681 Development of a topical Hedgehog inhibitor for prevention of new surgically eligible basal cell carcinomas in patients with Gorlin Syndrome: Phase 3 trial

Abstract

Identification of PTCH1 gene mutations in the Gorlin syndrome two decades ago led to the development of small molecule Hedgehog (HH) inhibitors that replace the function of the mutant gene. These drugs have remarkable oral efficacy against advanced BCCs and off-label vs. the multiple BCCs in patients with Gorlin syndrome. Unfortunately, on target, extra-cutaneous adverse effects cause patients to stop these drugs, after which BCCs in complete clinical and histologic remission generally recur. Therefore, PellePharm is developing a small molecule HH inhibitor for topical use. Our goal is to develop a drug that produces skin concentrations high enough to inhibit HH signaling but not so high that circulating levels produce the unwanted adverse effects. We have incorporated the cyclopamine derivative patidegib into a gel that in two Phase 2 trials has demonstrated efficacy potential vs. BCCs - complete response (12 of 45 tumors in patidegib topical gel arms vs. 0 of 16 in vehicle) and fewer new BCCs (3 out of 12 subjects in patidegib topical gel arms vs. 3 out of 5 in vehicle; ITT one-sided P=0.05); with none of the significant oral HH inhibitor class adverse events observed. Very low to undetectable systemic exposure of the drug has been observed - circulating levels 500-1000x lower than those when patidegib is administered orally. These data suggest that the benefit-risk of patidegib topical gel in patients with Gorlin syndrome is positive. Therefore, we have initiated a Phase 3 Trial in North America and Europe with the aim of enrolling 150 Gorlin subjects randomized 1:1 for application of active vs. placebo gel to the face for a year, testing prevention of the development of new surgically eligible BCCs (ClinicalTrials.gov Identifier: NCT03703310). Patients interested in participating and clinicians interested in more details can contact us at [email protected]