Basal Cell Carcinoma
Newer formulations of Itraconazole may offer a significant alternative therapy to vismodegib, which is an oral drug marketed by Roche/Genentech, for treatment of locally advanced and metastatic basal cell carcinoma (BCC) or sonidegib, which is another oral drug marketed by Sun Pharma for locally advanced BCC.
Vismodegib was the first FDA-approved Hedgehog inhibitor-based therapy. However, it has many reported toxicities and is associated with side effects that can result in suspension of chronic dosing. As a result, basal cell tumors reoccur and patients are faced with the choice of returning to vismodegib therapy or, if and when possible, surgical alternatives. Sonidegib, the second FDA-approved Hedgehog inhibitor based-therapy, is also associated with significant toxicities, based on clinical trial reports, and is associated with side effects similar to those of vismodegib that may also result in suspension of dosing after only short periods of treatment or reluctance to use the drug at all.
INHIBITOR first targeted testing of SUBA-Itraconazole for treatment of BCC tumors in patients with Gorlin Syndrome, specifically BCCNS (a genetic disease which causes chronic BCC tumors) to address an unmet need in this patient population since neither vismodegib or sonidegib appear to be tolerable for other than short term therapy due to side-effects. We focused on the BCCNS population of approximately 10,000 patients in the United States, which has qualified SUBA-Itraconazole oral capsules for orphan drug designation as of May 2016. After the successful completion of the Phase 2b study in BCCNS, further clinical development of SUBA-Itraconazole was licensed to our corporate partner, Mayne Pharma with plans to initiate global Phase 3 testing during 2020.
Basal Cell Carcinoma
INHIBITOR has now entered into the second year of an Option Agreement with the University of Connecticut for exclusive world-wide rights to newly discovered and patented itraconazole analogues. The optioned field of use includes all therapeutic, prophylactic, and diagnostic uses for cancerous and non-cancerous cell proliferation disorders in humans. During the term of this exclusivity, UConn will not offer third parties the opportunity to license the patent portfolio or have rights to pending patents within this field of use. The option agreement continues for an exclusive option period of up to one more year while UConn and INHIBITOR collaborate on preclinical testing efforts for human BCC.
The itraconazole analogues, which are being developed by Dr. M. Kyle Hadden, Associate Professor of Medicinal Chemistry, Department of Pharmaceutical Sciences at UConn, have modifications to particular regions of the itraconazole scaffold. The patents and patent applications include compositions of matter claims covering the itraconazole analogues and method claims covering their use for the treatment of cancer. Data from Dr. Hadden’s laboratory suggest that certain of these analogues maintain potent Hedgehog Pathway inhibition while exhibiting improved pharmacokinetic parameters and reduced off-target side effects sometimes associated with itraconazole. Of particular interest to INHIBITOR are two U.S. patents issued to UConn in May and December of 2017 regarding itraconazole analogues and their methods of use and newly applied for patents for analogues with potentially higher Hedgehog pathway inhibition and greater in vivo solubility characteristics.
INHIBITOR and UConn continue to collaborate with Dr. Hadden’s lab to study the potential anti-cancer properties of these analogues on a pre-clinical basis with an initial focus on BCC. This effort is intended to help us determine the potential for these analogues as new itraconazole-based drugs which inhibit the Hedgehog pathway in human cells. The formulations of these analogues may also reduce the concern regarding the associated use of many other drugs that are contraindicated for patients being dosed with itraconazole. This effort by UConn is synergistic with INHIBITOR’s regulatory strategy to repurpose itraconazole as an anti-cancer therapy and has the potential to lead to the development of the next generation of itraconazole therapies for INHIBITOR. We believe that there is a significant opportunity for an even lower toxicity itraconazole therapy that would offer advantages over the use of vismodegib and sonidegib in BCC tumors that are poorly operable, and without prior treatment, would lead to surgical deformity, particularly BCC lesions that occur on the face and neck.
According to the Skin Cancer Foundation in 2018, there were over 4 million new cases of BCC in the U.S. and over 5 million procedures were used for treatment, with surgery being the primary approach to a cure. According to industry sources, there are approximately 65,000 cases of inoperable or poorly operable BCC lesions that could benefit from hedgehog pathway inhibition as an adjunct therapy to surgery which, if effective, could reduce the size of BCC tumors such that surgical disfigurement could be minimized. INHIBITOR believes that a low-toxicity formulation of a key itraconazole analogue developed by UConn might offer significant advantages over the currently approved Hh pathway inhibitors and lead to an expansion of this type of treatment for use as an adjunct therapy for BCC treatments that are normally only treated with surgery.