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Philip J Rosenfeld, Jason S Slakter, David S Boyer, David M Brown, Nauman A Chaudhry, Michael J Elman, Sunil S Patel, Denis O’Shaughnessy; A Phase 1 Safety Study of an Orally Available Tyrosine Kinase Inhibitor X-82 in Previously Treated Wet AMD Patients. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4804.
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A phase 1 dose-escalation study to investigate the safety of systemic administration of X-82, an orally active tyrosine kinase inhibitor with activity against all PDGF and all VEGF subtypes.
Thirty five previously treated subjects with wet AMD were enrolled and received X-82 for up to 6 months at the following doses: 50 mg qod (3 subjects), 50 mg qd (8 subjects), 100 mg qod (4 subjects), 100 mg qd (10 subjects), 200 mg qd (7 subjects) and 200 mg qd (3 subjects). Subjects were seen every 4 weeks and underwent ETDRS VA measurement and SD-OCT assessment to determine the need for ranibizumab rescue therapy at each visit. SD-OCT images were read by DARC, which acted as the independent reading center (IRC).
Twenty-seven of the 35 randomized subjects completed the full 24-week treatment period and 2 subjects are still ongoing. The remaining 6 subjects either withdrew consent or discontinued the study before reaching the 24-week study period. The majority of all patients maintained or improved their baseline visual acuity scores and 24 of the 27 subjects (89%), who completed the 24 week treatment period, did not require any rescue therapy with ranibizumab during the treatment period. Eight subjects (1 who received 100 mg, 5 who received 200 mg and 2 who received 300 mg) experienced significant reductions in fluid on SD-OCT within the first weeks of starting X-82, and these observations were confirmed by the Independent Reading Center (DARC, NY). Three subjects experienced transaminase elevations within the first month of starting therapy, and these parameters returned to normal when X-82 was discontinued. There was no dose relationship in these three cases (1 occurred at 50 mg, 1 at 100 mg and 1 at 200 mg) and none was associated with any other laboratory abnormality or clinical symptoms. One patient on the 300 mg dose discontinued treatment due to grade 2 diarrhea.
The stability of vision without the need for rescue therapy strongly suggests a therapeutic effect for this oral anti-VEGF/PDGF, and the significant reductions in fluid on SD-OCT provide objective support for its activity in previously and frequently treated wet AMD patients. X-82 may offer an alternative way of delivering anti-VEGF and anti-PDGF therapy to patients with wet AMD. Further randomized controlled studies are warranted.
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