Oral Drug X-82 Shows Promise for Wet Age-Related Macular Degeneration

A safe and effective oral treatment for neovascular age-related macular degeneration (nAMD) would avoid repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents and the anxiety and stress that result from having a needle regularly inserted into the eye. One option that may be less burdensome than intravitreal shots for clinicians and patients is the oral tyrosine kinase inhibitor X-82.

Timothy Jackson (pictured) , PhD, FRCOphth, a reader in retinal research at King’s College, London, UK, led a team that recently completed a Phase I, open-label, dose-escalation study of X-82 in 35 patients at 5 US centers. The team enrolled patients at these centers between November 2012 and March 2015. The patients’ mean age was 77 years, and most were white women.

For 24 weeks, patients orally received one of several dosages of X-82, which inhibits both VEGF and platelet-derived growth factor by inhibiting their binding to cell surface receptors in the eye. Dosages included 50 mg on alternate days in 3 patients, 50 mg daily in 8 patients, 100 mg on alternate days in 4 patients, 100 mg daily in 10 patients, 200 mg daily in 7 patients, and 300 mg daily in 3 patients.

During the study, patients could also receive intravitreal injections of anti-VEGF agents according to predefined retreatment criteria. Monthly assessments included measurement of best-corrected visual acuity, fundus examination, and spectral-domain optical coherence tomography.

Although the main outcomes of interest in this uncontrolled study were adverse events, others included visual acuity, central subfield retinal thickness, and the number of anti-VEGF injections required.

Of the 35 patients, 24 (71%) completed the study. Of the non-completers, 6 revoked consent or dropped out because of adverse side effects attributed to X-82 — 2 each discontinued for leg cramps or elevated alanine aminotransferase levels, and 1 each for diarrhea or nausea/anorexia.

The adverse events most commonly attributed to X-82 during the study included diarrhea, nausea or fatigue, and elevated transaminase levels. The investigators could not find a dose relationship between X-82 and elevated transaminase levels, which returned to normal after patients discontinued X-82.

Regarding efficacy, by study end, all except 1 of the 24 completers (96%) had stable or better visual acuity compared with their baseline value. Mean improvement in visual acuity was 3.8 letters with a standard deviation (SD) of 9.6 letters. Furthermore, the mean number of anti-VEGF intravitreal injections needed was 0.7, and 15 of the 24 completers, or 60%, needed no anti-VEGF shots.

In addition, by study end, mean central subfield thickness decreased by 50 μm (SD, 97 μm). Moreover, in 8 patients who received at least 100 mg of X-82 daily, reductions in mean central subfield thickness were sustained even though these patients received no intravitreal injections of anti-VEGF agents.

Because those who completed the study required fewer anti-VEGF injections than expected, the investigators concluded that X-82 warrants further study, and a Phase II randomized trial of this oral drug is currently in progress. In addition, because X-82 may result in reversible elevations in liver enzyme levels, the investigators also concluded that liver function testing is required to pinpoint patients who should not continue to receive X-82.

A report on the study, “Oral tyrosine kinase inhibitor for neovascular age-related macular degeneration,” appeared last month in JAMA Ophthalmology.

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