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CHICAGO – in a phase 2 study, and did so without causing the problematic adverse events that prompt many Gorlin patients to discontinue systemic hedgehog inhibitor drugs, Ervin Epstein Jr., MD, said at the annual meeting of the American College of Mohs Surgery.
He characterized patidegib, a small-molecule cyclopamine derivative, as “a Goldilocks drug, a topical hedgehog inhibitor with percutaneous absorption that’s just right: sufficient to have anti-hedgehog and anti–basal cell carcinoma efficacy, but not enough to cause systemic exposure or systemic adverse events.”
A complete response – tumor clinical disappearance – occurred in 25% of the BCCs in the two active treatment arms. In contrast, none of the BCCs in the control group cleared. Patients on patidegib developed one or more new surgically eligible BCCs after study week 2 at a rate of 0.4 tumors per patient, markedly less than the rate of 1.4 tumors per patient in controls.
“We think that prevention is really the place to go with this drug,” said Dr. Epstein, cofounder and chief medical officer at PellePharm, the company based in Menlo Park, Calif., that is developing patidegib.
Indeed, he envisions patidegib gel as lifetime therapy for Gorlin patients.
Tumor shrinkage was significantly greater with 2% patidegib than with the 4% concentration. But so was treatment adherence: Patients in the 2% patidegib arm missed on average just 2 days of therapy over the course of 6 months, while those in the 4% arm missed 50 days. Dr. Epstein attributed this discrepancy to a freak of randomization that can occur in such a small study: 5 of 6 patients in the 2% patidegib group were women, while most in the 4% arm were men. And the men were far less adherent to treatment, possibly because men are less accustomed to applying a product on their face daily, he noted.
In any case, it’s the 2% gel formulation that is moving on to a phase 3, double-blind, randomized trial. The 150-patient U.S. and European study, scheduled to start this summer, will have as its primary endpoint the rate of new BCCs over the course of 1 year. The Food and Drug Administration has granted topical patidegib Breakthrough Drug and Orphan Drug status.
Dr. Epstein said that, in the phase 2 study, BCC shrinkage occurred only in patients whose hedgehog pathway activity decreased after 6 weeks of topical therapy as evidenced by a reduction in the GLI1 mRNA biomarker. Of note, circulating blood levels of patidegib in study participants were more than 500-fold lower than when the drug is given orally. And of greatest importance, rates of the hallmark side effects of oral hedgehog inhibitor therapy that cause so many patients to discontinue therapy – muscle cramps, taste loss, and hair loss – were no different in patients on patidegib gel than in those on placebo.
“In the randomized trial of vismodegib [Erivedge], half of patients stopped taking it within 1 year despite good results. And indeed, when they stopped taking the drug, the basal cell carcinomas returned,” the dermatologist noted.
Dr. Epstein is an employee of PellePharm, which is developing patidegib. Dermatologists with patients with Gorlin syndrome who are interested in participating in the phase 3 trial can contact him at [email protected].
CHICAGO – in a phase 2 study, and did so without causing the problematic adverse events that prompt many Gorlin patients to discontinue systemic hedgehog inhibitor drugs, Ervin Epstein Jr., MD, said at the annual meeting of the American College of Mohs Surgery.
He characterized patidegib, a small-molecule cyclopamine derivative, as “a Goldilocks drug, a topical hedgehog inhibitor with percutaneous absorption that’s just right: sufficient to have anti-hedgehog and anti–basal cell carcinoma efficacy, but not enough to cause systemic exposure or systemic adverse events.”
A complete response – tumor clinical disappearance – occurred in 25% of the BCCs in the two active treatment arms. In contrast, none of the BCCs in the control group cleared. Patients on patidegib developed one or more new surgically eligible BCCs after study week 2 at a rate of 0.4 tumors per patient, markedly less than the rate of 1.4 tumors per patient in controls.
“We think that prevention is really the place to go with this drug,” said Dr. Epstein, cofounder and chief medical officer at PellePharm, the company based in Menlo Park, Calif., that is developing patidegib.
Indeed, he envisions patidegib gel as lifetime therapy for Gorlin patients.
Tumor shrinkage was significantly greater with 2% patidegib than with the 4% concentration. But so was treatment adherence: Patients in the 2% patidegib arm missed on average just 2 days of therapy over the course of 6 months, while those in the 4% arm missed 50 days. Dr. Epstein attributed this discrepancy to a freak of randomization that can occur in such a small study: 5 of 6 patients in the 2% patidegib group were women, while most in the 4% arm were men. And the men were far less adherent to treatment, possibly because men are less accustomed to applying a product on their face daily, he noted.
