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    Article Date: 10/1/2014

    New Approaches to Treating Wet AMDCombination therapies and gene replacement hold promise.BY JERRY HELZNER, SENIOR CONTRIBUTING EDITOR

    Almost a decade after the introduction of anti-VEGF drugs that revolutionized the treatment of wet AMD, the stage appears set for the next big advance in combating this vision-robbing disease. Among the many new treatment concepts being tested, two that have shown significant promise in clinical trials are drug combinations administered by intravitreal injection and gene replacement.

    Until now, anti-VEGF agents have been used successfully in many patients as monotherapy, but numerous studies have shown that about two-thirds of the patients who receive anti-VEGF injections fail to show 3-line vision improvement and a minority can be classified as non-responders to anti-VEGF therapy. In addition, the chronic nature of wet AMD remains an issue, with the need for regular intravitreal injections imposing a burden on both patients and retina specialists. One potential answer to reducing the injection burden is to employ complementary drug combinations (preferably delivered in a single injection), which in early and mid-stage clinical trials have demonstrated a better and/or more durable response than anti-VEGF monotherapy.

    The other encouraging area of research is gene replacement, where progress has already been made against otherwise untreatable eye diseases that result in blindness such as retinitis pigmentosa. Companies currently pursuing gene replacement believe the concept can also be used in wet AMD, where the effects of one-time gene therapy may eventually be proven to be measurable in years instead of weeks or months (See Gene Therapy: The Promise of Potential Cures).


    Five US-based companies are either currently conducting or are planning clinical trials with combination treatments for retinal disease using intravitreal injections: Allegro, Allergan, Genentech, Ophthotech, and Regeneron. All of these efforts essentially have the same primary goal: using two drugs instead of one to achieve longer-lasting and increased vision improvement with no compromise in safety. Another aim is to deliver the combination in a single injection, thereby eliminating the need for an additional injection for the second drug.

    The most advanced combination currently in clinical trials is an anti-VEGF and anti-PDGF (platelet-derived growth factor) combo. The appeal of this combination is that the anti-VEGF drug works to attack leaking blood vessels and dry the macula while the anti-PDGF drug is at the same time combating the pericytes shielding those same leaking blood vessels, thus optimizing the effectiveness of both drugs. An anti-VEGF with a proprietary anti-PDGF is currently the combination of choice for Allergan, Ophthotech, and Regeneron.

    WHERE THEY STANDOphthotech

    Ophthotech’s anti-PDGF aptamer Fovista in combination with ranibizumab (Lucentis, Genentech) has shown excellent results in both a phase 1/2a clinical trial of 22 wet AMD patients who were not responsive to anti-VEGF monotherapy and in a large phase 2 study encompassing 449 patients, where investigator Pravin Dugel, MD, reported a combination of Fovista and ranibizumab was 62% more efficacious than ranibizumab monotherapy. In this prospective, randomized, controlled trial, patients receiving the combination of Fovista and Lucentis gained a mean of 10.6 letters of vision on the ETDRS standardized chart at 24 weeks, compared to 6.5 letters for patients receiving Lucentis monotherapy. No significant safety issues arose for either treatment group in the trial.

    Ophthotech’s anti-VEGF and Fovista combination, now in three separate large-scale phase 3 studies for wet AMD, are intended to be effective with any of the current anti-VEGF therapies coupled with Fovista. The combination therapy currently requires two separate injections, given 30 minutes apart. Ophthotech recently entered into a partnership with Novartis to commercialize Fovista, once approved, outside the United States.


    Although it has had one of the most successful drug launches in history with the anti-VEGF drug aflibercept (Eylea) for wet AMD, Regeneron is not content to rest on its laurels. Recognizing that combination therapies for retinal disease were likely to be the next advance in treatment, the company moved quickly to buy the exclusive rights to an anti-PDGF antibody it had developed in its own laboratory but whose ownership was shared with Sanofi. Regeneron paid Sanofi $10 million up front and agreed to pay Sanofi up to $40 million more in potential future milestone payments and royalties to obtain these exclusive rights.

    Gene Therapy: The Promise of Potential Cures

    The appeal of gene replacement for wet AMD is that it offers the potential for cures for what has up to now been approached and treated as a chronic disease. Though evidence of the effectiveness of gene therapy in retinal diseases in humans is still anecdotal and limited, early results have been promising in treating inherited blinding diseases, which has encouraged a number of companies to enter this area of research.

    One of the most significant recent endorsements of gene replacement has come from Regeneron Pharmaceuticals, whose anti-VEGF drug Eylea (aflibercept) has become one of the leading treatments for wet AMD. Regeneron and privately owned Avalanche Biotechnologies have formed a broadly based collaboration to discover, develop, and commercialize novel gene therapy products for the treatment of eye diseases. The partnership may signal that Regeneron 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 perform 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.”

    The new collaboration covers novel gene therapy vectors and proprietary molecules, discovered jointly by Avalanche and Regeneron, 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.

    Avalanche has advanced its AAV-101 gene replacement treatment into a 40-patient phase 2a trial for wet AMD following a successful phase 1 study that demonstrated both safety and efficacy. Data from the phase 2a trial is expected next year.

    Applied Genetic Technologies Corporation has its own AAV-based platform and is targeting three orphan retinal diseases, with human trials scheduled to begin in 2015.

    The three inherited retinal diseases selected as initial targets are x-linked retinoschisis (XLRS), achromatopsia (ACHM), and x-linked retinitis pigmentosa (XLRP). AGTC based its selections on proof-of-concept data in animal models, which demonstrated that AAV gene therapy could improve the vision in animals with these diseases. These data, including successful studies with primates, suggest that similar success may be possible in treating human disease.

