PellePharm (United States)

We appreciate the comments shared by Wang and colleagues.1Here we provide responses to the key comments that were raised and highlight relevant aspects in our original publication2and from our research.The first point highlighted by Wang et al was regarding the limitations associated with using diagnosis codes for the identification of rheumatoid arthritis (RA) and herpes zoster (HZ) cases.1

e21626 Background: Oral hedgehog (HH) inhibitors can produce complete clinical and histologic remission of non-advanced basal cell carcinomas (BCCs) in patients with Gorlin syndrome. However, class-specific hair loss, taste loss, and muscle cramps cause most patients to discontinue treatment, following which BCCs recur. PellePharm's goal is to develop a topical HH inhibitor with sufficient percutaneous absorption to have anti-HH/BCC-preventive activity, but without enough absorption to produce the characteristic systemic AEs. This would be a first in class topical drug to manage the chronic burden of continuously developing BCC tumors in Gorlin patients. We report here the first Phase 2 double-blind, vehicle controlled randomized trial of topical patidegib, a small molecule HH inhibitor derived from plant-produced cyclopamine. Methods: In this Phase 2 clinical trial, patients with Gorlin syndrome applied vehicle (n = 5), 2% patidegib (n = 6), or 4% patidegib (n = 6) gel twice daily for six months to their entire face, including 4 evaluable target surgically-eligible BCCs (SEBs). The primary endpoint was change in BCC diameter; secondary endpoints were prevention of new tumors, percent of existing target tumors with complete clinical response (CR), and safety/dermal irritation. Results: In a modified ITT analysis, 2% gel shrank SEBs compared with vehicle (P = 0.04); 2% and 4% gels caused tumor CR in 25% of existing SEBs (P = 0.02). No vehicle-treated SEB disappeared. 3 of 5 (60%) patients applying vehicle gel developed a new facial SEB; 2 of 12 (16%) patients applying 2% or 4% gel developed a new facial SEB (p = 0.02 for prevention). Shrinkage of SEBs only occurred in those in whom HH pathway activity was reduced after 6 weeks of topical application. Importantly, unlike oral HH inhibitors, topical patidegib caused no hair loss, taste loss, or muscle cramps and produced circulating blood levels three orders of magnitude lower than those with oral patidegib. Conclusions: Topical patidegib gel has the potential to prevent and mitigate facial BCCs in Gorlin patients. These results will be confirmed in a Phase 3 trial enrolling approximately 150 patients in the United States and Europe. Clinical trial information: NCT02762084.