Oral Tyrosine Kinase Inhibitor for Neovascular Age-Related Macular Degeneration: A Phase 1 Dose-Escalation Study

Abstract

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 50 mg alternate days (n = 3), 50 mg daily (n = 8), 100 mg alternate days (n = 4), 100 mg daily (n = 10), 200 mg daily (n = 7), and 300 mg 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 outcome was 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 100 mg 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.

Trial registration: ClinicalTrials.gov NCT02146222.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Liang, O’Shaughnessy, and Parsons are employees of Tyrogenex. Drs Slakter and Rosenfeld are consultants to Tyrogenex. Dr Slakter received research grant support for image evaluations for the trial. Drs Boyer, Brown, Chaudhry, Elman, and Patel were principal investigators and their practices received site payments for participants enrolled on this study. No other disclosures were reported.

Figures

Figure 1.. CONSORT Flow Diagram

CONSORT flow diagram showing disposition of participants. Relatedness determined by site clinician. All participants included in safety analysis. AE indicates adverse event.

Figure 2.. Change in Visual Acuity From Baseline to Week 24

The figure shows the mean change in Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity from baseline to week 24 in the 25 participants who completed 24 weeks of X-82 treatment. Error bars show the standard error of the mean.

Figure 3.. Mean Number of Intravitreal Rescue Injections vs X-82 Dose

The graph shows the mean (SEM) number of intravitreal antivascular endothelial growth factor rescue injections required by dose group. The light blue columns show the 25 participants who completed 24 weeks of X-82 therapy vs all 35 participants (shown in dark blue).

Figure 4.. Change in Central Subfield Thickness Over 24 Weeks of Dosing

Optical coherence tomography central subfield thickness for all participants who completed the 24 weeks of dosing. Thickness decreased somewhat overall as compared with baseline measurements, most notably in the treatment naive patients. Graph shows the mean (SEM).