Focus on Retina

Four key advances in the battle against retinal disease

Gene therapy, combination drugs, and sustained-release platforms move closer to the clinic.

By Jerry Helzner, Senior Contributing Editor

CREDIT: SOPHIE JACOPIN / SCIENCE SOURCE

The impressive and steady advances made in the treatment of a range of retinal diseases over the past decade may be accelerating if events of the past few months are a harbinger of things to come. Four potentially important steps, recounted here, involve two major partnerships, one novel drug-delivery system and a new protocol for administering intravitreal injections.

“These are extremely positive developments that open up whole new avenues,” says Pravin Dugel, MD, of Retinal Consultants of Arizona in Phoenix. “Smaller companies with extremely exciting products are demonstrating that their concepts are worth pursuing.”

ADVANCE #1 Collaborative effort focuses on gene therapy for retinal disease

Regeneron Pharmaceuticals Inc. (Tarrytown, N.Y.) and privately owned Avalanche Biotechnologies Inc. (Menlo Park, Calif.) have formed a broadly based collaboration to discover, develop and commercialize novel gene therapy products for the treatment of ocular diseases. The partnership may signal that Regeneron, the developer of Eylea (aflibercept), now views a range of retinal diseases as potentially curable rather than chronic.

“We feel that the eye is one of the most attractive places to do gene therapy,” said George Yancopoulos, MD, PhD, Regeneron’s chief scientific officer. “The advantages include the ability to apply the therapy locally, deliver the gene therapy to the specific cells of interest and directly observe its effect. Ultimately, the goal would be to have long-lasting effects or even cures.”

Next-generation platform

The new collaboration covers novel gene therapy vectors and proprietary molecules, discovered jointly by Avalanche (Menlo Park, Calif.) and Regeneron (Tarrytown, N.Y.), and developed using the Avalanche Ocular BioFactor, an adeno-associated virus (AAV)-based, proprietary, next-generation platform for the discovery and development of gene therapy vectors for ophthalmology.

The collaboration covers up to eight distinct therapeutic targets. Regeneron will have exclusive worldwide rights for each product it moves forward in clinical development. In addition, Avalanche has the option to share in development costs and profits for products directed toward two therapeutic targets selected by Avalanche.

As part of the agreement, Regeneron has a time-limited right of first negotiation for certain rights to AVA-101, Avalanche’s gene therapy product targeting vascular endothelial growth factor currently under development for the treatment of wet AMD, upon completion of the ongoing phase 2a trial.

ADVANCE #2 Anti-VEGF, anti-PDGE combination therapy

Novartis, the Swiss company that owns the international rights to the anti-VEGF drug Lucentis (ranibizumab, Genentech, South San Francisco, Calif.), has acquired the foreign rights to the promising anti-PDGF drug Fovista from Ophthotech (New York). The licensing deal gives Ophthotech a major partner that can bring its expertise to advancing the development of combination therapies to treat retinal disease.

Fovista, an aptamer currently in three large-scale phase 3 trials, is designed to prevent platelet-derived growth factor (PDGF) from binding to its natural receptor on pericytes, causing pericytes to be stripped from newly formed abnormal blood vessels. Left unprotected, the endothelial cells are highly vulnerable to the effects of anti-VEGF drugs.

Fovista is years away from commercialization, but delivered good results in its earlier trials. Ophthotech reported that in a phase 2b study of 449 patients, a combination of Fovista and Lucentis, each delivered by separate intravitreal injection, produced significantly greater vision gains at 24 weeks than Lucentis monotherapy. The combination achieved a mean gain of 10.6 letters, while Lucentis monotherapy demonstrated a mean increase of 6.5 letters, according to the company.

Proprietary coformulation

Novartis says it is developing a proprietary coformulation of Fovista and a Novartis proprietary anti-VEGF treatment that can be delivered in a single injection. If Novartis can deliver on coformulating the two drugs, it would overcome a major hurdle that has constituted a challenge for Ophthotech.

Ophthotech will continue to lead the global Fovista phase 3 wet AMD pivotal clinical program, which it says is expected to have initial, topline data available in 2016.

ADVANCE #3 Sustained-release implant to deliver anti-VEGF therapy

Results of the first clinical study of a sustained-release implant to deliver Lucentis were described as “encouraging” by Roman Rubio, MD, head of ophthalmology at Genentech. The study found 0.5-mg dosing from a refillable reservoir (ForSight Vision4, Menlo Park, Calif.) produced vision gains comparable to intravitreal injections of the same drug.

“Almost 50% of the 20 patients in the study were able to show 3-line gains at 12 months,” says Dr. Rubio. “The average number of refills per patient was 4.8 over 12 months, or a refill every two to three months done in the office. Sustained-release offers the promise of equivalent exposure to monthly dosing of Lucentis without the need for frequent clinic visits or injections.”

