Chemistry:Ponatinib

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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.[1] It was developed by Ariad Pharmaceuticals. It is a multi-targeted tyrosine-kinase inhibitor.[2] 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.[3]

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

Medical uses

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

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]

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.[8] The EPIC trial was later canceled in October 2013.[9] 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.[10] Recently, an analogue of ponatinib was developed that retained anti-tumor efficacy but had reduced cardiovascular toxicity in experimental models.[11]

Clinical trials

The PACE (Ponatinib Ph+ ALL and chronic myeloid leukemia Evaluation) pivotal phase II trial started enrolling patients in September 2010 and is designed to provide definitive clinical data for regulatory approval in this setting. Good results were reported in December 2012.[12][13]

The EPIC (Evaluation of Ponatinib versus Imatinib in chronic myeloid leukemia) phase-III trial began in June 2012 [14] and was halted[clarification needed][9] on October 18, 2013.

Mechanism of action

Society and culture

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.[12] 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]

Economics

The medication costs $138,000 per year.[15][16]

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,[17] and has not been appraised by the National Institute for Health and Care Excellence (NICE), who noted the small expected patient population.[18] 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. Ponatinib has generic drug available in some countries like Bangladesh and that are manufactured by some reputed Bangladeshi pharmaceuticals companies under the brand names such as Ponaxen and Ponatinix.[19]

References

  1. ↑ 1.0 1.1 Cite error: Invalid <ref> tag; no text was provided for refs named Iclusig FDA label
  2. ↑ "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 53 (12): 4701–4719. June 2010. doi:10.1021/jm100395q. PMID 20513156. 
  3. ↑ "AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance". Cancer Cell 16 (5): 401–412. November 2009. doi:10.1016/j.ccr.2009.09.028. PMID 19878872. 
  4. ↑ "Drug Approval Package: Iclusig (ponatinib) 15 mg and 45 mg Tablets NDA #203469". 21 December 2012. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203469Orig1s000TOC.cfm. 
  5. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Iclusig EPAR
  6. ↑ "FDA grants accelerated approval to ponatinib with chemotherapy for new". 19 March 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ponatinib-chemotherapy-newly-diagnosed-philadelphia-chromosome. 
  7. ↑ "Cancer Accelerated Approvals". 1 October 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/ongoing-cancer-accelerated-approvals. 
  8. ↑ Carroll J (9 October 2013). "UPDATED: Ariad hammered on toxicity concerns for leukemia drug Iclusig". Fierce Biotech (FierceBiotech). http://www.fiercebiotech.com/story/tox-issues-force-ariad-slam-brakes-enrollment-slash-dosing-iclusig/2013-10-09. 
  9. ↑ 9.0 9.1 "Ariad Announces Discontinuation of the Phase 3 Epic Trial of Iclusig in Patients with Newly Diagnosed Chronic Myeloid Leukemia". http://investor.ariad.com/phoenix.zhtml?c=118422&p=irol-newsArticle&ID=1865879&highlight=. 
  10. ↑ 10.0 10.1 "FDA Grants Ponatinib Full Approval for Rare Leukemias". 29 November 2016. http://www.onclive.com/web-exclusives/fda-grants-ponatinib-full-approval-for-rare-leukemias. 
  11. ↑ "Reengineering Ponatinib to Minimize Cardiovascular Toxicity". Cancer Research 82 (15): 2777–2791. August 2022. doi:10.1158/0008-5472.CAN-21-3652. PMID 35763671. 
  12. ↑ 12.0 12.1 Gever J (Dec 14, 2012). "Ponatinib Wins Early FDA Nod". Oncology/Hematology. MedPageToday.com. http://www.medpagetoday.com/HematologyOncology/Leukemia/36462. 
  13. ↑ Gever J (Dec 10, 2012). "Ponatinib Retains Luster in Leukemia". Oncology/Hematology. MedPageToday.com. http://www.medpagetoday.com/MeetingCoverage/ASHHematology/36368. 
  14. ↑ "Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia". 5 November 2014. http://clinicaltrials.gov/ct2/show/NCT01650805. 
  15. ↑ Pollack A (April 25, 2013). "Doctors Denounce Cancer Drug Prices of $100,000 a Year". The New York Times. https://www.nytimes.com/2013/04/26/business/cancer-physicians-attack-high-drug-costs.html. 
  16. ↑ Experts in Chronic Myeloid Leukemia (May 2013). "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 121 (22): 4439–4442. doi:10.1182/blood-2013-03-490003. PMID 23620577. 
  17. ↑ "National Cancer Drugs Fund list Ver4.3". NHS England. 5 June 2015. http://www.england.nhs.uk/wp-content/uploads/2015/07/ncdf-list-may15-ver4-3.pdf. 
  18. ↑ "Consultation on Batch 33 draft remits and draft scopes and summary of comments and discussions at scoping workshops". National Institute for Health and Care Excellence.. http://www.nice.org.uk/media/default/About/what-we-do/NICE-guidance/NICE-technology-appraisals/Block-scoping-reports/Batch-33-block-scoping-report.pdf. 
  19. ↑ "Ponatinib Price & Cost". Emergency Drug. https://emergencydrug.com/generic/ponatinib/. 



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