What’s Next? Combination Therapy for Retinal Disease

Aerpio combo seeks to impact diabetic eye disease.

BY JERRY HELZNER, CONTRIBUTING EDITOR

When the history of the effort to combat retinal diseases is written, the decade from 2005 to 2015 will surely go down as the era of anti-VEGF monotherapy, highlighted by the stunning success of Lucentis and Avastin (both Genentech, South San Francisco, CA) and Eylea (Regeneron, Tarrytown, NY). However, in recent years, more and more respected voices in the retina community are saying that the time has come to advance into the next phase of therapies — a phase in which a greater percentage of patients can be successfully treated and in which the treatment burden can be reduced.

And though interesting concepts such as gene therapy, stem cells, sustained-release drug delivery, eyedrops, and radiation are all now in human clinical trials for a variety of retinal diseases, the treatment concept closest to becoming a reality in the United States is combinations of two drugs that complement and optimize each other.

“Anti-VEGF monotherapy is reaching its limits,” says Anthony P. (Tony) Adamis, a noted anti-VEGF pioneer and global head of ophthalmology for Genentech. “Combination drugs may constitute a new paradigm for treatment.”

“We should never minimize the importance of anti-VEGF therapy but one day we may look back at it the way we look at the Wright Brothers as compared to today’s jet planes,” adds Menno van Lookeren Campagne, PhD, principal scientist, Genentech Immunology,” acknowledging the range of new therapeutic concepts that may one day supplant anti-VEGF monotherapy.

COMBINATION THERAPY: THE CURRENT LANDSCAPE

Most of the early interest in combinations has centered upon the use of an anti-platelet-derived growth factor (anti-PDGF) as the second drug in combination with an anti-VEGF to combat wet AMD. This makes sense because many studies have shown that the neovascular structure responds to anti-VEGF treatment by creating pericytes that form a sort of armor around the blood vessels. The pericytes then inhibit the effectiveness of anti-VEGF drugs. Introducing an anti-PDGF ideally strips the pericytes and allows the anti-VEGF agent to be much more effective.

Currently, Ophthotech (New York, NY) is well into three large-scale phase 3 wet AMD trials that use the company’s anti-PDGF Fovista in combination with an anti-VEGF (Ophthotech is agnostic about the choice of an anti-VEGF). Though results from these trials are still many months away, earlier phase 2 trials conducted by Ophthotech have shown the anti-VEGF/Fovista combination to be highly effective.

Other companies pursuing combinations for the treatment of retinal disease are in earlier-stage human clinical trials. Regeneron is studying an Eylea/anti-PDGF combination that can be coformulated in a single injection. Allergan (Irvine, CA) is developing a combination for wet AMD that includes an anti-VEGF called DARPin with an anti-PDGF. Allegro Ophthalmics (San Juan Capistrano, CA) has developed an integrin peptide called Luminate that is intended to stop the proliferation of unwanted blood vessels at an early stage. The company is studying Luminate in combination with Avastin for DME and Luminate monotherapy for wet AMD. In earlier preclinical trials, Luminate has been shown to demonstrate a durable response of up to six months with a single injection.

Ohr Pharmaceutical (New York, NY) has conducted a phase 2 study combining an anti-VEGF aminosterol eyedrop called squalamine with intravitreal Lucentis. A phase 3 trial is now being planned.

The above-mentioned are the most prominent — but by no means all — of the current initiatives in using combinations. More and more, the overall concept of employing combination therapy is being adopted throughout the retina community. For example, a combination of an anti-VEGF and the Ozurdex (Allergan) sustained-release corticosteroid implant is now being used routinely — and effectively — for treating DME.

AERPIO HAS A UNIQUE APPROACH

Most recently, Aerpio Therapeutics (Cincinnati, OH) has demonstrated promising results in a phase 2a clinical trial using a combination to combat DME. The company reported that its AKB-9778 (Figure 1, previous page) small molecule, which restores proper functioning of the Tie2 receptor by inhibiting a tyrosine phosphatase enzyme, had successful three-month results in combination with Lucentis.

Figure 1. The AKB-9778 molecule.

Aerpio said, in its 144-patient TIME-2 study, that the combination outperformed ranibizumab monotherapy in both reducing central subfield thickness and achieving vision gains equal to or better than three lines. Aerpio is planning a dose-ranging phase 2b study of longer treatment duration for this combination.

Aerpio CEO Joseph H. Gardner, PhD, provided a bit of company history.

“I was with Procter & Gamble when they ended their Discovery Program in 2006,” he recalls. “The program has produced two promising molecules that interested me a great deal, one of which was what we now call AKB-9778. So we purchased these molecules and formed a company called Akebia Therapeutics. Aerpio was spun off from Akebia in 2009.”

Dr. Gardner says that Aerpio is primarily focused on DME and diabetic retinopathy but that the company is also planning a pilot program in wet AMD. A unique aspect of the combination trials is that the Lucentis is delivered intravitreally and the AKB-9778 is self-administered subcutaneously, a method that diabetic patients have handled well after brief training. For the 2b combination trial, subjects will self-administer the AKB-9778 once a day rather than the twice-daily dosing used in the 2a study.

“We have spent a decade studying the function of the Tie2 receptor and are very confident that AKB-9778 is the key to combating multiple retinopathies. It is the only approach that addresses the two biggest needs in diabetic eye disease, new MOAs and a delivery method that does not require being in a doctor’s office. We have chosen to pursue diabetic eye disease first because systemic loss of Tie2 activity is so profound in these patients and these patients are used to administering subcutaneous injections (Figure 2). Regardless of the retinopathy in question we expect AKB-9778 to be additive to any anti-VEGF therapy, whether it’s the currently utilized intravitreal injections or therapies that are on the horizon such as the DARPins, ECT (Encapsulated Cell Technology, Neurotech, Cumberland, RI), or gene therapy.”

Figure 2. The patient will inject AKB-9778 subcutaneously him- or herself.

Until now, Aerpio has been funded by venture capital investors. But with the company planning a greatly expanded clinical trials program in the near future, including possible sustained-release delivery and AKB-9778 monotherapy for diabetic retinopathy, Dr. Gardner says Aerpio will require additional financing.

“We are studying all of our options,” he says. “It’s going to be an exciting year for Aerpio and the retina community as a whole. ” RP