Regorafenib Eye Drops Show Promise in Primate AMD Model

Marlene Busko

May 15, 2015

Topical eye drops of regorafenib (Bayer HealthCare), a multikinase inhibitor targeting vascular endothelial growth factor 2, were safe and effective when given to monkeys that had laser-induced choroidal neovascularization, according to a new study presented in a poster May 4 at the Association for Research in Vision and Ophthalmology 2015 Annual Meeting.

Because existing treatments require intravitreal injections given by physicians, "potentially, regorafenib eye drops offer an innovative, self-administered, noninvasive treatment option for [wet age-related macular degeneration (AMD)]," Dr Michael K. Bötger, from Bayer HealthCare, Wuppertal, Germany, and colleagues conclude.

However, these are early days. "The project is in early development phase," Dr Kerstin Crusius, head of Global Science and Healthcare Communication, Bayer HealthCare Pharmaceuticals, Berlin, Germany, cautioned Medscape Medical News. Looking into the future, "if everything goes well and once approved, regorafenib eye drops...could become a valuable extension to the current treatment options for wet AMD," he said. The company had positive results in a phase 1 clinical trial in healthy male volunteers, and a phase 2 clinical trial was initiated in August 2014.

Asked to comment on the abstract, Sunir J. Garg, MD, from the Retina Service of Wills Eye Hospital and associate professor of Ophthalmology at Thomas Jefferson University, Philadelphia, Pennsylvania, said, "[I]t's a tremendously exciting time for the treatment of wet AMD." Just a few years ago, there were no treatments for this eye disease. Now ranizumab (Lucentis, Genentech, Novartis) and aflibercept (Eylea, Regeneron, Bayer HealthCare) have been approved by the US Food and Drug Administration (FDA), and bevacizumab (Avastin, Genentech, Roche) is used off-label. "Our hope [for the future] is to get patients better results with greater ease of administration," he said.

A New, More Convenient Delivery

Ranizumab, aflibercept, and bevacizumab all inhibit vascular endothelial growth factor (VEGF), a substance that stimulates the growth of abnormal and leaky vessels in the back of the eye of patients with wet AMD, whereas regorafenib blocks VEGF and platelet-derived growth-factor receptors, Dr Crusius explained. The FDA approved oral regorafenib (Stivarga, Bayer HealthCare Pharmaceuticals Inc) for the treatment of refractory colorectal cancer and gastrointestinal stroma tumors.

In the current study, 57 monkeys underwent laser-induced choroidal neovascularization. Then 23 monkeys received vehicle (control) and 16 monkeys received a 20 mg/mL oily suspension of regorafenib; 50 µL of the respective eye drops were instilled in the affected eye twice daily for 21 days, starting 4 hours after the laser treatment.

Another 18 monkeys (comparator drug group) received one intravitreal injection of ranibizumab (Novartis; 10 mg/mL, 50 µL injection volume) once, 4 hours after the laser induction.

At 21 days, the occurrence of grade IV lesions was significantly reduced in the primates treated with the regorafenib vs the primates that received control eye drops: 7% ± 13% (mean ± SD) vs 21% ± 18%, respectively (P = .013). The improvement with regorafenib was similar to that seen with intravitreal ranizumab. There were no adverse reactions in any of the treated animals.

Where Does This Fit With Current Treatments?

At this time, the two FDA-approved treatments, ranibizumab and aflibercept, cost about $2000 per dose, whereas bevacizumab, which is approved by the FDA for treating certain cancers, can be obtained for about $60 a dose from a compounding pharmacy that follows USP guidelines, Dr Garg explained.

Bevacizumab is quite commonly used off-label, but "the FDA is in the process of trying to stringently regulate the availability of commercially aliquoted bevacizumab, which will make it harder to use this medicine, [which] will not only add to the cost of providing care but also deprive a number of patients the only treatment available to them," Dr Garg noted.

Meanwhile, the research into a new drug, regorafenib, with a new format, "looks promising, [and] patients would like the convenience," Dr Garg said. However, "drops getting to the back of the eye without being inactivated by metabolism and getting in sufficient quantity to the retina is [difficult to achieve]," he noted. For example, a previous attempt with a different drug failed in clinical trials.

He looks forward to seeing results from trials of regorafenib in humans.

The study was funded by Bayer HealthCare, and Dr Böttger and coauthors are employees of Bayer and hold patents related to the data. Dr Garg reports serving as a consultant for ThromboGenics and Deciphera and as a speaker for Thrombogenics and Allergan, and receiving research support from Genentech, Xoma, Allergan, and Johnson & Johnson.

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