# Identification of first in class small molecule GFRAL blockers for the prevention and reversal of Cancer Anorexia-Cachexia

> **NIH NIH R43** · BYOMASS, INC. · 2020 · $55,000

## Abstract

Project Summary
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 α-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.

## Key facts

- **NIH application ID:** 10091640
- **Project number:** 3R43CA239961-01A1S1
- **Recipient organization:** BYOMASS, INC.
- **Principal Investigator:** Vivienne Margaret Jackson
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $55,000
- **Award type:** 3
- **Project period:** 2019-09-11 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091640

## Citation

> US National Institutes of Health, RePORTER application 10091640, Identification of first in class small molecule GFRAL blockers for the prevention and reversal of Cancer Anorexia-Cachexia (3R43CA239961-01A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10091640. Licensed CC0.

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