February 2016




Oral AMD treatment shows promise

by Michelle Dalton EyeWorld Contributing Writer

old woman and pill

A phase 1 safety study suggests an oral treatment may be successful

An orally administered treatment has potential for patients with age-related macular degeneration (AMD), said Jason S. Slakter, MD, New York. X-82 (Tyrogenex, Needham, Mass.) is a dual inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF); data from a phase 1 safety study found that on average, the compound was able to maintain or improve vision in subjects who received the drug for the 6-month study duration.

To date, X-82 is the only orally administered treatment in development for wet AMD, and it has the potential to offer an alternative to frequent eye injections and affect the quality of life of patients with wet AMD, he said.

About X-82

X-82 is an oral tyrosine kinase inhibitor derived from an anti-cancer agent (sunitinib malate), which is already marketed for the treatment of advanced renal cell carcinoma, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumors. The compound has a lower toxicity compared with other tyrosine kinase inhibitors, and because its an oral treatment, it can target bilateral disease, said Tim Jackson, PhD, London.

In vitro studies have shown X-82 has the ability to inhibit phosphorylation of VEGF and PDGF receptors and to inhibit growth of human umbilical vein endothelial cells. Further, inhibition was achieved at very low concentrationsabout 50 nM, Prof. Jackson said. X-82 was efficacious in the Matrigel-induced choroidal neovascularization model in rats when dosed orally once daily, he said. There was more than 80% inhibition at 10 mg/kg, Prof. Jackson said. Findings were confirmed in a mouse model where X-82 inhibited retinal neovascularization by 71% compared to vehicle.

In a phase 1 study, 35 patients refractory to anti-VEGF intravitreal injections were enrolled in 1 of 4 dose levels: 50 mg every other day and once daily; 100 mg every other day and once daily, 200 mg once daily, and 300 mg once daily. Follow-up was every 4 weeks with both best corrected visual acuity and spectral domain optical coherence tomography to determine the need for anti-VEGF rescue therapy. For this study, patients were considered refractory if they were unable to achieve a dry macula; rescue therapy was provided if patients had a 1-line decrease in vision or a 50-micron increase in fluid.

Most patients maintained or improved vision while receiving X-82, and 60% (15 patients) who completed 6 months of treatment did not require any rescue therapy, Prof. Jackson said. Mean letter gains from baseline to month 6 were around 5 letters for those who did not undergo rescue treatment and about 4 letters overall for all patients, he said. At the 300 mg dose, none of the patients needed additional injections; those in the 50 mg group had a mean of 2.6 injections per eye.

The overall mean decrease in foveal thickness was about 40 microns, with treatment-nave patients showing more than an 80-micron reduction. Ten patients failed to complete the 24-week study, 6 for treatment- related adverse events, Prof. Jackson said, including diarrhea, nausea, and transaminase elevations. In short, this phase 1 study showed both refractory and treatment-nave patients were able to maintain or improve vision with few or no injections, Prof. Jackson said. There were no dose-limiting toxicities observed, and there was a significant proof-of-concept improvement in both OCT and VA outcomes.

Future studies

X-82 is currently under investigation in a phase 2 dose-finding study, dubbed APEX. This randomized, double-masked, placebo-controlled study will evaluate the safety and efficacy in the prevention of vision loss in about 132 patients who had previously been treated with aflibercept; the study will enroll patients at 20 sites in the U.S. and 5 sites in the U.K. The primary outcome will be the change in visual acuity score from day 1 to 52 weeks; another endpoint will be the reduction of the number of injections needed for the duration of the study. Secondary endpoints will be the number of aflibercept injections at 1 year and anatomical changes on OCT, Prof. Jackson said. Rescue therapy will be offered if there is at least a 10% increase in fluid or new/increased macular hemorrhage. Vision loss not accompanied by the presence of fluid, hemorrhage, or fluorescein angiography leakage will not be treated with aflibercept, he said. Subject to confirmatory studies, the possibility of a pill for wet AMD will be welcomed by the large number of patients who otherwise require repeated eye injections to control their disease, he said.

Editors note: Dr. Slakter and Prof. Jackson have financial interests with Tyrogenex.

Contact information

: t.jackson1@nhs.net
Slakter: 212-861-9730
Tyrogenex: teri@tyrogenex.com

Oral AMD treatment shows promise Oral AMD treatment shows promise
Ophthalmology News - EyeWorld Magazine
283 110
220 345
True, 2