Drugs for AMD and DME still in center court

Take home

Much of the developments in pharmacologic therapy for retina disease revolved around age-related macular degeneration and diabetic macular edema in 2014.

By Lynda Charters; Reviewed by Pravin U. Dugel, MD, and Michael S. Ip, MD

The spotlight in 2014 in the retina area remained on drug therapy for diabetic macular edema (DME) and age-related macular degeneration (AMD).

Advances in DME

Interestingly, there has been renewed interest in the use of corticosteroids to treat DME.

“We had virtually abandoned this approach to treating DME several years ago,” Michael Ip, MD, said, and explained that the results of the Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocol B study were not favorable regarding the use of corticosteroids for treating DME.

“It is interesting how we have come full circle. The conventional wisdom abandoned the use of corticosteroids; however, some companies vigorously pursued this therapy and found success in two recently approved products,” he said. Dr. Ip is associate professor, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison.

These products are two steroid delivery devices that offer patients with DME two additional treatment options. The first, dexamethasone intravitreal implant (Ozurdex, Allergan), received FDA approval to treat DME in late September 2014. Ozurdex lasts 3 to 5 months after implantation. The second, fluocinolone acetonide (Iluvien, Alimera Sciences), which also was approved in September 2014, can provide drug in the eye for up to 3 years after implantation, according to Pravin Dugel, MD.

Dr. Ip is anticipating the release of the DRCRnet protocol T results in the near future. This study compared intravitreal aflibercept (Eylea, Regeneron Pharmaceuticals), bevacizumab (Avastin, Genentech), and ranibizumab (Lucentis, Genentech) for treating DME.

“This is a very important comparative-effect research trial that will help guide the management of DME for some time,” he said.

Dr. Ip also is impressed with the potential for targeting different molecular pathways to treat DME.

“Many of these pathways are quite interesting and involve pathways other than vascular endothelial growth factor (VEGF). Targeting other pathways will lead to a higher percentage of patients with DME achieving a response to therapy,” he said.

This is important because many patients with DME do not respond to anti-VEGF monotherapy.

Development of a Tie2 activator (AKB-9778, Aerpio Therapeutics, Inc.) for DME is one of those pathways being investigated.

“This is a very exciting drug that is in the pipeline. This product is exciting because it is administered by subcutaneous injection and it works systemically in both eyes,” Dr. Dugel explained. He is Managing Partner, Retinal Consultants of Arizona, Phoenix, and Clinical Professor of ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles.

The first patient received this drug in February 2014 in the phase II clinical trial that is investigating the effects of AKB-9778 alone and combined with ranibizumab. The company explains that AKB-9778 is an inhibitor of human protein tyrosine phosphatase beta that activates the Tie2 pathway to promote vascular stability, which prevents abnormal blood vessel growth and vascular leakage.

Steps forward in treating wet AMD

In treatment of AMD, the potential availability of a PDGF inhibitor is near, Pravin Dugel, MD, pointed out. The results achieved with Fovista (Ophthotech Corp.), an anti-platelet-derived growth factor aptamer, in a phase 2B study are quite remarkable, he noted.

“This is the only superiority study that I am aware of that has shown a 62% improvement in visual acuity with combination treatment of Fovista and ranibizumab compared with ranibizumab alone for treating wet AMD. This is a major highlight of the last year not only in retina but also in drug therapy in general,” he stated.

Novartis recently reached a licensing and commercialization agreement with Ophthotech Corp. to market the drug outside of the United States.

The results with the Alcon Pharmaceutical/Novartis drug, RTH258, for treating neovascular AMD are also encouraging. Dr. Dugel presented the preliminary results obtained with the drug at the American Academy of Ophthalmology and the American Society of Retina Specialists annual meetings. He reported that this small molecule, previously called ESBA 1008, when administered at two higher doses was found to be noninferior to ranibizumab at week 4 and 6 of treatment. The drug was found to have a sustained duration of action and higher increases in visual acuity with the 6-mg dose compared with the 0.5-mg dose of ranibizumab.

Ophthalmologists are looking forward to the results of the study that compared aflibercept with RTH258 for treating neovascular AMD in 2015.

“RTH258 is a single-chain antibody fragment that is about half the size of the ranibizumab molecule and amenable for use in sustained drug delivery devices. This is a very exciting advance,” Dr. Dugel said.

Another drug for treating AMD is being investigated in the DARPin Study. This is also a small anti-VEGF molecule that is exciting because it is not just for use as an anti-VEGF therapy, but it is a library that will allow investigators to use the platform to make other drugs, he explained.

Therapy for dry AMD

Oral drug delivery in pill form for treating dry AMD is a potential treatment. Acucela Inc. has been working on ACU-4429 (Emixustat), which Dr. Dugel considers exciting. “Oral delivery is very attractive compared with intraocular injections,” Dr. Dugel said.

There has been some discussion, he pointed out, that treating wet AMD for the long run may cause some dry macular changes, for which, combination treatment also makes sense.

A second drug, lampalizumab (Genentech) is also being investigated for dry AMD.

“This drug is the only one I am aware of that has been shown to have a positive effect on dry macular degeneration to date in an early-phase study and in a specific subgroup of patients with a mutation in complement factor I,” Dr. Dugel explained.

A large phase III study is under way to study these patients.

Pravin U. Dugel, MD

E: pdugel@gmail.com

Dr. Dugel is a consultant to Alcon, Novartis, Acucela, Allergan, Alimera, and Genentech and is a consultant to and a minor shareholder in Ophthotech and Aerpio Therapeutics.

Michael S. Ip, MD

E: msip@wisc.edu

Dr. Ip is a consultant to Allergan.