In animal models and in human testing in lung cancer, itraconazole has demonstrated an anti-angiogenic effect (i.e., inhibiting the formation of new blood vessels), which may be important in controlling the proliferation of cancerous cells and tumors in humans based upon its interaction with certain cell-based growth factors. Itraconazole also appears to induce changes related to the mTOR pathway, an important regulator of cell growth, proliferation and survival which, when unregulated, can also lead to cancer.
The Hedgehog signaling pathway is a major regulator of many fundamental cellular processes in vertebrates, primarily at the embryonic stage of development, but also as it relates to stem cell maintenance, cell differentiation, tissue polarity, and cell proliferation. Research has shown that activation of the Hedgehog pathway can lead to the formation of cancerous tumors (a process known as tumorigenesis), contributing to prostate, lung, brain, gastrointestinal, breast, and basal cell cancers. Hedgehog signaling from the tumor to the surrounding cell structures has been shown to sometimes promote further tumorigenesis as reported in recent scientific publications regarding this pathway and has also been shown to regulate proliferation of cancer stem cells and increase tumor invasiveness.
Research indicates that inhibiting the Hedgehog pathway could delay or possibly prevent the development of certain cancers in humans. Therefore, we believe that the targeted inhibition of Hedgehog signaling may be effective in the treatment and prevention of many types of human cancers. The orally available drug, Erivedge® (vismodegib capsules, developed by Genentech, a subsidiary of Roche), was the first Hedgehog inhibitor-based therapy approved for treatment of advanced stages of basal cell carcinoma by the U.S. Food and Drug Administration (FDA) in 2012.
In 2015, FDA approved a second Hedgehog inhibitor, oral Odomzo® (sonidegib capsules developed by Novartis Pharmaceuticals Corporation and sold to Sun Pharma in 2017) for treatment of patients with locally advanced BCC that has recurred following surgery or radiation therapy or for patients who are not candidates for surgery or radiation therapy. While both vismodegib and sonidegib have demonstrated remarkable reductions of BCC tumor burden, they are also associated with adverse effects including alopecia, dysgeusia, weight loss and fatigue, necessitating periodic breaks where chronic treatment is required and challenges with compliance, which we believe will continue to limit use of either drug.
In Phase 2 testing conducted by INHIBITOR, SUBA-Itraconazole demonstrated BCC target tumor inhibition without causing the classical Hedgehog (Hh) pathway adverse events in patients with BCCNS, leading to the promise of improved tolerability and the potential to maximize efficacy enabled by continuous Hedgehog pathway inhibition to manage this genetic condition. INHIBITOR’s majority shareholder and licensing partner, Mayne Pharma, assumed further development for this indication and is currently planning the launch global Phase 3 testing of SUBA-Itraconazole for treatment of BCC lesions in patients with BCCNS in 2020.