Itraconazole’s mechanism of action as a treatment for BCCNS involves inhibition of the Hedgehog (Hh) pathway.
The discovery of this activity was made at Johns Hopkins University, Baltimore, in a program designed to identify existing medications that have known acceptable toxicity profiles (FDA-approved or post-phase I drugs) as possible cancer therapeutics.
“The Hh signaling pathway is important in the initiation, local growth, and spread of multiple tumor types, and in the case of BCC, the Hh pathway really drives the tumor,” said Dr. O’Donnell, who did his ophthalmology residency training at Wilmer Eye Institute, Johns Hopkins University School of Medicine. “An agent that inhibits the Hh pathway has the potential to prevent BCCs from developing and cause existing tumors to shrink or disappear.
“The finding that itraconazole was an inhibitor of the Hh pathway was a surprise considering inhibition of fungal sterol biosynthesis was thought to be its only therapeutic activity,” he added.
SUBA-Itraconazole is a proprietary formulation licensed by HedgePath Pharmaceuticals from Mayne Pharma. It uses polymer-drug dispersion technology that was developed to improve the bioavailability of poorly soluble oral medications and thereby deliver predictably consistent blood levels using a lower dose that would minimize side effects while improving efficacy.
SUBA stands for “super bioavailability,” and SUBA-Itraconazole lives up to its name. Pharmacokinetics testing shows it has 95% bioavailability compared with 55% for generic itraconazole.
When deciding to pursue the development of SUBA-Itraconazole, Virca and colleagues at HedgePath Pharmaceuticals sought to educate themselves about BCCNS by learning firsthand what affected patients were experiencing.
That interest led to a collaboration with Kristi Schmitt Burr, a BCCNS patient and executive director of the BCCNS Life Support Network. Many patients enrolled in the study were identified through this support organization.
“Based on discussions with personnel at the FDA and a focus panel of patients with BCCNS, our goal was to develop an itraconazole product that could achieve a blood level higher than that needed for efficacy as an antifungal treatment while maintaining a favorable safety profile,” Virca said. “Because of itraconazole’s known safety profile, we proposed to the FDA that we could move immediately into a phase IIb clinical trial and were granted permission to do so.”