Ponatinib

Overview

Ponatinib, sold under the brand name Iclusig, is a medication used for the treatment of chronic myeloid leukemia and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia. It was developed by Ariad Pharmaceuticals. It is a multi-targeted tyrosine-kinase inhibitor. Some forms of chronic myeloid leukemia, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.[1][2][3] WP

Ponatinib was approved for medical use in the United States in December 2012, and in the European Union in July 2013.[4][5] WP

Uses, dosage and effects

Medical uses

Ponatinib is indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia and chronic myeloid leukemia.[1] WP

In March 2024, the FDA expanded the indication to include the treatment, with chemotherapy, for adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.[6][7] WP

Risks and side effects

Adverse effects

The US Food and Drug Administration (FDA) issued a partial clinical hold on new trial enrollment for ponatinib in October 2013, due to an increased number of blood clots observed in patients taking the drug. The EPIC trial was later canceled in October 2013. Subsequent studies of 449 patients treated during 4 years with ponatinib for chronic phase chronic myelogenous leukemia found the following adverse reactions. 150 Patients experienced cardiac vascular (21% of patients), peripheral vascular (12%), and cerebrovascular (9%) arterial occlusive events. Venous thromboembolic events occurred in 6% of patients. The most common all-grade adverse events included hypertension (69%), rash (63%), abdominal pain (48%), fatigue (47%), headache (43%), arterial ischemia (42%), dry skin (42%), constipation (41%), arthralgia (32%), nausea (28%), pyrexia (26%), peripheral neuropathy (24%), myalgia (24%), pain in extremity (23%), back pain (21%), and diarrhea (20%). In addition, there have been reported cases of the posterior reversible encephalopathy syndrome. Recently, an analogue of ponatinib was developed that retained anti-tumor efficacy but had reduced cardiovascular toxicity in experimental models.[8–11] WP

Pharmacology

Mechanism of action

The primary target for ponatinib is BCR-ABL, an abnormal tyrosine kinase that is the hallmark of chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia. Chronic myeloid leukemia is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, chronic myeloid leukemia typically evolves to more aggressive phases such as accelerated or blast crisis. Philadelphia-positive acute lymphoblastic leukemia is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than chronic myeloid leukemia and is often treated with a combination of chemotherapy and tyrosine kinase inhibitors. Because both of these diseases express the BCR-ABL protein, this would render them potentially susceptible to treatment with ponatinib. BCR-ABL is detected in 95% of patients with chronic myeloid leukemia. WP⚠ Wikipedia itself has flagged this text: citation needed.

Legal status

Legal status

Ponatinib was approved by the US FDA in December 2012, for people with resistant or intolerant chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia, based on results of the PACE phase II trial. Based on additional studies, the FDA granted full approval in 2016, and updated the label to include people with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia for whom no other tyrosine kinase inhibitor therapy is indicated. Approval was also granted for T315I-positive and T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia.[10][12] WP

Economics

The medication costs $138,000 per year.[13][14] WP

As of 2015, ponatinib is available in England for the treatment of chronic myeloid leukemia (chronic phase, accelerated phase or blast phase) and Philadelphia-positive acute lymphoblastic leukemia in patients with documented T315I mutation under the Cancer Drugs Fund, and has not been appraised by the National Institute for Health and Care Excellence (NICE), who noted the small expected patient population. NICE estimated that ponatinib would cost approximately £61,000 per year, but the price paid under the Cancer Drugs Fund is confidential and may be different.[15][16] WP

Chemistry

Formula

C29H27F3N6O PC

CAS number

943319-70-8 PC

Molar mass (g/mol)

532.6 PC

IUPAC name (computed by PubChem)

3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide PC

SMILES

CC1=C(C=C(C=C1)C(=O)NC2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)C#CC4=CN=C5N4N=CC=C5 PC

InChIKey

PHXJVRSECIGDHY-UHFFFAOYSA-N PC

PubChem CID

24826799

IUPAC name

3-(2-Imidazo WP

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Iclusig- ponatinib hydrochloride tablet, film coated. 10 November 2022
2. Journal / agency Huang WS, Metcalf CA, Sundaramoorthi R, Wang Y, Zou D, Thomas RM, Zhu X, Cai L, Wen D, Liu S, Romero J, Qi J, Chen I, Banda G, Lentini SP, Das S, Xu Q, Keats J, Wang F, Wardwell S, Ning Y, Snodgrass JT, Broudy MI, Russian K, Zhou T, Commodore L, Narasimhan NI, Mohemmad QK, Iuliucci J, Rivera VM, Dalgarno DC, Sawyer TK, Clackson T, Shakespeare WC. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. Journal of Medicinal Chemistry. June 2010. doi:10.1021/jm100395q · PMID 20513156
3. Journal / agency O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. November 2009. doi:10.1016/j.ccr.2009.09.028 · PMID 19878872 · PMC2804470
4. Journal / agency Drug Approval Package: Iclusig (ponatinib) 15 mg and 45 mg Tablets NDA #203469. 21 December 2012
5. Journal / agency Iclusig EPAR. 2 February 2010
6. Journal / agency FDA grants accelerated approval to ponatinib with chemotherapy for new. 19 March 2024
7. Journal / agency Cancer Accelerated Approvals. 1 October 2024
8. Other Carroll J. UPDATED: Ariad hammered on toxicity concerns for leukemia drug Iclusig. 9 October 2013
9. Other Ariad Announces Discontinuation of the Phase 3 Epic Trial of Iclusig in Patients with Newly Diagnosed Chronic Myeloid Leukemia
10. Other FDA Grants Ponatinib Full Approval for Rare Leukemias. 29 November 2016
11. Journal / agency Hnatiuk AP, Bruyneel AA, Tailor D, Pandrala M, Dheeraj A, Li W, Serrano R, Feyen DA, Vu MM, Amatya P, Gupta S, Nakauchi Y, Morgado I, Wiebking V, Liao R, Porteus MH, Majeti R, Malhotra SV, Mercola M. Reengineering Ponatinib to Minimize Cardiovascular Toxicity. Cancer Research. August 2022. doi:10.1158/0008-5472.CAN-21-3652 · PMID 35763671 · PMC9620869
12. Other Gever J. Ponatinib Wins Early FDA Nod. Dec 14, 2012
13. Other Pollack A. Doctors Denounce Cancer Drug Prices of $100,000 a Year. April 25, 2013
14. Journal / agency Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood. May 2013. doi:10.1182/blood-2013-03-490003 · PMID 23620577 · PMC4190613
15. Other National Cancer Drugs Fund list Ver4.3. 5 June 2015
16. Other Consultation on Batch 33 draft remits and draft scopes and summary of comments and discussions at scoping workshops

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