Calpain Inhibitors for Cancer Related Neuropathies

DESCRIPTION (provided by applicant): Principal Investigator/Program Director: Glass, Jonathan D. Project Summary/Abstract Axona, Inc. is a new small-business engaged in the early stages of developing small molecules for the prevention of axonal degeneration and peripheral neuropathy. Axonal degeneration (or degeneration of axons) is a common pathological process that leads to disconnection of neurons from their targets, such as muscles or sensory organs. Peripheral neuropathy refers to the disease process of sensory loss, pain, and weakness that occurs in the legs and hands that is largely due to axonal degeneation in the peripheral nervous system. Peripheral neuropathy is a major side toxic effect of exposure to chemotherapy agents that are used for the treatment of cancers, and is termed "chemotherapy-induced peripheral neuropathy" or CIPN. There are currently no treatments. CIPN results in significant added morbidity for cancer patients and may require the clinician to reduce or even stop the dosing of the anti-cancer medications, potentially reducing their effectiveness in killing cancer cells. Axona has identified a small molecule calpain inhibitor, AK295, which prevents axonal degeneration and peripheral neuropathy in an animal model of CIPN. Calpains are calcium-activated proteases that are central to the process of axonal degeneration. Axona's long-term objective is to develop AK295 into a clinical drug for the prevention of CIPN. This Phase I STTR proposal describes research goals that are required on the path to approval of an IND applcation for testing AK295 in people. Our preliminary data show efficacy for the prevention of CIPN with continuous subcutaneous administration. Here we will test efficacy and measure dose-response using intravenous (IV), oral, or a combination of IV/oral administration. Our dose escalation toxicology studies show encouraging safety data for AK295. Here we will perform the necessary genotoxic (chromosomal aberration AMES tests) and channel inhibition (hERG) studies. Finally, we will develop methods for large-scale chiral synthesis of AK295, and other ketoamides, that will be needed for future clinical studies. Should we find AK295 unsuitable for further development, Axona has a library of over 120 Calpain inhibitor compounds that we would then further characterize. AK295 will be a "first in class" drug for the prevention of axonal degeneration and CIPN, an indication for which there are currently NO drugs on the market. An indication for CIPN will likely lead to trials in other neurological disorders such as stroke and diabetic neuropathy, which represent much larger markets. for STTR Resubmission for "Calpain Inhibitors for Cancer Related Neuropathies": This work is directly relevant to public health, as our research attempts to find treatments for the side-effects of chemotherapy. Such treatments may lead to more efficacious treatments for cancer, as more people will be able to tolerate either higher levels of chemotherapy or longer courses of treatment. The overall number of cancer cases is projected to grow driven largely by aging population growth, as nearly 80% of all cancers are diagnosed in people ages 55 and older. The Census Bureau has said that two thirds of all people who ever lived past 65 were alive in 2001, and rapid growth of the population age 65 and over will begin in 2011, when the first of the baby-boom generation reaches age 65, continuing for many years thereafter.