Cachexia pharmacotherapy: GDF-15 blockade, anamorelin, olanzapine
Cachexia pharmacotherapy covers three drug approaches to cancer wasting: a new antibody that blocks the hormone suppressing appetite, an appetite hormone mimic approved only in Japan, and a very cheap old tablet. None is yet standard everywhere; all beat what came before.
Historic options (progestins, corticosteroids, cannabinoids) improve appetite briefly but add fat or water, not muscle, and carry thrombotic or catabolic harms. Anamorelin, an oral ghrelin receptor agonist, increased lean body mass by about 1 kg over placebo in the ROMANA 1 and 2 phase 3 trials in NSCLC (Lancet Oncology 2016) without improving handgrip strength, which led the EMA to refuse it in 2017; Japan approved it in 2021 and real-world use there is substantial. Ponsegromab, a GDF-15-neutralising antibody, increased weight by 2.8 kg versus placebo at the highest dose over 12 weeks in a 187-patient phase 2 trial in patients with elevated GDF-15 (NEJM 2024), with gains in appetite, activity and lean mass, and is in phase 2/3 in pancreatic cancer cachexia. Low-dose olanzapine (2.5 mg) improved appetite and weight in a 124-patient randomised trial at Tata Memorial (JCO 2023) and was added to ASCO guidance in 2024 as a reasonable option. The field's endpoint problem, whether weight or lean mass gains translate into function and survival, is being addressed through regulatory endpoint qualification and combination with exercise and nutrition.
How it works
GDF-15 acts on GFRAL in the hindbrain to suppress appetite and drive catabolism; ghrelin agonism stimulates growth hormone and appetite; olanzapine antagonises serotonergic and histaminergic appetite-suppressing pathways and blocks nausea.
- First mechanism-based cachexia drug (ponsegromab) with a selection biomarker
- Olanzapine is generic, oral and available everywhere
- Anamorelin's lean mass effect is reproducible
- Weight gain has not yet been shown to prolong survival
- Anamorelin unavailable outside Japan
- Ponsegromab phase 3 data pending; cost will matter
Latest papers
topQuery for this technology: (TITLE:"Cachexia pharmacotherapy: GDF-15 blockade, anamorelin, olanzapine" OR ABSTRACT:"Cachexia pharmacotherapy: GDF-15 blockade, anamorelin, olanzapine") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Cachexia pharmacotherapy: GDF-15 blockade, anamorelin, olanzapine, not a curated reading list.