- Cachexia is a multifactorial syndrome driven by anorexia and systemic inflammation, causing weight loss, muscle wasting and impaired physical function.
- The GDF-15 GFRAL signalling axis is a primary mediator of cachexia and a promising target for antibody therapies.
- Ponsegromab, a selective anti-GDF-15 monoclonal antibody, improved body weight and cachexia symptoms; further anti-GDF-15 and anti-GFRAL agents need rigorous trials and endpoints.
Annu Rev Med. 2026 Aug 4. doi: 10.1146/annurev-med-042325-042958. Online ahead of print.
ABSTRACT
Cachexia is a complex, multifactorial syndrome driven by anorexia and systemic inflammation, ultimately resulting in a catabolic state characterized by weight loss, decreased muscle mass, and impaired physical function. Many chronic comorbidities are implicated in the pathophysiology of cachexia, with malignancy being one of the most common. Although approved cachexia-directed therapies are limited to date, the growth differentiation factor 15 (GDF-15)-glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) signaling axis has been identified as a primary mediator of cachexia and is an interesting pathway for cachexia-directed therapies and antibodies. Ponsegromab, a monoclonal antibody that is a highly selective and potent inhibitor of GDF-15, has resulted in improved body weight and other cachexia-related symptoms in patients with cancer. Other anti-GDF-15 and anti-GFRAL therapies are currently under investigation. Through the development of these treatments, many unexpected potential therapeutic applications have been identified, highlighting the broad, systemic impacts of cachexia. As research continues, it is imperative to focus on clear trial design and endpoints.
PMID:42552253 | DOI:10.1146/annurev-med-042325-042958
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