A recent interim analysis of data collected in a phase 2b study shows that a novel oral formulation of itraconazole (SUBA-Itraconazole, HedgePath Pharmaceuticals) acting as a Hedgehog (Hh) pathway inhibitor is providing dramatic benefit for patients with Basal Cell Carcinoma Nevus Syndrome (BCCNS, aka Gorlin Syndrome) and with a favorable safety profile.
Launched in September 2015, the multicenter, open-label, single-arm study has enrolled 37 patients. As summarized in a recent submission to the FDA, the interim analysis was based on 35 patients who had been taking SUBA-Itraconazole daily for a median duration of 32 weeks. Each patient had at least 10-15 pre-existing tumors that were of a size and location that made them surgically eligible. Together, the enrolled patients had a total of approximately 475 “target” BCCs. Prior to the study, the average number of surgically removed BCCs per patient was 195; overall, they had a total of approximately 6,800 prior surgical excisions.
Efficacy assessments showed that all patients achieved a measurable decrease in target tumor burden. Overall, 28 percent of target lesions completely disappeared, another 28 percent shrunk by ≥30 percent from baseline, only four lesions exhibited >20 percent growth (measured from the nadir), and the rest remained stable. Only one of the approximately 475 target BCCs required surgical resection.
Data from follow-up visits scheduled monthly for two months and then every two months thereafter showed the treatment has potential for rapid benefit. For example, in the first enrolled patient, seven of eight facial BCCs had disappeared at the month four visit.
Serious adverse events occurred in three patients, but all were determined to not be drug related. Side effect data show mostly Grade 1 toxicities that are typical for itraconazole. Higher grade (Grade 3) toxicities occurred in just a few patients. They included peripheral leg edema that required discontinuation of treatment, and liver enzyme elevations that were all manageable with dose reduction.
“Individuals with BCCNS face a lifelong constant battle with BCC management, and the challenges of their disorder make them desperate for intervention other than disfiguring surgery. Experience with SUBA-Itraconazole is still early, but the available data indicate it might provide a safe, well-tolerated, and effective oral agent for long-term treatment to suppress new tumor development, growth of existing BCCs, and perhaps for achieving clearance of some tumors,” says Elizabeth M. Billingsley, M.D., study investigator and professor of dermatology, Pennsylvania State University College of Medicine, Hershey, Penn.
Nick Virca, president and CEO of HedgePath Pharmaceuticals in Tampa, Fla., says, “The net clinical impact of SUBA-Itraconazole is that it has stabilized or greatly reduced the tumor burden for patients with BCCNS while causing minimal side effects and allowing them to avoid disfiguring surgery.
“Its development is one of the most meaningful projects that I have had the pleasure and honor to be involved with in the oncology space.”
The discovery that itraconazole inhibits the Hh pathway was made at Johns Hopkins University, Baltimore, Md., in a program designed to identify existing medications that have known acceptable toxicity profiles (FDA-approved or post-phase 1 drugs) as possible cancer therapeutics. The finding was a surprise considering that inhibition of fungal sterol biosynthesis was thought to be itraconazole’s only therapeutic activity.
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, Mr. 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 Burr, a BCCNS patient and executive director of the BCC Nevus Syndrome Life Support Network. Many of the 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. Because of itraconazole’s known safety profile, we proposed to the FDA that we could move immediately into a phase 2b clinical trial and were granted permission to do so,” Mr. Virca says.