Exploring the Keys to Combination Therapies in Retina

OIS@AAO - Combination Therapies for Wet AMD & DME

The keys to developing combination therapies to treat retinal diseases lie in clinicians being able to better identify biomarkers for disease progression, developing strategies for staging disease, and finding a place for agents that act on disease pathways other than vascular endothelial growth factor, say ophthalmology leaders.

Participants at a breakfast panel at OIS@AAO explored a host of combination strategies for treatment of age-related macular degeneration (AMD) and diabetic macular edema (DME) in phase II and III studies.

On the Precipice of Change
“We really are on the precipice of changing our paradigm; the reason for that is in many ways our treatment strategy has hit the ceiling,” says Pravin Dugel, MD, in that treatments are limited to intravitreal anti-VEGF agents. Dr. Dugel is managing partner of Retinal Consultants of Arizona and a clinical professor at the University of Southern California Eye Institute, Keck School of Medicine.

To break through that ceiling for AMD, he’s looking forward to seeing results of platelet-derived growth factor (PDGF) inhibitors in trial, while he thinks targeting the ANG-TIE2 pathway holds the most promise for diabetic retinopathy and macular edema.

Likewise, Donald D’Amico, MD, also thinks PDGF inhibitors hold great promise for treatment of non-diabetic retinal disease. “They have demonstrated the strongest preregistration trial data of any of the compounds,” says Dr. D’Amico, ophthalmology chair at Weill Cornell Medical College in chief of ophthalmology at New York-Presbyterian Hospital.

Dr. D’Amico notes that the diseases retina specialists have treated with anti-VEGF therapy develop via three different pathways: AMD via an inflammatory pathway that involves mechanical properties across the Bruch’s membrane, diabetes via a metabolic disorder and retinal vein occlusion via a mechanical cascade. As thinking evolves to acknowledge the unique pathogenesis of different retinal disease, clinicians will be more welcoming of combination therapies to treat them.

Reading the Glaucoma Playbook
Panel moderator Joseph Schwartz says the outlook for new retinal disease treatments is falling into two camps: those who believe longer-acting VEGF inhibitors are the answer, and those who think new drugs and regimens are in order. Mr. Schwartz is managing director, biotechnology, for Boston equity firm Leerink.

Treatment is moving away from what Knut Sturmhoefel, head of business development and licensing in retina for Novartis, calls a uni-causal approach to a multi-faceted approach. “We’re hitting an era that is similar to oncology where clinicians will try to approach the disease from different angles with different modalities,” he says. “That will lead to more personalized approaches to therapy.”

Dr. D’Amico says that longer-acting anti-VEGF therapy is unlikely to act on all the different mechanisms of retinal disease, and Dr. Dugel says such drugs are “part of the solution.” Combination therapy makes sense because the longer vessels are exposed to anti-VEGF agents, the more resistant they become treatment, Dr. Dugel says.

But developers of retina drugs may need to take a page out of the glaucoma playbook, says Dr. D’Amico. “We’re going to have new agents, second agents, third agents, and I’m not sure we understand how they work in combination,” he says. To understand how glaucoma drugs work in combination, investigators “broke them up, we went back to their individual components,” he says.

A key element in understanding combination therapies for retinal disease is learning how the disease develops in stages, not unlike the approach oncologists use for breast cancer. “With DME, we know there are different stages and they behave differently,” Dr. Dugel says. “The same with AMD. We’ll learn to stage these diseases. We’ll learn to have appropriate biomarkers depending on the stage.”

Looking for Biomarkers
But if drug therapy gets segmented, Mr. Schwartz says, that raises another question: Do the tools exist for identifying biomarkers of how patients will respond to therapy?

One such biomarker, Dr. Dugel says, is permeability of the blood vessels in the retina. The parallel evolution of optical coherence tomography (OCT) and anti-VEGF therapy is “serendipity” in that respect, he says. “OCT is a fantastic barometer for measuring vascular permeability and anti-VEGFs treat vascular permeability.”

