Addressing an unmet need
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.
Scenarios for use
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.
Regulatory status report
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.