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.

• Authors: 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
• Journal: JAMA ophthalmology (JAMA Ophthalmol) Vol. 135 Issue 7 Pg. 761-767 (07 01 2017) ISSN: 2168-6173 [Electronic] United States
• PMID: 28570723 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Protein-Tyrosine Kinases

Topics

• Administration, Oral
• Aged
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (administration & dosage)
• Female
• Fluorescein Angiography
• Follow-Up Studies
• Fundus Oculi
• Humans
• Macular Degeneration (diagnosis, drug therapy, physiopathology)
• Male
• Middle Aged
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Retrospective Studies
• Time Factors
• Tomography, Optical Coherence
• Treatment Outcome
• Visual Acuity