Ponatinib

• AP24534
• Iclusig
• IUPAC: 3 - ( imidazo [1,2- b] pyridazin-3 - ylethynyl )-4- methyl-N- (4 - ( (4- methylpiperazin -1-yl ) methyl ) -3 - (trifluoromethyl ) phenyl) benzamide

L01XE24

Cytostatic

Tyrosine kinase inhibitor

Template: Infobox chemical / molecular formula search available

Ponatinib (trade name Iclusig; manufacturer Ariad Pharmaceuticals) is a drug which is used in the treatment of chronic myeloid leukemia ( CML), or BCR -ABL -positive acute lymphoblastic leukemia (ALL ) are used.

Mechanism of action

Ponatinib is a tyrosine kinase inhibitor ( TKI) with antiangiogenic and antineoplastic effects. The orally administrable substance inhibits multiple tyrosine kinases, including those from the ABL, SRC, VEGFR and FGFR family.

Ponatinib is mainly therefore of great therapeutic interest, because the substance is also in the BCR -ABL T315I mutation effect in all other currently approved TKIs ( imatinib, nilotinib, dasatinib, Bosutinib ) are ineffective. The substance is effective in daily doses of 45 mg once.

History of development

Ponatinib was developed by the pharmaceutical company Ariad Pharmaceuticals, initially under the internal designation AP24534. The request in August 2012 to the U.S. Food and Drug Administration ( FDA) request for accelerated approval was positively decided in December 2012. The approval was for the treatment of patients with chronic myeloid leukemia ( CML) or BCR -ABL - positive acute lymphoblastic leukemia ( ALL) who are resistant to other tyrosine kinase inhibitors, or where they can not be administered due to incompatibility issued. Basis were the results of the PACE trial. The medicine arrived in the U.S. under the trade name Iclusig on the market. In July 2013, the approval for the same application areas followed by the EU Commission for the European market.

The in November 2013, published in the New England Journal of Medicine updated results of the PACE trial study showed in a group of 449 heavily pretreated patients with CML or BCR -ABL - positive ALL, in which nilotinib and dasatinib were intolerant of, or has been ineffective or the BCR -ABL mutation contributed T351, a wholly remarkable effectiveness. However, the effect was significantly worse in CML in blast crisis and ALL than in CML in chronic phase. Arterial thrombotic events were observed in 9% of patients treated with ponatinib patients, of whom 3% were attributed to the treatment.

As part of the EPIC trial ( Evaluation of Imatinib in Chronic Myeloid Ponatinib versus Leukemia ), efficacy of ponatinib compared to imatinib in previously untreated CML patients, ie tested in the first line. On October 18, 2013 Ariad Pharmaceuticals announced the early termination of this study revealed after it had come to a high incidence of arterial thrombosis in patients treated with ponatinib. The company announced include any new patients in ongoing clinical trials, up in collaboration with the FDA, new dosage recommendations (maybe 30 mg or 15 mg instead of 45 mg ) and security measures for the application, such as simultaneous Antikoagulantiengabe, had been prepared.

Side effects

The most commonly observed in more than 1 % of patients side effects, including serious, skin changes (rash, dryness ), abdominal pain, fever, anemia, changes in blood count (neutropenia, thrombocytopenia, pancytopenia ), inflammation of the pancreas were (pancreatitis ), heart attack, diarrhea and lipase increased.

An increase of arterial ( cardiovascular, cerebrovascular and peripheral vascular ) and venous thrombotic events was observed in the long-term follow-up of patients in the ongoing Phase 1 and Phase 2 clinical trials, which in December 2013 introduction of appropriate use restrictions and safety measures for patients with cardiovascular risk factors resulted.