In order to bring Interlaced Therapy™ to the bedside as quickly as possible, Tau’s strategy is to reposition a previously marketed T-type calcium channel blocker in Interlaced Therapy™ for the treatment of solid tumor cancers, beginning with brain cancer.
Mibefradil dihydrochloride (mibefradil) is Tau’s repurposed drug, a T-type calcium channel blocker with a broad spectrum of anti-cancer potential. Mibefradil was used by hundreds of thousands of patients worldwide for the treatment of hypertension. It is a well-tolerated drug and was the first marketed T-type calcium channel blocker. It was marketed until 1998, when interactions with other drugs prevented its continued use for hypertension. For cancer patients, Tau believes these interactions will not prohibit approval or materially diminish the use of mibefradil. Tau has demonstrated the utility of mibefradil for Interlaced Therapy™ in a number of in vivo model systems.
Tau is currently studying mibefradil in a Phase I trial in normal healthy volunteers. A Phase Ib dose finding trial of mibefradil in patients with recurrent high-grade glioma is being conducted with the National Cancer Institute.
In collaboration with the Preston Robert Tisch Brain Tumor Center at Duke University and with support from the Accelerate Brain Cancer Cure Foundation, Tau has investigated Interlaced Therapy™ in animal models of glioblastoma multiforme (GBM), the most common form of brain cancer, using mibefradil in sequence with temozolomide, the standard of care chemotherapy for GBM. Mibefradil was given prior to temozolomide to arrest and synchronize cancer cells just prior to the S phase, the phase of the cell cycle in which cancer cells are susceptible to temozolomide. This administration of mibefradil caused the cancer cells to hold in place just prior to the S phase of the cell cycle. Mibefradil was then withdrawn and temozolomide was given. The withdrawal of mibefradil allowed the bolus of cancer cells to enter S phase, the point at which they are vulnerable to temozolomide’s toxicity.
In extensive preclinical studies of Interlaced Therapy™ with mibefradil at Duke University, human GBM tumor cell lines implanted both subcutaneously and intracranially in immunocompromised mice produced outstanding results, including a dramatic increase in lifespan.
One of the key elements of Interlaced Therapy™ with mibefradil is its ability to overcome temozolomide resistance. Temozolomide alkylates DNA, causing damage that can be repaired by methylguanine methyltransferase (MGMT) among other pathways. Over half of patients with brain cancer have expression of MGMT at the time of diagnosis, causing their cancers to be resistant to therapy with temozolomide. In animal models, Interlaced Therapy™ overcomes temozolomide resistance by limiting the time available for DNA repair.