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
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Pages like this
not linked directly; found by shared links- IdeaConfirm low-dose olanzapine for appetite and weight in advanced cancer worldwide
Shares Low-dose olanzapine for cancer anorexia (Tata Memorial), Tata Memorial Centre, Cachexia, toxicity and the limits of the patient, No incentive to repurpose cheap drugs.
- IdeaCombine the new anti-wasting antibody with exercise and protein
Shares Ponsegromab phase 2 in cancer cachexia, Resistance training and protein for cachexia and sarcopenia, Cachexia, toxicity and the limits of the patient, Pfizer (incl. Seagen).
- TechnologyOncology nutrition assessment and medical nutrition therapy
Shares Sarcopenia, Body composition (lean mass, fat mass, visceral fat), Nutrition support and cachexia management, Cancer cachexia.
- TermNutrition impact symptoms
Shares Antiemetics for chemotherapy-induced nausea and vomiting, Low-dose olanzapine for cancer anorexia (Tata Memorial), Cancer cachexia, Cachexia, toxicity and the limits of the patient.
- IdeaTreat cachexia before it starts
Shares Ponsegromab phase 2 in cancer cachexia, Cancer cachexia, Gastric & gastro-oesophageal junction cancer, Pancreatic ductal adenocarcinoma.
- IdeaA dietitian in every gastrointestinal and head and neck tumour board
Shares Nutrition support and cachexia management, Cancer cachexia, Cachexia, toxicity and the limits of the patient, Gastric & gastro-oesophageal junction cancer.
- TechnologyExercise & lifestyle oncology
Shares Qualify a physical function endpoint so anti-wasting drugs can be approved, Treat cachexia as a disease: GDF-15 blockade plus anabolic and nutrition bundles, Get the one approved appetite drug licensed beyond a single country, Cachexia-directed therapy (GDF-15 blockade).
- TermMalnutrition screening tools (MUST, NRS-2002, MST, PG-SGA)
Shares Sarcopenia, Nutrition support and cachexia management, Cancer cachexia, Cachexia, toxicity and the limits of the patient.