Anorexia-cachexia is a debilitating, life-threatening disease, associated with pronounced loss of appetite, skeletal muscle and fat mass. Anorexia-cachexia constitutes a major unmet medical need, as 80% of patients with advanced cancers exhibit cachexia and 20% of mortalities are derived from cachexia rather than tumor burden. Patients are less tolerant to radiotherapy, chemotherapy, pharmacotherapy and surgery. There are no approved treatments representing a high unmet medical need. The etiology of cancer anorexia-cachexia is attributed to abnormal metabolism, induced by tumor-derived cytokines. Patients with elevated plasma levels of tumor-derived GDF-15 and Activin-A are associated with weight loss and poor survival. GDF-15 and Activin-A are causal factors mediating anorexia and muscle wasting, respectively. Overexpressing GDF-15 and Activin-A results in anorexia and muscle atrophy. Blocking endogenous GDF-15 and Activin-A in tumor-induced weight loss models, reverses cachexia and dramatically prolongs survival. The goal is to identify bispecific antibodies against GDF-15 and Activin-A. A successful outcome will be to prioritize 10 diverse leads. The clinical candidate will suppress plasma levels of GDF-15 to <1 ng/mL and Activin-A to <0.4 ng/mL in cancer patients. Suppressing GDF-15 and Activin-A will increase appetite, decrease catabolism, reverse muscle atrophy, increase bone strength and suppress metastatic lesions. Collectively, this unique profile will enable patients to receive optimal anti-cancer therapy to increase survival and quality of life.
