{"entity":{"id":"ponatinib","kind":"drug","name":"Ponatinib","aka":[],"tldr":"Ponatinib is the only BCR::ABL1 inhibitor that covers the T315I resistance mutation. In 2024 it became the preferred pill for newly diagnosed Ph-positive ALL.","summary":"PhALLCON (n=245): ponatinib vs imatinib with reduced-intensity chemotherapy in newly diagnosed Ph+ ALL, MRD-negative CR at end of induction 34.4% vs 16.7%; accelerated approval March 2024. Also approved in CML (T315I and resistant disease) since 2012, with a 2013 temporary market suspension for arterial occlusive events that led to dose-reduction strategies (OPTIC). Ponatinib + blinatumomab chemotherapy-free regimens (MD Anderson) report near-universal molecular remission without transplant.","status":"approved","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Ponatinib","links":[{"label":"FDA label (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Ponatinib"}],"tags":[],"related":["bcr-abl1-t315i"],"cancers":["all-leukemia","cml-advanced-phase"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["bcr-abl","abl1"],"drugs":[],"companies":["takeda"],"institutions":[],"pathways":[],"terms":["ph-positive-all"],"trials":["phallcon","nct04233346","nct03934372"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"brand":"Iclusig","modality":"Small-molecule kinase inhibitor (pan-BCR::ABL1 incl. T315I)","mechanism":"Type II TKI binding inactive ABL1 with a carbon-carbon triple bond that accommodates the T315I gatekeeper; also inhibits FGFR, VEGFR, SRC.","approvals":[{"region":"US","year":2012,"indication":"CML and Ph+ ALL resistant to prior TKIs or with T315I"},{"region":"US","year":2024,"indication":"Newly diagnosed Ph+ ALL with chemotherapy (accelerated)"}],"mechanismSteps":["Ponatinib binds the ATP pocket of BCR::ABL1, including T315I mutants","Constitutive kinase signalling (STAT5, RAS, PI3K) stops","Ph+ lymphoblasts undergo apoptosis","Dose is reduced once response is achieved to limit vascular events"],"dosing":{"route":"Oral","schedule":"Ph+ ALL: 30 mg daily with chemotherapy, reduced to 15 mg once MRD-negative CR is achieved; CML: 45 mg daily reducing to 15 mg on response (OPTIC)","monitoring":"Arterial occlusive events, venous thromboembolism, heart failure, hepatotoxicity (boxed warnings); blood pressure; lipase","source":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Iclusig"},"toxicity":[{"event":"Arterial occlusive events","anyGradePct":26,"source":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Iclusig","note":"CML long-term data at 45 mg; lower with response-based dose reduction"},{"event":"Hypertension","anyGradePct":68},{"event":"Pancreatitis / lipase elevation","anyGradePct":40},{"event":"Hepatotoxicity","note":"Boxed warning"}],"access":[],"regulatoryEvents":[{"date":"2012-12-14","type":"accelerated-approval","region":"US","note":"Resistant CML/Ph+ ALL","indication":"Adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia resistant or intolerant to TKI therapy or or Philadelphia chromosome positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy"},{"date":"2013-10-31","type":"withdrawal","region":"US","note":"Temporary marketing suspension for arterial occlusion; returned with narrowed label December 2013"},{"date":"2016-11-28","type":"conversion","region":"US","note":"Confirmed: the accelerated approval of 2012 converted to traditional approval 4.0 years after it was granted.","indication":"Adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia resistant or intolerant to TKI therapy or or Philadelphia chromosome positive acute lymphoblastic leukemia resistant or intolerant to prior TKI therapy"},{"date":"2024-03-19","type":"accelerated-approval","region":"US","note":"Frontline Ph+ ALL (PhALLCON), accelerated The confirmatory requirement was still open 2.5 years later, when the FDA's table was read.","indication":"Adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy."