Outlook for Combination Therapies in Retinal Disease

When Regeneron Pharmaceuticals and Bayer announced their collaboration to develop and commercialize a combination therapy using Regeneron’s vascular endothelial growth factor (VEGF) trap aflibercept (Eylea) and its angiopoietin2 (ANG-2) antibody, nesvacumab, it was the latest in a rash of endeavors – at least seven at last count – to marry different compounds and anti-VEGF agents to improve the efficacy of treatments for retinal disease.

As part of their agreement, Regeneron and Bayer are conducting two separate Phase II clinical trials to evaluate the combination therapy as a co-formulated, single intravitreal injection in patients with neovascular (wet) age-related macular degeneration (AMD) or diabetic macular edema (DME).

This combination approach, which echoes the historical development of therapies in oncology, may be a harbinger of what’s to come for treating a number of retinal diseases, says Pravin Dugel, MD, managing partner of Retinal Consultants of Arizona and a clinical professor at the University of Southern California Eye Institute, Keck School of Medicine.

Currently, the two major approaches to combination therapy for retinal disease include combining anti-VEGF with anti-platelet-derived growth factor (PDGF) agents, and combining anti-VEGF agents with drugs that work on the ANG-Tie2 pathway. Other approaches include combining anti-VEGF agents with steroids or integrins.

Has Monotherapy Reached Its Limit?
Monotherapy may have reached its limit for retinal disease. “Combination therapy for AMD is inevitable,” Dr. Dugel says. “We are seeing a ceiling effect with anti-VEGF monotherapy for two reasons: in terms of a treatment strategy, monotherapy involves a significant treatment burden, making it challenging for patients to receive the frequency of injections that they need; and in terms of physiology, anti-VEGF agents decrease vascular permeability but don’t address the primary cause of wet AMD, which is angiogenesis.”

Dr. Dugel is looking forward to seeing the results of trials combining anti-VEGF therapy with PDGF inhibitors for wet AMD and trials combining anti-VEGF therapy with drugs targeting the ANG-Tie2 pathway for diabetic retinopathy and DME. Although concepts such as gene therapy, stem cells, sustained-release drugs, eye drops, and radiation are also being investigated for treating retinal disease, combination therapy is the furthest along.

Donald D’Amico, MD, ophthalmology chair at Weill Cornell Medical College and chief of ophthalmology at New York-Presbyterian, is another believer in the promise of combination therapy. At the most recent OIS@AAO, he stated that longer-acting anti-VEGF therapy alone is unlikely to act on all the different mechanisms of retinal disease.

Lessons from Oncology
Combination therapy makes sense because the longer vessels are exposed to anti-VEGF agents, the more resistant they become to anti-VEGF treatment. “It’s important to understand the physiology of how neovascularization occurs,” says Dr. Dugel. “Anti-VEGF monotherapy upregulates PDGF, which causes the neovascular complex to hypermature; in turn, a hypermature neovascular complex protects against further VEGF inhibition.” Specifically, the neovascular structure responds to anti-VEGF monotherapy by recruiting and maturing pericytes, which form a protective armor around the neovascular complex, inhibiting the effectiveness of anti-VEGF drugs. Anti-PDGF agents strip the pericytes, exposing endothelial cells and allowing VEGF inhibition to proceed more effectively.

“This process has been recognized in the field of oncology for some time, which is why anti-VEGF agents aren’t used as monotherapy in oncology,” Dr. Dugel notes. “Instead, VEGF inhibition is used to hypermature the neovascular complex, and then some other agent is used to target the cell. So it’s not at all surprising that we are seeing a movement away from anti-VEGF monotherapy in ophthalmology as well.”

Another key element in understanding combination therapies for retinal disease, as Dr. D’Amico explained at OIS@AAO last year, is learning how the disease develops in stages, not unlike 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.”

Combination Therapies in the Pipeline
A number of combination anti-VEGF and anti-PDGF agents are in development. Ophthotech is well into three large-scale Phase III wet AMD trials of the company’s anti-PDGF Fovista in combination with all three approved anti-VEGF agents.

Another Regeneron and Bayer collaboration of an Eylea/anti-PDGF combination that can be co-formulated in a single injection is in Phase II clinical trials for patients with wet AMD. Allergan is developing a dual anti-PDGF/VEGF DARPin therapy for wet AMD. Ohr Pharmaceutical has initiated a Phase III trial of its Squalamine ophthalmic solution with intravitreal Lucentis (ranibizumab, Genentech). Santen also has a combination anti-VEGF/anti-PDGF therapy moving into Phase II trials.

The Regeneron-Bayer collaboration is just one of several combination anti-VEGF and ANG-Tie2 pathway drugs in development. Angiopoietins, which are a family of vascular growth factors, act in concert with the VEGF family to promote the formation and maturation of blood and lymphatic vessels in the eye. Drugs that inhibit the ANG-Tie2 pathway show promise in influencing vascular permeability, which may be especially useful for treating diabetic retinopathy and DME. “If we can stabilize vessels and treat diabetic retinopathy early on and prevent diabetic macular edema, that’s really exciting,” Dr. Dugel says.

Roche and Aerpio Therapeutics each have anti-VEGF/ANG-Tie2 pathway drugs in development. According to Dr. Dugel, the Aerpio drug, AKB-9778, is particularly interesting because of its mechanism of action – it restores proper functioning of the Tie2 receptor by inhibiting a tyrosine phosphatase enzyme – and because it is given subcutaneously instead of intravitreally. For people with bilateral disease, such as diabetic retinopathy, subcutaneous delivery may offer an advantage.

At the most recent OIS@AAO, Dr. D’Amico expressed his interest in the potential of combining VEGF inhibition with steroids – if steroidal agents can be developed that involve less risk for glaucoma and cataract formation. As an example of this approach, combining intravitreal sustained-release dexamethasone and an anti-VEGF agent has been shown to improve visual acuity and prolong the time between injections for patients with retinal vein occlusion.1,2

Allegro Ophthalmics 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 (bevacizumab, Genentech) for DME and Luminate monotherapy for wet AMD.

REFERENCES
1. Singer MA, Bell DJ, Woods P, et al. Effect of combination therapy with bevacizumab and dexamethasone intravitreal implant in patients with retinal vein occlusion. Retina. 2012;32:1289–94.
2. Singer MA, Tyler L, Woods P, et al. Long-term analysis of combination therapy using anti-VEGF agents and dexamethasone intravitreal implant in retinal vein occlusion. Paper presented at 29th Meeting of Club Jules Gonin, September 5, 2014, Zurich, Switzerland, and 47th Annual Scientific Meeting of Retina Society, September 14, 2014, Philadelphia, PA.

Michael Smolinsky is Chief Content Officer at Ethis Communications.