Dr. Rubio presented data from the phase 1 proof of concept study in April at the World Ophthalmology Congress in Tokyo. He said results from the study, conducted in Latvia, were positive overall and spurred plans for a larger phase 2 study, which will be conducted at sites in the United States.

Need for implant modification

“We will be making some improvements in the implantation technique and will also modify some of the implantation tools for the phase 2 study, as the serious adverse events we saw were primarily attributed to implantation of the reservoir,” Dr. Rubio says.

The phase 2 trial may also encompass higher doses of Lucentis to extend the interval between refills to a target goal of four months. However, like many in the retinal community, Genentech would like to better understand the relationship between anti-VEGF treatment and geographic atrophy (GA) and is currently analyzing data from the HARBOR trial to determine whether a relationship between the two indeed exists.

1 Neovascular AMD manifests with the development of choroidal neovascularization. Visual loss in AMD ensues with the possible development of edema, hemorrhage, atrophy, and/or fibrosis.

2 Ocriplasmin, here in its molecular form, contains a recombinant protease that dissolves the proteins binding the vitreous to the macula and causing traction to induce vitreous liquification.

Results from the CATT study showed an association between an increased incidence of GA with more frequent dosing of anti-VEGF drugs.

“The GA question has yet to be answered,” Dr. Rubio says. “The answers will become more clear with further data.”

In contrast to Regeneron, which has publicly stated that it has little interest in sustained-release formats for its successful drug for retinal disease, aflibercept (Eylea), Genentech has a group focused on sustained-release ocular delivery. Dr. Rubio says the company is exploring other drug-delivery formats in addition to the ForSight refillable reservoir.

ADVANCE #4 Fine-tuning indications for VMA, VMT treatment

Two recent studies, one conducted by an arm of the American Society of Retina Specialists, sought to identify the incidence and types of adverse events associated with Jetrea (ocriplasmin, ThromboGenics, Iselin, N.J.), a proteolytic enzyme the FDA approved for treatment of symptomatic vitreomacular adhesion and vitreomacular traction.

Investigators presented their findings at ARVO 2014 in Orlando, Fla. One study, which the Therapeutic Surveillance Committee (TSC) of the ASRS conducted, reviewed adverse event reports for both pre-marketing (999 injections) and post-marketing (4,387 injections) use of ocriplasmin.¹

The study identified eight categories of adverse events. Acute reduction in visual acuity, electroretinogram changes, dyschromatopsia, retinal tears and detachments, lens subluxation or phacodonesis, impaired pupillary reflex, and retinal vessel findings were reported in both the pre- and post-marketing experiences. Ellipsoid zone (inner segment/outer segment) findings were only reported in the post-marketing experience. Rates of post-marketing reports were lower than in the pre-marketing data. Adverse events were transient, and their characteristics were similar between the pre- and post-marketing experience.

Pre-marketing safety profile holds up

The TSC concluded that the post-marketing safety profile following ocriplasmin administration has so far been consistent with the pre-marketing clinical trial program. The TSC urged all practitioners to practice informed management of patient expectations and active post-market surveillance.

The second study, a web-based survey conducted by researchers at Rutgers Robert Wood Johnson Medical School, New Brunswick, N.J., drew 270 responses covering a total of 1,056 eyes treated with ocriplasmin.²

Respondents identified the following adverse events they had encountered in using Jetrea:

• Acute decline in visual acuity (179 eyes, 17%).

• Development of submacular fluid or serous retinal detachment (108 eyes, 10.2%).

• Dyschromatopsia (96 eyes, 9%).

• Progression of VMT to macular hole (92 eyes, 8.7%).

• Retinal detachment (28 eyes, 2.7%).

• Retinal tear (21 eyes, 2%).

• Afferent pupillary defect (19 eyes, 1.8%).

• ERG abnormalities (6 eyes, 0.6%).

• Crystalline lens instability (4 eyes, 0.4%).

Safety study under way

The researchers concluded, “Although the incidence of many ocular adverse events reported in this study are comparable to those reported in the phase 3 registration trials, additional phase 4 safety studies are warranted to better understand the pathophysiology of ocular adverse events of ocriplasmin.”

In the meantime ThromboGenics has begun conducting a large-scale and ongoing safety study of Jetrea, encompassing reports from five different adverse event registries. These will include the company’s own 1,500-patient ORBIT study. Dr. Dugel and Carl Regillo, MD, will oversee the initiative and issue regular reports on their findings.

The goal of this initiative is to further characterize the nature of the adverse events associated with ocriplasmin, identify potential at-risk patients and help inform additional safety studies. OM

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