    “Success with primates is a major step for us,” says Sue Washer, AGTC CEO. “The primate eye is very similar to the human eye, much more so than the eyes of lower mammals used in preclinical testing. Using our AAV delivery system successfully in primates with good safety and specific targeting gives us confidence to move ahead.”

    The three diseases are classified as orphan, but combining the number of patients in the United States and Europe indicates each disease has 20,000 to 40,000 afflicted individuals.

    Ms. Washer says that because all three of the diseases have a common mechanism — mutations within genes that produce proteins that play key roles in the retina — the success of gene therapy in treating one of the diseases could translate into success in treating all three.

    It should also be mentioned that AGTC had a previous relationship with Genzyme, a division of Sanofi, in developing an AAV program for wet AMD but that partnership has ended and both companies are now working independently on their own AAV initiatives.

    Two other companies currently pursuing investigational gene replacement therapies are Hemera Biosciences and GenSight Biologics.

    Hemera has developed an AAV vector that it believes can rebalance the complement pathway of the retina with a single injection of the disease-fighting CD59 protein and provide lifetime protection against progression of either the wet or dry form AMD. In preclinical studies, an injection of CD59 was able to inhibit the production of membrane attack complex (MAC), which has been found in elevated levels in the retinas of individuals with wet or dry AMD.

    GenSight has targeted two blinding diseases Leber’s hereditary optic neuropathy (LHON) and retinitis pigmentosa. The company has initiated a phase 1/2 clinical trial for LHON using an injection of the retinal protein halorhodospin to stimulate dormant cone photoreceptors into activity with the result of restored vision.

    “Blind people can eventually retrieve sight,” says Bernard Gilly, GenSight CEO.

    The companies mentioned in this article are having no difficulty in attracting financial backing, an indication of the growing confidence in the future of gene replacement therapy. Funding sources have included venture capital, selling shares to the public and partnerships such as the recent Regeneron/Avalanche deal.

    Given that most drug and drug-delivery efforts continue to approach wet AMD as a chronic disease, the truly “disruptive” technology involved in gene replacement has significant appeal to those seeking a giant step forward in the treatment of this increasingly prevalent disease. ❑

    Regeneron recently announced its initial, early-stage combination trial with a single, co-formulated injection of its proven anti-VEGF drug Eylea and the company’s internally developed anti-PDGF drug.


    Allergan’s anti-VEGF DARPin (designed ankyrin repeat protein) drug, developed along with partner Molecular Partners, showed significant efficacy as well as a potential 3-month dosing interval in treating wet AMD as monotherapy in a phase 2 study. The priority now is to advance the anti-VEGF DARPin (abicipar pegol) into phase 3 trials. Longer-range, the companies plan to combine the anti-VEGF DARPin with an anti-PDGF DARPin in a dual-action combination therapy.

    In its most recent update on the DARPin program, Allergan said it has completed the top-line analysis of data from the stage 3, phase 2 study of abicipar pegol in wet AMD. The analysis showed that after 16 weeks, mean visual acuity improvement from baseline was 8.2 letters for abicipar pegol 2 mg, 6.3 letters for abicipar pegol 1mg, and 5.3 letters for ranibizumab. After 20 weeks, (12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection) mean visual acuity improvement from baseline was 9.0 letters for abicipar pegol 2 mg, 7.1 letters for abicipar pegol 1 mg, and 4.7 letters for ranibizumab. These data, along with data from earlier studies, were reviewed with the FDA at an end of phase 2 meeting where the FDA was in accord with Allergan’s decision to advance abicipar pegol to phase 3 clinical trials and approved the proposed phase 3 study design.

    Allegro Ophthalmics

    Allegro Ophthalmics says its integrin peptide (ALG-1001) is unique in that it is designed to shut off VEGF production at its source, producing a more durable response than anti-VEGF agents. The initial human study of ALG-1001 for wet AMD was as monotherapy. A 3.2 mg dose produced the best results, including interim data showing a mean gain of eight letters 60 days after administration of the last dose. Before the first wet AMD study, Allegro conducted a study in end-stage DME subjects in which eight of 15 individuals experienced a 3- to 5-line improvement in BCVA at 90 days off treatment.

    More recently, the company initiated a phase 1b/2a study using a combination of ALG-1001 and bevacizumab (Avastin, Genentech) to treat DME. This cohort will be compared with a group receiving bevacizumab monotherapy.


    Genentech says it will soon begin a phase 1 clinical trial of what it describes as a single-molecule, biospecific combination that will include an anti-VEGF component as well as an anti-PDGF agent or other targeted therapeutic. The two drugs would be delivered via a single injection. The company has described the science behind the biospecific combination as “elegant technology” with very low systemic exposure.

    The Potential of Combinations

    Given the strong credibility, experience, and financial resources of the major companies currently developing combination therapies, it appears as though the next significant advance in treating retinal diseases will be one or more of the intravitreally administered combination therapies mentioned in this article.

    However, the five initiatives reviewed here may just be the vanguard of the move to combinations. Other companies are sure to be heard from, perhaps employing sustained-release formats or other novel drug-delivery methods. For just one example, Novartis and Alcon recently completed a highly promising 194-patient phase 2 trial for a small-molecule anti-VEGF drug called ESBA-1008. The principal investigator for that trial, Dr. Dugel, says that ESBA-1008 has the potential to be delivered as intravitreal monotherapy, in a sustained-release implant, or possibly in a combination format. ■

    Retinal Physician, Volume: 11 , Issue: October 2014, page(s): 5-7
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