Combination Therapies Show Promise For Retinal Diseases

Four companies move ahead with trials.

Combination Therapies Show Promise For Retinal Diseases

Four companies move ahead with trials.


Although the advent of anti-VEGF therapies almost a decade ago for the treatment of a range of retinal diseases has been hailed as a milestone in the annals of drug development, just about everyone in the retina community — and especially doctors and patients — has looked forward to the day when at least the frequency of intravitreal injection treatments could be significantly reduced.

Until now, anti-VEGF agents have been used successfully as monotherapy, but the chronic nature of the major retinal diseases — wet AMD, DME, and RVO — remains an issue, with the need for regular intravitreal injections imposing a burden on both patients and retina specialists. One answer to reducing the injection burden is to employ complementary drug combinations in which, ideally, each drug would optimize the effectiveness of the other.

As retina specialist David Boyer, MD, of Los Angeles, explains it: “I think that we now have anti-VEGF drugs available that do an excellent job of reducing leakage and neovascularization progression.

To improve on our results in AMD, retinal vascular disease, and diabetes, we need to explore other modes of action or longer-acting anti-VEGF drugs. The anti-PDGF [platelet-derived growth factor] agents, integrin peptide inhibitors and Ang-2 inhibitors all work on different pathways that may enhance the effect of anti-VEGF or block vessel growth in a different and possibly longer way.”


Two Injections or One?

The four companies currently conducting or about to begin clinical trials with combination treatments for retinal dis-ease using intravitreal injections — Ophthotech (Princeton, NJ), Allegro, (San Juan Capistrano, CA), Regeneron (Tarrytown, NY), and Allergan (Irvine, CA) — essentially share the same goal: Using two drugs instead of one to achieve longer-lasting and increased vision improvement with no compromise in safety.

The most advanced combination in clinical trials, the anti-VEGF and anti-PDGF combo developed by Ophthotech and now in phase 3 studies, currently requires two separate injections, given 30 minutes apart. Regeneron believes it can begin its initial combination trial late this year with a single, co-formulated injection of aflibercept (Eylea) and the company's internally developed anti-PDGF drug.

It would be remiss not to mention Genentech (Roche, South San Francisco, CA), because the company is one of the pioneering and dominant players in the development of anti-VEGF drugs to combat retinal diseases. Genentech says it is currently in preclinical development with what it describes as a singlemolecule, biospecific combination that would include an anti-VEGF component as well as another targeted therapeutic. The two drugs would be delivered via a single injection. A phase 1 human clinical trial could begin next year, according to the company.

Other types of potentially useful combination therapies for retinal disease, including those involving radiation with anti-VEGF, sustained-release formats, eyedrops, or oral medications, are beyond the scope of this article.



If the competition to develop a successful combination treatment for retinal diseases were a horse race, Ophthotech would have to be considered one of the early favorites. The company has a great deal going for it, including the same top management team that successfully navigated the pioneering anti-VEGF eye drug Macugen (pegaptanib sodium, Valeant Pharmaceuticals, Bridgewater, NJ) through the FDA approval process, strong finances bolstered by venture capital, a recent successful public stock offering, promising phase 2b clinical trial data, and the recent initiation of three large-scale phase 3 trials.

Belief in the company’s combination of an anti-VEGF agent plus the anti-PDGF drug Fovista was spurred by a large phase 2b trial. Ophthotech said results from that 449-patient trial showed the statistically significant superior efficacy and durability of a ranibizumab (Lucentis, Genentech) and Fovista combination over Lucentis monotherapy for the treatment of wet AMD.

In the 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, representing a 62% additional benefit. No significant safety issues arose for either treatment group in the trial.

Trial data showed enhanced visual outcomes of the combination therapy compared to Lucentis monotherapy at every monthly time point. In addition, the relative magnitude of visual benefit continued to increase over time. The visual benefit of combination therapy compared to Lucentis monotherapy was greater at six months than at three months. The increasing divergence of the efficacy curves suggested the benefit of repeated anti-PDGF combination therapy.

Pravin Dugel, MD, of Phoenix, AZ, who served as a lead investigator in the Ophthotech phase 2b clinical trials, explains that the formation of pericytes over time can greatly diminish the effectiveness of anti-VEGF drugs, forming a protective armor that shields the neovascular complex from anti-VEGF drugs.

“The combination of the anti-VEGF and anti-PDGF agents targets the pericytes and endothelial cells, achieving more neovascular regression than either agent would have accomplished alone,” says Dr. Dugel.


Moving on to Phase 3

Based on its phase 2b data, Ophthotech has registered three large pivotal phase 3 studies with the FDA. The company will recruit a total of 1,866 treatment-naïve patients to take part in the three trials, with 622 patients designated for each of the studies. Two identical trials will each compare 311 patients treated with 1.5 mg Fovista and 0.5 Lucentis intravitreal injections to 311 receiving 0.5 mg Lucentis monotherapy. Both trials are already recruiting patients.

The third trial, which is not yet recruiting, will similarly compare a 1.5-mg Fovista injection and 2-mg Eylea or 1.5-mg Fovista and 1.35-mg bevacizumab (Avastin, Genentech) combination to Eylea or Avastin monotherapy. The primary endpoints will be improvement in visual acuity at 12 months and safety. The trials will be conducted over a 24-month period with final data expected to be available in July 2016.

