Oral Tyrosine Kinase Inhibitor for Neovascular Age-Related Macular Degeneration: A Phase 1 Dose-Escalation Study
| Autor: | Michael J. Elman, Chris Liang, David S. Boyer, Philip J. Rosenfeld, Nauman A Chaudhry, E. C. M. Parsons, Sunil S. Patel, Denis O'Shaughnessy, Timothy L Jackson, Jason S. Slakter, David M. Brown |
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| Rok vydání: | 2017 |
| Předmět: |
Male
medicine.medical_specialty Visual acuity Time Factors genetic structures Nausea Fundus Oculi Visual Acuity Administration Oral Angiogenesis Inhibitors Asymptomatic law.invention 03 medical and health sciences Macular Degeneration 0302 clinical medicine Randomized controlled trial law Internal medicine Ophthalmology medicine Humans Enzyme Inhibitors Fluorescein Angiography Adverse effect Protein Kinase Inhibitors Original Investigation Aged Retrospective Studies Dose-Response Relationship Drug business.industry Retrospective cohort study Macular degeneration Middle Aged Protein-Tyrosine Kinases medicine.disease eye diseases Treatment Outcome 030220 oncology & carcinogenesis 030221 ophthalmology & optometry Female sense organs Liver function medicine.symptom business Tomography Optical Coherence Follow-Up Studies |
| Zdroj: | JAMA ophthalmology. 135(7) |
| ISSN: | 2168-6173 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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