PATIDEGIB, A POTENT HEDGEHOG INHIBITOR
All basal cell carcinomas (BCCs) are addicted to the hedgehog signaling pathway. Inhibiting the hedgehog pathway rapidly and potently shrinks BCCs.
Our founders demonstrated the therapeutic potential of targeting hedgehog signaling in Gorlin Syndrome by conducting a double blind, randomized, placebo-controlled trial of oral vismodegib, an FDA-approved hedgehog inhibitor for the treatment of advanced and metastatic BCCs, in a clinical trial of Gorlin Syndrome.1
In this clinical trial, vismodegib robustly reduced the BCC tumor burden and completely blocked the growth of new BCCs in patients with Gorlin Syndrome. Unfortunately, the adverse events associated with treatment (muscle cramps, taste loss, hair loss) led to discontinuation in >50% of treated patients. While these class-specific side effects are tolerable with patients with metastatic or locally advanced/surgically-ineligible BCCs (the indication for which the FDA has approved the use of vismodegib) but not for persons with Gorlin Syndrome, whose chronic (genetic) basis requires life-long treatment, or for those with sporadic BCCs.
To avoid the systemic side effects of oral hedgehog inhibitors, we have developed a topical gel formulation of a proprietary hedgehog inhibitor. An oral formulation of this hedgehog inhibitor was shown in a Phase 1 clinical trial to dramatically reduce the volume of tumors in BCC patients.2 Our topical formulation of this hedgehog inhibitor is stable at room temperature, achieves high dermal concentrations with minimal systemic exposure, and was as efficacious as the oral hedgehog inhibitors in a mouse model of Gorlin Syndrome. These data de-risk our clinical development plan.
We envision that Gorlin Syndrome patients will apply our topical hedgehog inhibitor daily to their skin (especially to the face and neck) for a lifetime to treat and prevent BCCs, thereby avoiding extensive surgeries and markedly improving their quality of life.
Tang, J. T., et al. (2012) N. Engl. J. Med. 366: 2180-2188
Jimeno, A., et al. (2013) Clin. Cancer Res. 19:2766-2774