Allegro Ophthalmics

Although Allegro Ophthalmics has been keeping a low profile, small but impressive early-stage human trials of its internally developed ALG-1001 integrin peptide inhibitor have suggested the company has a good chance of achieving long-term success. What makes ALG-1001 unique is that, as company COO Marc Kirshbaum explains, it attacks the “machinery” that creates neovascularization directly, as well as the signaling of VEGF itself.

“By interfering with the machinery that creates these unwanted blood vessels, ALG-1001 makes it more difficult for that machinery to come back on-line and restart,” says Mr. Kirshbaum. “We believe this is why we are seeing such a durable response of three to six months without the need for retreatment in many of the patients in the study.”

Mr. Kirshbaum attributes the company’s focus on integrin inhibition to Allegro cofounder and CEO Hampar Karageozian, MS, MBA, who has had a long career in ophthalmic drug development. Mr. Kirshbaum says other companies had previously targeted the integrins implicated in angiogenesis but were unable to develop a small enough molecule that binds sufficiently to achieve long-lasting efficacy.

The initial human study of ALG-1001 for wet AMD was as monotherapy for treatment of the disease, where a 3.2-mg dose produced the best results, including interim data showing a mean gain of 8 letters 60 days after the last dose was administered. 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 90 days off treatment.

More recently, the company has initiated a phase 1b/2a study using a combination of ALG-1001 and bevacizumab to treat DME. This cohort will be compared with a group receiving bevacizumab monotherapy. In October, Allegro announced it was starting a phase 2 study with ALG-1001 for wet AMD that may include both monotherapy and combination arms.

“We are studying ALG-1001 as both monotherapy and in combination with anti-VEGF,” says Mr. Kirshbaum. “We are looking at both because of the large population of patients with wet AMD who either are nonresponders or limited responders to anti-VEGF. We think ALG-1001 could have a beneficial effect on those patients.”

Competitors Have Deep Pockets

Mr. Kirshbaum acknowledges that Allegro is in a highly competitive arena in which the three other major players are publicly owned and have ample financial resources to stay the course. Allegro funded itself through its founders and private investors and has not taken a penny of venture capital as yet, although Mr. Kirshbaum says that Allegro will continue to evaluate its options as the clinical trials of ALG-1001 progress.

Allegro achieved a coup in obtaining an initial “eight-figure” licensing fee from Senju (Woodland Hills, CA) in exchange for the Japanese rights to its integrin peptide therapy. Allegro would receive future milestone and royalty payments from Senju if integrin peptide therapy is a commercial success in Japan.

“We are impressed with the competition but not intimidated,” Mr. Kirshbaum says. “We recognize that others may be ahead of us today in terms of advancing through clinical trials, but we strongly believe in our scientific and business approach and we recognize that patients can benefit from multiple winners in the treatment of retinal diseases.”

Mr. Kirshbaum adds that integrin peptide therapy could also have a role in treating vitreomacular traction (VMT), where early tests with ALG-1001 in severe diabetics has shown a 55% success rate in achieving total posterior vitreous detachment with one to three injections. In October, Allegro announced it was beginning a phase 2 study with ALG-1001 for VMT.


Although it has had one of the most successful drug launches in history with the anti-VEGF drug 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 (Bridgewater, NJ). Regenron 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.

Regeneron has also announced that it will soon initiate early-stage clinical trials using Eylea with its anti-PDGF drug in combination to treat wet AMD. The advantage Regeneron has is that Eyela is already proved and whatever additional efficacy the anti-PDGF drug may add would make Regeneron an even more formidable competitor in this space. In public statements, Regeneron appears committed to advancing its combination therapies but, interestingly, has shown little interest in pursuing a sustained-release delivery system. The company has expressed broad reservations about the feasibility and safety of this method of drug delivery. Sustained release is a format that Regeneron’s main current competitor, Genentech, has been actively pursuing in cooperation with companies specializing in developing sustained-release delivery concepts.

In a recent interview with Retinal Physician, Gary Sternberg, MD, therapeutic area head for ophthalmic medical affairs for Genentech, said, “new methods of drug delivery are a high priority with us. For drug delivery, we are taking multiple shots on goal.”



Allergan, in collaboration with Molecular Partners (Zurich, Switzerland), is exploring the use of a dual DARPin (designed ankyrin repeat proteins) with both anti-VEGF and anti-PDGF for treatment of wet AMD. A single molecule blocks both targets, and the companies have reported the molecule has shown efficacy and a long intravitreal pharmacokinetics half-life in preclinical animal models of disease. The full program is still in preclinical development, although an anti-VEGF DARPin developed by the partnership has already had a promising phase 2a trial.

This DARPin anti-VEGF drug proved itself to be safe and well tolerated, with no dose-limiting toxicity, after a single administration. Moreover, preliminary efficacy results from this study suggested an impressive dosing interval of up to three months.

Allergan announced earlier in the year that the anti-VEGF DARPin would not move into a phase 3 trial until an additional stage of the multi-stage phase 2 trials was completed.

“We plan to perform additional phase 2 work to more completely access safety and efficacy and to guide the phase 3 study design,” says Scott Whitcup, MD, Allergan executive vice president and chief scientific officer.

The Future of Combinations

Given the strong credibility and ample financial resources of the companies pursuing combination therapies, barring a startling and unexpected breakthrough, it looks increasingly as though the next advance in treating retinal diseases will be one or more of the intravitreally administered combination therapies.

One additional possibility is that new, more patient-friendly delivery systems will be perfected for combination therapies, allowing for a further reduction in the burden of intravitreal injections. RP