-VEGF. Researchers from the University of Santiago de Campostela in Santiago, Spain, conducted the largest meta-analysis to date comparing patients who received antibiotic prophylaxis prior to anti-VEGF injections and patients who did not. Of the more than 276,000 injections reviewed, about 40% received antibiotic prophylaxis and about 60% did not.

The researchers found that patients who got the antibiotic had a 1.7x greater chance of developing endophthalmitis than those who did not. The percentages were not significantly affected by the type of procedure site — operating room or outpatient clinic. The researchers, who presented their data at ARVO 2017, concluded that antibiotic prophylaxis is unnecessary, possibly harmful, and also contributes to increasing the cost of the procedure.

Clinical trials site adds disclaimer. After 3 women suffered severe bilateral vision loss following a stem cell treatment for AMD gone wrong, the National Institute of Health has added a prominent disclaimer to the home page of its clinicaltrials.gov website cautioning visitors that the listing of a trial “does not necessarily constitute endorsement by the NIH.”

The women said they had found the BioHeart. Inc., trial listed on clinicaltrials.gov and assumed that the listing constituted a government endorsement. The treatment used fat cells that had been taken from the women’s stomachs through a liposuction procedure, then converted into stem cells and injected into their eyes. The incident was reported on March 15 in the New England Journal of Medicine.

Ohr updates schedule for trial data release. Ohr Pharmaceutical (New York City), developer of Squalamine topical therapy for the treatment of wet AMD, said it will release initial 9-month data from its phase 3 MAKO trial at year-end 2017 or early 2018. The data will encompass the 200+ patients who had entered the study before the trial was paused in March. The primary endpoint will be assessment of visual acuity at 9 months.

In addition, the company said it has raised $14.175 million from a common stock offering that will fully fund company operations into 2018.

Clearside begins combination RVO trial. Clearside Biomedical, Inc. has announced the enrollment of the first patient in a phase 3 clinical trial of Zuprata, its proprietary suspension formulation of the corticosteroid triamcinolone acetonide, used together with Eylea (aflibercept) for the treatment of macular edema associated with RVO.

The 460-patient trial, named SAPPHIRE, will assess the efficacy and safety of suprachoroidally administered Zuprata used together with intravitreally administered Eylea in subjects with RVO. After 24 weeks, patients will be followed for approximately an additional 6 months. The primary objective of this trial will be to determine the proportion of patients in each arm with a BCVA improvement of at least 15 letters from baseline at 8 weeks after initial treatment.

In related news, Clearside said recent trial results from other industry participants pursuing anti-VEGF/anti-PDGF combination therapy agents for wet AMD have led Clearside to reconsider the viability of further development of its proprietary suspension formulation of axitinib. Accordingly, while the company plans to continue to investigate axitinib and other compounds for the treatment of wet AMD, it no longer expects to submit an Investigational New Drug Application to the FDA for axitinib. Instead, Clearside will shift research and development resources away from wet AMD toward its more advanced DME program.

William J. Link, PhD, joins Allegro board. William J. Link, PhD, one of the earliest and most respected pioneers in ophthalmic industry venture capital investing, has been named to the board of directors of Allegro Ophthalmics. Allegro’s integrin peptide therapy Luminate is now in late-stage trials for both retinal disease and vitreomacular traction (VMT).

Dr. Link is a principal at Versant Ventures, one of the leading ophthalmic venture capital firms. He is also one of the founders of the Ophthalmology Innovation Summit (OIS) and has served as CEO of both Chiron Vision and American Medical Optics.

In other Allegro news, the company announced completion of enrollment in the second stage of its DEL MAR trial evaluating the safety and efficacy of Luminate in combination and as an adjunctive therapy with anti-VEGFs in patients with DME. Top-line results from the DEL MAR stage 1 monotherapy trial, in which Luminate met its primary and secondary endpoints, demonstrating equivalence to bevacizumab monotherapy with half the number of injections, were released in October.

The DEL MAR stage 2 study is a 5-month, 75-patient phase 2b trial designed to evaluate the safety and efficacy of intravitreal injections of Luminate 0.5 mg or 1.0 mg in combination with bevacizumab 1.25 mg and as an adjunctive therapy after treatment with a single treatment with bevacizumab 1.25 mg in patients with DME. The company expects to report top-line data in the first half of 2017.

Second Sight hires head of R&D. Second Sight Medical, the developer of the Argus II retinal prosthesis, has hired David Jacques as vice president of Research and Development. Mr. Jacques, who had been acting as a consultant to Second Sight, is an industry veteran with more than 30 years of experience. An electrical engineer, Mr. Jacques will focus on coordinating the company’s engineering teams as a complement to Second Sight’s continuing efforts to commercialize the Argus II.