Oral tyrosine kinase inhibitor for neovascular age-related macular degeneration: A phase 1 dose-escalation study

Timothy L. Jackson, David Boyer, David M. Brown, Nauman Chaudhry, Michael Elman, Chris Liang, Denis O'Shaughnessy, Edward C. Parsons, Sunil Patel, Jason S. Slakter, Philip J. Rosenfeld

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


IMPORTANCE: An oral treatment for neovascular age-related macular degeneration would be less burdensome than repeated intravitreous injections. X-82 is an oral tyrosine kinase inhibitor active against vascular endothelial growth factor (VEGF) and platelet-derived growth factor. OBJECTIVE: To undertake safety testing of oral X-82 administered for the treatment of neovascular AMD. DESIGN, SETTING, AND PARTICIPANTS: Phase 1, open-label, uncontrolled, dose-escalation study at 5 US retinal clinics between November 2012 and March 2015 (Retina-Vitreous Associates Medical Group, Beverly Hills, California; Blanton Eye Institute, Houston Methodist Hospital, Retina Consultants of Houston, Houston, Texas; New England Retina Associates, Guilford, Connecticut; Elman Retina Group, Baltimore, Maryland; and Retina Research Institute of Texas, Abilene). Thirty-five participants with neovascular age-related macular degeneration, 7 of whom were treatment naive. INTERVENTIONS: Participants received oral X-82 for 24 weeks at 50mg alternate days (n = 3), 50mg daily (n = 8), 100mg alternate days (n = 4), 100mg daily (n = 10), 200mg daily (n = 7), and 300mg daily (n = 3), with intravitreous anti-VEGF therapy using predefined retreatment criteria. Every 4 weeks, participants underwent best-corrected visual acuity measurement, fundus examination, and spectral-domain optical coherence tomography. MAIN OUTCOMES AND MEASURES: The main outcomewas adverse events. Other outcomes included visual acuity, central subfield retinal thickness, and number of anti-VEGF injections. RESULTS: Of the 35 participants, the mean age was 76.8 years, 16 were men and 19 were women, and 33 were white and 2 were nonwhite. Of 25 participants (71%) who completed the 24 weeks of X-82 treatment, all except 1 maintained or improved their visual acuity (mean [SD], +3.8 [9.6] letters). Fifteen participants (60%) required no anti-VEGF injections (mean, 0.68). Mean [SD] central subfield thickness reduced by -50 [97] μm, with 8 participants (all receiving at least 100mg daily) demonstrating sustained reductions despite no anti-VEGF injections. The most common adverse events attributed to X-82 were diarrhea (n = 6), nausea (n = 5), fatigue (n = 5), and transaminase elevation (n = 4). A dose relationship to the transaminase elevations was not identified; all normalized when X-82 was discontinued. All but 1 were asymptomatic. Ten participants withdrew consent or discontinued prematurely, 6 owing to adverse events attributed to X-82 including leg cramps (n = 2), elevated alanine aminotransferase (n = 2), diarrhea (n = 1), and nausea/anorexia (n = 1). CONCLUSIONS AND RELEVANCE: X-82 can be associated with reversible, elevated liver enzymes; hence, liver function testing is needed to identify those unsuited to treatment. Although 17%of participants discontinued X-82 owing to AEs, those who completed the study had lower than expected anti-VEGF injection rates. Further studies appear justified, with a phase 2 randomized clinical study under way.

Original languageEnglish (US)
Pages (from-to)761-767
Number of pages7
JournalJAMA Ophthalmology
Issue number7
StatePublished - Jul 2017

ASJC Scopus subject areas

  • Ophthalmology


Dive into the research topics of 'Oral tyrosine kinase inhibitor for neovascular age-related macular degeneration: A phase 1 dose-escalation study'. Together they form a unique fingerprint.

Cite this