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New pathways to cancer therapy


A novel oral formulation of itraconazole (SUBA-Itraconazole, HedgePath Pharmaceuticals) is providing dramatic benefit for patients with basal cell carcinoma nevus syndrome (BCCNS, also known as Gorlin syndrome) and with a favorable safety profile, according to a recent interim analysis of data collected in a phase IIb study.

Reviewed by Frank E. O’Donnell Jr., MD

A novel oral formulation of itraconazole (SUBA-Itraconazole, HedgePath Pharmaceuticals) is providing dramatic benefit for patients with basal cell carcinoma nevus syndrome (BCCNS, also known as Gorlin syndrome) and with a favorable safety profile, according to a recent interim analysis of data collected in a phase IIb study.

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 to 15 pre-existing tumors of a size and location that made them surgically eligible. Together, the enrolled patients had a total of about 475 “target” basal cell carcinomas (BCCs). Prior to the study, the average number of surgically removed BCCs per patient was 195. Overall, they had a total of about 6,800 prior surgical excisions.

Efficacy assessments showed that all patients achieved a measurable decrease in target tumor burden. Overall, 28% of target lesions completely disappeared and another 28% shrunk by ≥30%. Only 4 lesions exhibited >20% growth with the rest remaining stable. Only 1 of about 475 target BCCs required surgical resection.

Data from follow-up visits scheduled at weeks 4, 8, and every 8 weeks thereafter showed treatment can have a rapid onset of benefit. For example, in the first enrolled patient, 7 of 8 facial BCCs had disappeared at the week 16 visit.

Serious adverse events occurred in 3 patients, but all were determined not to 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.

“BCCNS is an autosomal dominant condition that affects an estimated 10,000 people in the United States,” said Frank E. O’Donnell, Jr., MD, formerly chairman, Department of Ophthalmology, St. Louis University School of Medicine, St. Louis, MO, and now manager of Hopkins Capital Group LLC, an investment company whose mission is identification and development of disruptive innovations in healthcare.

“These patients can develop hundreds to thousands of BCCs on the head, neck, and body over a lifetime--treatment for which has historically been surgical,” he said. “SUBA-Itraconazole is an exciting advance because it is showing promise for becoming the first oral treatment that can both address existing tumors and be used as chronic therapy to prevent the development of new BCCs for patients with this genetically driven disease.”

“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,” said Nick Virca, president and chief executive officer, HedgePath Pharmaceuticals, Tampa, FL.

Drug development


Drug development

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.

BCC tumor response of 50% reduction after 4 weeks of SUBA-Cap dosing in the company's clinical trial to study the effect of its oral therapy on BCC lesions in patients with BCCNS. Images courtesy of HedgePath Pharmaceuticals.

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.”

Addressing unmet need


Addressing unmet need

HedgePath Pharmaceuticals is pursuing treatment of BCCNS as its initial indication, although the molecular defect responsible for this genetic disease is also present in about 90% of sporadic BCCs and has been found in prostate, lung, and other tumors.

Two Hh pathway inhibitors are FDA approved--vismodegib (Erivedge, Genentech) and sonidegib (Odomzo, Sun Pharmaceutical). Both have indications for the treatment of adults with locally advanced BCC that has recurred following surgery or who are not candidates for surgery. Vismodegib is also approved to treat metastatic BCC.

In contrast to itraconazole, vismodegib and sonidegib are more potent Hh pathway inhibitors, but because of that activity, they are associated with more significant toxicity.

“In adults, the Hh pathway is also involved in tissue maintenance functions, and its inhibition by vismodegib and sonidegib causes hair loss, taste disturbances, muscle contraction, and nausea,” Virca said. “In clinical trials of vismodegib for BCCNS, there was a 54% dropout rate due to serious or intolerable side effects.”

Even if patients with BCCNS are able to obtain off-label insurance coverage for vismodegib and sonidegib, they may not be able to continue with chronic use that is needed to suppress tumor growth and development, Virca noted.

Because of a predilection for BCCs to develop on sun-exposed skin, an ophthalmologist may be the first physician to identify a patient with BCCNS, according to Dr. O’Donnell.

“Therefore, any ophthalmologist who sees a patient, especially a young person, with multiple BCCs around the eyes or elsewhere on the face should immediately suspect the diagnosis of BCCNS,” he said.

“The eyelid is one location where development of these tumors has real functional implications,” Dr. O’Donnell added. “There are just so many times that a patient can undergo surgical resection of eyelid lesions without developing exposure keratopathy and become at risk for irreversible loss of vision.”

Regulatory status report


Regulatory status report

HedgePath plans to submit a complete background package for its phase IIb study results to the FDA by the middle of June, and the agency has indicated it plans to provide a written response by the end of July 2017 with further guidance on steps necessary for completing the study and reporting final data. 






Frank E. O’Donnell Jr., MD
E: feomdjr@gmail.com
Dr. O’Donnell is a consultant to HedgePath Pharmaceuticals and a shareowner.

Nick Virca
E: nvirca@hedgepathpharma.com
Virca is an employee of and owns shares in HedgePath Pharmaceuticals.

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