The goal of the project is to identify for the first time, a brain-penetrant small molecule antagonist against Glial cell line-derived neurotrophic factor Family Receptor ?-Like (GFRAL) for the prevention and reversal of cancer anorexia-cachexia. Anorexia-cachexia is a debilitating, life threatening disease, associated with pronounced loss of appetite, skeletal muscle and fat mass. Cancer anorexia-cachexia constitutes a major unmet medical need, as 80% of patients with advanced cancers exhibit cachexia and 20% of cancer-related mortalities are derived from cachexia rather than direct tumor burden. Patients are less tolerant to radiotherapy, chemotherapy, pharmacotherapy and surgery. As a result, patients receive lower doses, reduced duration of treatment or are not eligible for treatment, indirectly decreasing survival. There is currently no approved treatment for anorexia-cachexia thus representing a high unmet medical need. The etiology of cancer anorexia-cachexia is attributed to abnormal metabolism, induced by tumor- derived cytokines. Precachectic and cachectic patients have elevated levels of Growth Differentiation Factor-15 (GDF-15) which is correlated with poor survival. GDF-15 has emerged as critical factor mediating anorexia-cachexia. Preclinically, GDF-15 causes anorexia in mice, rats and primates while blocking endogenous GDF-15 in cancer cachexia models, prevents and reverses anorexia-cachexia with an impressive 100% survival. Recently, it has been identified that GDF-15 mediates its effects via GFRAL located within the brainstem. Blocking the effect of GDF-15 via GFRAL with a small molecule versus a biologic offers the best opportunity to access the brain and achieve sufficient concentrations to block >90% of GFRAL. BYOMass is in a unique position for success in identifying druggable small molecule antagonists facilitated by our knowledge of crucial GDF-15 and GFRAL binding regions. A key advantage of a GFRAL antagonist versus other mechanisms tested to date in clinical trials, is that for the first-time a.) cachexia can be cured rather than address symptoms of cachexia and b.) a precision medicine approach can be used to identify patients based on their plasma GDF-15 levels to increase efficacy and the number of responders. A successful outcome of Phase 1 will be hit identification from 1-2 lead chemical series that reverses cancer cachexia in mice. Pending a Phase 2 grant, Phase 1 leads will be optimized to deliver a clinical candidate for Investigational New Drug enabling studies. The once daily, oral candidate will block >90% GFRAL in cancer patients with elevated levels of GDF-15 (<1 ng/mL). Blocking GFRAL will increase appetite, decrease catabolism and increase muscle mass, to enable optimal anti-cancer therapy and increase survival.

Public Health Relevance

The goal is to identify for the first time, a brain-penetrant small molecule blocker of GFRAL to treat anorexia- cachexia. Anorexia-cachexia is a debilitating, life-threatening disease that affects >5 million people in the US. There is no approved treatment, thus representing a high unmet medical need. Suppressing GDF-15 binding to GFRAL in cancer patients with elevated GDF-15 levels will increase appetite, decrease catabolism and increase muscle mass. This profile will enable patients to receive optimal anti-cancer therapy and prolong survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Weber, Patricia A
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Byomass, Inc.
United States
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