Novo Biosciences has identified three small molecule therapies that we are seeking to advance into clinical trials. Our lead small molecule, MSI-1436, has applications for stimulating the repair and regeneration of heart muscle following acute heart attack and for the slowing of muscle wasting in patients with Duchenne muscular dystrophy, as well as for other indications such as stimulating wound healing and reducing wound scarring. Our new lead molecules, ZF198 and ZF760, offer novel treatments for peripheral neuropathy induced by chemotherapy, diabetes and other conditions.
The human heart has little ability to repair itself after a myocardial infarction, or heart attack: the damaged heart muscle is replaced by nonfunctional scar tissue. Current therapies focus on minimizing damage, preventing secondary heart attacks and treating resultant heart failure; there are no approved treatments to stimulate the repair and regeneration of heart muscle.
Research in lower vertebrates and mice has demonstrated that MSI-1436 stimulates the regeneration of heart, skeletal muscle, skin, bone, nerve, connective and vascular tissue. Studies have demonstrated that the administration of MSI-1436 to mice 24 hours after artificially induced myocardial infarction greatly increases survival, stimulates cardiomyocyte (heart muscle cell) proliferation in the infarct border by threefold, improves heart function by twofold, reduces ventricular wall thinning and reduces infarct size by 55 percent four weeks post-MI. Tissue regrowth is stimulated without altering complex patterning or inducing tumor formation.
MSI-1436 is a readily synthesized, naturally occurring compound. As the subject of extensive pharmacological and toxicological study, it has been significantly de-risked by comparison with other pre-clinical stage drug candidates. Phase 1 and 1b clinical trials for an unrelated application have demonstrated that it is well tolerated by humans with no adverse effects. The doses that are effective in inducing heart repair and regeneration in animals are 50 times lower than the maximum safe human dose.
MSI-1436 also has the advantages of being relatively inexpensive, readily reversible and easy to administer.
ZF198 and ZF760
ZF198 and ZF760 can potentially be used to reverse peripheral neuropathy induced by cancer chemotherapy with paclitaxel, a widely used chemotherapeutic agent for breast, ovarian, lung and pancreas tumors, as well as AIDS-related Kaposi’s sarcoma. Currently, there are no effective treatments for the underlying causes of peripheral neuropathy, which affects approximately 70 percent of paclitaxel-treated patients.
Research in zebrafish has demonstrated that ZF198 and ZF760 prevent paclitaxel-induced neurotoxicity by inhibiting the activity of MMP-13 (matrix-metalloproteinase 13). MMP-13 is toxic to the nerves; it also increases the susceptibility of the skin on the hands and feet to injury from everyday stresses. The disruptions to the intricate interactions between the skin and nerves caused by the increase in MMP-13 are thought to contribute to paclitaxel-induced nerve damage.
When given with paclitaxel, these small molecules prevent the degeneration of peripheral neurons and restore the touch response in zebrafish. Studies in mice and studies in human skin tissue with collaborators at the Mayo Clinic are now underway.
ZF198 and ZF760 also have potential applications for treatment of peripheral neuropathy induced by other types of cancer chemotherapy and by diabetes, traumatic injury and other conditions.