{"entity":{"id":"nirogacestat","kind":"drug","name":"Nirogacestat","aka":[],"tldr":"Nirogacestat is the first approved medicine for desmoid tumours, locally invasive growths that do not spread but can be crippling; it works by blocking Notch signalling.","summary":"Nirogacestat is an oral gamma-secretase inhibitor that prevents cleavage of Notch receptors and release of the Notch intracellular domain; desmoid tumours, driven by CTNNB1 or APC mutations, depend on crosstalk between Notch and Wnt signalling. In the phase 3 DeFi trial it reduced progression with a PFS HR of 0.29 versus placebo, produced objective responses in 41% versus 8%, and improved patient-reported pain and physical function (NEJM 2023). The FDA approved it on 27 November 2023 as the first systemic therapy for progressing desmoid tumours, and the EU followed in 2025. Diarrhoea is common, and ovarian toxicity affected 75% of women of childbearing potential, largely reversing on stopping. SpringWorks developed it and was acquired by Merck KGaA. Desmoid tumours never spread but can be crippling, and this is the first medicine proven to shrink them.","status":"approved","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Nirogacestat","links":[{"label":"FDA label (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Nirogacestat"}],"tags":[],"related":[],"cancers":["sarcoma","desmoid-tumour"],"sections":[],"technologies":["kinase-inhibitors","gamma-secretase-inhibitors"],"targets":[],"drugs":[],"companies":["springworks"],"institutions":[],"pathways":["wnt"],"terms":[],"trials":["defi","nct07084896","nct07170644","nct07150091","nct07150104"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"brand":"Ogsiveo","modality":"Small-molecule gamma-secretase inhibitor","mechanism":"Inhibits gamma-secretase, preventing Notch receptor cleavage and NICD release; desmoid tumours (CTNNB1 or APC mutant) depend on Notch/Wnt crosstalk.","approvals":[{"region":"US","year":2023,"indication":"Progressing desmoid tumours requiring systemic treatment"},{"region":"EU","year":2025,"indication":"Progressing desmoid tumours"}],"mechanismSteps":["Nirogacestat binds the gamma-secretase complex","Notch receptors are not cleaved after ligand binding","No Notch intracellular domain reaches the nucleus","Desmoid fibroblast proliferation and matrix production fall","Tumours shrink slowly over months"],"dosing":{"route":"Oral","schedule":"150 mg twice daily continuously","monitoring":"Diarrhoea, ovarian function/hormones, phosphate, liver enzymes, skin, non-melanoma skin cancer"},"toxicity":[{"event":"Diarrhoea","anyGradePct":84,"grade3PlusPct":16,"note":"DeFi"},{"event":"Ovarian toxicity","anyGradePct":75,"note":"women of childbearing potential; mostly resolved on stopping"},{"event":"Rash","anyGradePct":68},{"event":"Hypophosphataemia","anyGradePct":65}],"access":[],"regulatoryEvents":[{"date":"2023-11-27","type":"approval","region":"US","note":"First systemic therapy for desmoid tumours (DeFi)","source":"https://www.onclive.com/view/fda-approves-nirogacestat-for-desmoid-tumors"},{"date":"2025","type":"approval","region":"EU","note":"European Commission approval","source":"https://www.onclive.com/view/nirogacestat-wins-eu-approval-for-progressing-desmoid-tumors"}]},"route":"/drugs/nirogacestat/","neighbours":{"cancer":[{"id":"desmoid-tumour","kind":"cancer","name":"Desmoid tumour","route":"/cancers/desmoid-tumour/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"}],"technology":[{"id":"gamma-secretase-inhibitors","kind":"technology","name":"Gamma-secretase inhibitors","route":"/technologies/gamma-secretase-inhibitors/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"company":[{"id":"merck-kgaa","kind":"company","name":"Merck KGaA (EMD Serono)","route":"/companies/merck-kgaa/"},{"id":"springworks","kind":"company","name":"SpringWorks Therapeutics (Merck KGaA)","route":"/companies/springworks/"}],"pathway":[{"id":"notch","kind":"pathway","name":"Notch signalling","route":"/pathways/notch/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"trial":[{"id":"nct07170644","kind":"trial","name":"A Study of Nirogacestat in Japanese Adults With Desmoid Tumors/Aggressive Fibromatosis (DT/AF)","route":"/trials/nct07170644/"},{"id":"defi","kind":"trial","name":"DeFi","route":"/trials/defi/"},{"id":"nct04126200","kind":"trial","name":"Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple","route":"/trials/nct04126200/"},{"id":"nct07150104","kind":"trial","name":"Sub-study of Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Nirogacestat, Pomalidomide, and Dexamethasone in Participants Wi","route":"/trials/nct07150104/"},{"id":"nct07084896","kind":"trial","name":"Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Nirogacestat in Participants With RRMM","route":"/trials/nct07084896/"},{"id":"nct07150091","kind":"trial","name":"Sub-study of Belantamab Mafodotin (GSK2857916) in Combination With Nirogacestat, Lenalidomide, and Dexamethasone in Participants With RRMM","route":"/trials/nct07150091/"}],"idea":[{"id":"idea-desmoid-intermittent-dosing","kind":"idea","name":"Intermittent or stop-and-restart nirogacestat in desmoid tumours","route":"/ideas/idea-desmoid-intermittent-dosing/"}],"target":[{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"ctnnb1","kind":"target","name":"CTNNB1","route":"/targets/ctnnb1/"},{"id":"gamma-secretase","kind":"target","name":"Gamma-secretase (PSEN1)","route":"/targets/gamma-secretase/"}],"bottleneck":[{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}]}}