}]},"route":"/drugs/ponatinib/","neighbours":{"biomarker":[{"id":"bcr-abl1-t315i","kind":"biomarker","name":"BCR::ABL1 T315I","route":"/biomarkers/bcr-abl1-t315i/"},{"id":"bcr-abl1-transcript","kind":"biomarker","name":"BCR::ABL1 transcript (Philadelphia chromosome, quantitative PCR)","route":"/biomarkers/bcr-abl1-transcript/"}],"cancer":[{"id":"all-leukemia","kind":"cancer","name":"Acute lymphoblastic leukaemia","route":"/cancers/all-leukemia/"},{"id":"cml","kind":"cancer","name":"Chronic myeloid leukaemia (CML)","route":"/cancers/cml/"},{"id":"cml-advanced-phase","kind":"cancer","name":"Chronic myeloid leukaemia, accelerated and blast phase","route":"/cancers/cml-advanced-phase/"},{"id":"cml-chronic-phase","kind":"cancer","name":"Chronic myeloid leukaemia, chronic phase","route":"/cancers/cml-chronic-phase/"},{"id":"all-paediatric-ph-positive","kind":"cancer","name":"Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL)","route":"/cancers/all-paediatric-ph-positive/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"abl1","kind":"target","name":"ABL1","route":"/targets/abl1/"},{"id":"bcr-abl","kind":"target","name":"BCR::ABL1 (Philadelphia chromosome)","route":"/targets/bcr-abl/"},{"id":"stat5","kind":"target","name":"STAT5 (STAT5A, STAT5B)","route":"/targets/stat5/"}],"company":[{"id":"takeda","kind":"company","name":"Takeda","route":"/companies/takeda/"}],"term":[{"id":"abl1-kinase-domain-mutations","kind":"term","name":"BCR::ABL1 kinase domain mutations (T315I and others)","route":"/terms/abl1-kinase-domain-mutations/"},{"id":"gatekeeper-mutation","kind":"term","name":"On-target resistance mutations (gatekeeper, solvent-front, compound)","route":"/terms/gatekeeper-mutation/"},{"id":"ph-positive-all","kind":"term","name":"Ph-positive ALL","route":"/terms/ph-positive-all/"},{"id":"philadelphia-chromosome","kind":"term","name":"Philadelphia chromosome (Ph+, BCR::ABL1)","route":"/terms/philadelphia-chromosome/"}],"trial":[{"id":"phallcon","kind":"trial","name":"PhALLCON","route":"/trials/phallcon/"},{"id":"nct03934372","kind":"trial","name":"Safety and Efficacy of Ponatinib for Treatment of Pediatric Recurrent or Refractory Leukemias, Lymphomas or Solid Tumors","route":"/trials/nct03934372/"},{"id":"nct04233346","kind":"trial","name":"The Study for CML Who Failed Prior TKIs or With T315I Mutation or Ph+ ALL Who Failed Prior TKIs or With T315I Mutation","route":"/trials/nct04233346/"},{"id":"nct06813079","kind":"trial","name":"Using Tumor Models to Determine Treatments","route":"/trials/nct06813079/"}],"pairing":[{"id":"tki-plus-blinatumomab-ph-all","kind":"pairing","name":"BCR::ABL1 TKI + blinatumomab (chemotherapy-free Ph+ ALL)","route":"/pairings/tki-plus-blinatumomab-ph-all/"}],"idea":[{"id":"idea-transplant-free-ph-all","kind":"idea","name":"Transplant-free Ph-positive ALL for MRD-negative adults","route":"/ideas/idea-transplant-free-ph-all/"}],"pathway":[{"id":"bcr-abl1-signalling","kind":"pathway","name":"BCR::ABL1 (Philadelphia chromosome)","route":"/pathways/bcr-abl1-signalling/"},{"id":"cml-signalling","kind":"pathway","name":"Chronic myeloid leukaemia (KEGG map)","route":"/pathways/cml-signalling/"}],"paper":[{"id":"paper-pace-ponatinib-nejm-2013","kind":"paper","name":"PACE: ponatinib in Philadelphia chromosome-positive leukaemias resistant to earlier tyrosine kinase inhibitors","route":"/key-papers/paper-pace-ponatinib-nejm-2013/"}]}}