In any case, it’s the 2% gel formulation that is moving on to a phase 3, double-blind, randomized trial. The 150-patient U.S. and European study, scheduled to start this summer, will have as its primary endpoint the rate of new BCCs over the course of 1 year. The Food and Drug Administration has granted topical patidegib Breakthrough Drug and Orphan Drug status.
Dr. Epstein said that, in the phase 2 study, BCC shrinkage occurred only in patients whose hedgehog pathway activity decreased after 6 weeks of topical therapy as evidenced by a reduction in the GLI1 mRNA biomarker. Of note, circulating blood levels of patidegib in study participants were more than 500-fold lower than when the drug is given orally. And of greatest importance, rates of the hallmark side effects of oral hedgehog inhibitor therapy that cause so many patients to discontinue therapy – muscle cramps, taste loss, and hair loss – were no different in patients on patidegib gel than in those on placebo.
“In the randomized trial of vismodegib [Erivedge], half of patients stopped taking it within 1 year despite good results. And indeed, when they stopped taking the drug, the basal cell carcinomas returned,” the dermatologist noted.
Dr. Epstein is an employee of PellePharm, which is developing patidegib. Dermatologists with patients with Gorlin syndrome who are interested in participating in the phase 3 trial can contact him at [email protected].
CHICAGO – in a phase 2 study, and did so without causing the problematic adverse events that prompt many Gorlin patients to discontinue systemic hedgehog inhibitor drugs, Ervin Epstein Jr., MD, said at the annual meeting of the American College of Mohs Surgery.
He characterized patidegib, a small-molecule cyclopamine derivative, as “a Goldilocks drug, a topical hedgehog inhibitor with percutaneous absorption that’s just right: sufficient to have anti-hedgehog and anti–basal cell carcinoma efficacy, but not enough to cause systemic exposure or systemic adverse events.”
A complete response – tumor clinical disappearance – occurred in 25% of the BCCs in the two active treatment arms. In contrast, none of the BCCs in the control group cleared. Patients on patidegib developed one or more new surgically eligible BCCs after study week 2 at a rate of 0.4 tumors per patient, markedly less than the rate of 1.4 tumors per patient in controls.
“We think that prevention is really the place to go with this drug,” said Dr. Epstein, cofounder and chief medical officer at PellePharm, the company based in Menlo Park, Calif., that is developing patidegib.
Indeed, he envisions patidegib gel as lifetime therapy for Gorlin patients.
Tumor shrinkage was significantly greater with 2% patidegib than with the 4% concentration. But so was treatment adherence: Patients in the 2% patidegib arm missed on average just 2 days of therapy over the course of 6 months, while those in the 4% arm missed 50 days. Dr. Epstein attributed this discrepancy to a freak of randomization that can occur in such a small study: 5 of 6 patients in the 2% patidegib group were women, while most in the 4% arm were men. And the men were far less adherent to treatment, possibly because men are less accustomed to applying a product on their face daily, he noted.
In any case, it’s the 2% gel formulation that is moving on to a phase 3, double-blind, randomized trial. The 150-patient U.S. and European study, scheduled to start this summer, will have as its primary endpoint the rate of new BCCs over the course of 1 year. The Food and Drug Administration has granted topical patidegib Breakthrough Drug and Orphan Drug status.
Dr. Epstein said that, in the phase 2 study, BCC shrinkage occurred only in patients whose hedgehog pathway activity decreased after 6 weeks of topical therapy as evidenced by a reduction in the GLI1 mRNA biomarker. Of note, circulating blood levels of patidegib in study participants were more than 500-fold lower than when the drug is given orally. And of greatest importance, rates of the hallmark side effects of oral hedgehog inhibitor therapy that cause so many patients to discontinue therapy – muscle cramps, taste loss, and hair loss – were no different in patients on patidegib gel than in those on placebo.
“In the randomized trial of vismodegib [Erivedge], half of patients stopped taking it within 1 year despite good results. And indeed, when they stopped taking the drug, the basal cell carcinomas returned,” the dermatologist noted.
Dr. Epstein is an employee of PellePharm, which is developing patidegib. Dermatologists with patients with Gorlin syndrome who are interested in participating in the phase 3 trial can contact him at [email protected].
REPORTING FROM THE ACMS ANNUAL MEETING