But Dr. D’Amico describes himself as a “skeptic” about the need for frequent OCT imaging during treatment. He recalls the early days of photodynamic therapy for AMD treatment and how investigators relied fluorescein angiography to measure results. “We couldn’t figure out on fluorescein what was going on with those lesions,” he says. “There’s just not a reliable biomarker for everything that happens in the retina.”

Dr. Dugel acknowledge that clinicians have a tendency to rely on OCT findings “way too much,” and adds, “There’s not one study that shows that there’s a correlation in the maintenance phase between OCT and visual acuity.”

Where OCT may not help in identifying biomarkers, clinical trial findings might. Dr. Dugel notes that trial of squalamine eye drops (OHR-102, Ohr Pharmaceuticals) as combination therapy with ranibizumab (Lucentis, Genentech) for AMD found that the nature of neovascularization—whether classic, occult or large occult—may determine patient response. “We know there’s a segregation of patients,” he says. “We don’t have the biomarkers yet, but just understanding that has enormous implications in understanding the nature history of these diseases.”

Of course, combination therapy raises the question of how many injections a patient can tolerate, but Dr. D’Amico sees that as “no big deal” because retina specialists have already modified their practices and patients have become more accepting of intravitreal injections.

Steroids, TIE2 Inhibitors, Drops
As for future agents that could have a role in combination therapy, Dr. Dugel notes that those that inhibit the ANG-TIE2 pathway show promise in influencing vascular permeability. “If we can stabilize vessels and treat diabetic retinopathy early on and prevent diabetic macular edema, to me that’s really exciting,” he says.

Dr. D’Amico says steroid treatments are his area of excitement. There is no drug that has given us a wow effect like steroids in some diseases, but the problem is that we have been unable to disassociate that effect from the horrific glaucoma and cataract.” If research scientists develop steroidal agents that solve those concerns, “they would be blockbuster drugs, alone or in combination,” he says.

Mr. Sturmhoefel says topical treatments have potential promise in retinal disease, especially in combination with current and future treatment modalities. “They will not replace intravitreal injections; they will not replace existing drugs, but we will be able to use them in combination and especially in maintenance or prophylactic phases of therapy,” he says.

TABLE: Companies Developing Combination Therapies for Retinal Indications

Company Product Indications Status/Milestones
Ophthotech / Novartis Fovista (anti-PDGF) + Lucentis/Eylea/Avastin (anti-VEGF) Wet AMD Ph.3 pivotal data expected 4Q16
Ohr Pharmaceuticals Squalamine (anti-PDGF/VEGF/bFG) Wet AMD Ph.3 expected to initiate by YE15 (Ph.2 reported mixed results in 1H15)
Regeneron REGN2176-3 (anti-PDGF + Eylea coformulation) Wet AMD Ph.2 topline data expected in mid-2016
REGN910-3 (anti-Ang2 + Eylea coformulation) Wet AMD Ph.1 report data expected YE15
Roche RG7716 (anti-ANG2+VEGF bispecific mAb) Wet AMD Ph.2 AVENUE study expected data in mid-2017 (initiated in Aug, 2015)
Aerpio AKB-9778 (Tie2-agonist) + Lucentis (anti-VEGF) DME Ph.2 TIME-2 recently reported positive 3-months data; follow-on study being planned
Santen DE-120 (anti-PDGFR/VEGF) Wet AMD Ph.1 VAPOR-1 study data in expected mid-2016
PanOptica PAN-90806 (anti-VEGF/FGFR) Wet AMD Ph.1 data expected in 1H2016
Proliferative diabetic retinopathy Ph.1 data expected in 1H2016
Iconic Therapeutics ICON-1 (anti-tissue factor) + Lucentis (anti-VEGF) Wet AMD Ph.2 EMERGE study data expected in mid-2016
Opthea OPT-302 (anti-VEGF C/D) + Lucentis (anti-VEGF) Wet AMD Ph.1 data expected in 2H16
Molecular Partners DARPin (anti-PDGF/VEGF) Wet AMD Preclinical

Source: Courtesy Joseph Schwartz, Leerink
Key: AMD = age-related macular degeneration; DME = diabetic macular edema