A novel oral formulation of itraconazole designed to improve bioavailability is leveraging its activity as a Hedgehog pathway inhibitor to provide a low toxicity, effective treatment for patients with BCC Nevus Syndrome. Data show potential for rapid therapeutic benefit.
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.
Dr. Billingsley“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.
HedgePath Pharmaceuticals is pursuing treatment of BCCNS as its initial indication. In contrast, the two Hh pathway inhibitors that are FDA approved-vismodegib (Erivedge, Genentech) and sonidegib, (Odomzo, Sun Pharma)-are indicated 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.
Compared to itraconazole, vismodegib and sonidegib are more potent Hh pathway inhibitors, but more significant toxicity comes part and parcel with that greater activity.
“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. In clinical trials of vismodegib for BCCNS, there was a 54% dropout rate due to serious or intolerable side effects,” Mr. Virca says.
“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,” he adds.
Dr. Billingsley notes that toxicity has been a treatment-limiting issue with the use of vismodegib or sonidegib among patients with BCCNS.
“When vismodegib first became available, patients with BCCNS were very excited because it brought a first sense of hope that they might be able to minimize the need for surgery. And, in my experience, both vismodegib and sonidegib have been very effective for shrinking and clearing BCCs and more effective than SUBA-Itraconazole, presumably because they are more potent Hh pathway inhibitors,” Dr. Billingsley says.
“Nevertheless, many patients have been unable to continue vismodegib or sonidegib long-term because of their side effects. SUBA-Itraconazole has been incredibly well tolerated. Side effects have been minimal and the majority of patients tolerated the medication extremely well.”
James A. Solomon, M.D., Ph.D., an investigator in the SUBA-Itraconazole trial and professor dermatology, University of Central Florida College of Medicine, Orlando, says that in his patients, SUBA-Itraconazole has been associated with shrinkage or disappearance of some tumors while slowing the growth of others, but not all existing BCCs respond and the treatment has not completely prevented the appearance of new tumors.
Variability in BCC response that has been observed between patients and within patients may have a genetic explanation, Dr. Solomon says.
“We have found there is a subgroup of people with BCCNS who do not have an abnormality of the Hedgehog signaling pathway, including some individuals who have family with a PTCH mutation. The possibility also exists that individual BCCs may development independent of a Hh signaling abnormality in a person with BCCNS and a PTCH mutation,” he explains.
Should SUBA-itraconazole become available, dermatologists would likely come up with a variety of ways to integrate it into the care of patients with BCCNS. One potential role would be as a lower toxicity maintenance therapy for patients previously treated with vismodegib or sonidegib, although it remains to be seen whether SUBA-Itraconazole can maintain control of tumors that were shrunk by treatment with the more potent Hh inhibitors, Dr. Solomon says.
It is also appealing to think that SUBA-itraconazole could be used as a neoadjuvant to Mohs surgery in order to reduce tumor burden and size of the surgical defect. But, as with the other Hh inhibitors, it is yet to be determined whether this approach results in histological cure or is associated with an increased risk for leaving residual tumor cells that can lead to recurrence if the medication is stopped, Dr. Solomon says.
The potential for pediatric use is another area of interest. Sonidegib and vismodegib have not been studied in children and in animal studies were found to have toxic effects on a number of tissues. Itraconazole has been used as an antifungal treatment in children without evidence of serious toxicity. With that background and because itraconazole is a less potent Hh inhibitor than vismodegib and sonidegib, it may be easier to obtain FDA approval to conduct a study investigating SUBA-itraconazole in children, Dr. Solomon says.
“Nevertheless, we cannot overlook the possibility that there may be safety concerns associated with itraconazole in children with BCCNS that are not present in the general population or vice versa. Certainly, further study is needed to make sure that any benefit of treatment in children outweighs the risk,” he says.
Use of SUBA-itraconazole will also need to take into account its potential for drug interactions with other medications that are metabolized by the cytochrome P450 3A4 isoenzyme system.
“There are a number of drugs that are contraindicated for coadministration with itraconazole, and their use might exclude patients from treatment with SUBA-itraconazole. However, there are still plenty of people who could benefit from it,” Dr. Solomon says.
HedgePath Pharmaceuticals was granted an Orphan Drug Designation for SUBA-Itraconazole in May 2016 and received a written response from the FDA to its Type-C Meeting background package in 2017 that provided further guidance on steps necessary for completing the Phase 2b study and reporting final data.
The FDA confirmed FDA that HedgePath may follow the more streamlined 505(b)(2) regulatory pathway, agreed that no additional nonclinical toxicology studies appear necessary to support filing an NDA, and indicated it would accept a single study to support an NDA if results show a significant effect on a clinically meaningful endpoint, ie., evidence of an objective reduction in tumor burden that is durable. More information is available at www.hedgepathpharma.com.
Mr. Virca is an employee of and shareholder in HedgePath Pharmaceuticals.