Chemistry:Ponatinib

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Short description: Oral drug
Ponatinib
Ponatinib2DACS.svg
Ponatinib molecule ball.png
Clinical data
Pronunciation/poʊˈnætɪnɪb/ poh-NAT-i-nib
Trade namesIclusig
Other namesAP24534
AHFS/Drugs.comMonograph
MedlinePlusa613029
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityUnknown
Protein binding>99% (in vitro)
MetabolismLiver (CYP3A4, 2C8, 2D6, 3A5)
Elimination half-life12–66 hours
ExcretionFeces (87%), urine (5%)[2]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC29H27F3N6O
Molar mass532.571 g·mol−1
3D model (JSmol)

Ponatinib, sold under the brand name Iclusig, is a medication developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-targeted tyrosine-kinase inhibitor.[3] Some forms of CML, 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.[4]

The United States Food and Drug Administration approved the drug as a candidate in December 2012, but temporarily suspended sales in October 2013, because of "the risk of life-threatening blood clots and severe narrowing of blood vessels".[5][6] The suspension was partially lifted on in December 2013, with ponatinib being issued revised prescribing information, a new "Black Box Warning" and a "Risk Evaluation and Mitigation Strategy" in place to better evaluate the risks and benefits of using the drug.

Approvals and indications

Ponatinib was approved by the US FDA on December 14, 2012, for patients with resistant or intolerant CML and Ph+ ALL, based on results of the PACE phase II trial reported days earlier at the annual ASH meeting.[7] Because the approval was under the FDA Accelerated Approval program the applicant was required to carry out additional studies. Based on these additional studies, the FDA granted in 2016 full approval and updated the label to include patients 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.[8]

Adverse effects

The United States Food and Drug Administration issued a partial clinical hold on new trial enrollment for ponatinib on October 9, 2013, due to an increased number of blood clots observed in patients taking the drug.[9] The EPIC trial was later canceled on October 18.[10] 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.[8] Recently, an analogue of ponatinib was developed that retained anti-tumor efficacy but had reduced cardiovascular toxicity in experimental models.[11]

Clinical trials

In 2010 ARIAD announced result from a Phase I study of ponatinib in patients with resistant and refractory chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). The study demonstrated that in chronic-phase CML patients treated with ponatinib, 66 percent of patients in the trial achieved a major cytogenetic response, including 100 percent of patients who also had a T315I mutation.[citation needed]

The PACE (Ponatinib Ph+ ALL and CML 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.[7][12]

The EPIC (Evaluation of Ponatinib versus Imatinib in CML) phase-III trial began in June 2012 [13] and was halted[clarification needed][10] on October 18, 2013.

Mechanism of action

The primary target for ponatinib is BCR-ABL, an abnormal tyrosine kinase that is the hallmark of CML and Ph+ ALL. CML 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, CML typically evolves to more aggressive phases such as accelerated or blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML 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 CML.[citation needed]

Patients with CML currently receive front line therapies nilotinib and/or dasatinib though 22−33% of patients discontinue therapy by two years due to adverse events, treatment failure and other causes.[citation needed]

Discovery and origin

Ponatinib was designed using ARIAD's computational and structure-based drug design platform to inhibit the enzymatic activity of BCR-ABL with very high potency and broad specificity. Ponatinib was intended to target not only native BCR-ABL, but also its isoforms that carry mutations that confer resistance to treatment with existing tyrosine kinase inhibitors, including especially the T315I mutation for which no effective therapy exists.[14]

The road to discovery is linked to AP23464, one of the first of Ariad's ATP competitive dual Src/Abl inhibitors. AP23464 was identified using structure base drug design and focused synthetic libraries of trisubstituted purine analogs. The substance potently inhibits Src and Bcr-Abl kinases including many common imatinib-resistant Bcr-Abl mutations. AP23464 does not inhibit the T315I mutation, however, whereas ponatinib does.

Society and culture

Economics

Oncologists have complained that many patients cannot afford the "astronomical" cost of $138,000 a year, which makes it one of the most expensive drugs in medicine, and [in their view] far more expensive than what is needed to pay the development costs.[15][16]

As of 2015, ponatinib is available in England for the treatment of CML (chronic phase, accelerated phase or blast phase) and Ph+ ALL 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.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2014". 21 June 2022. https://www.tga.gov.au/resources/resource/guidance/prescription-medicines-registration-new-chemical-entities-australia-2014. 
  2. ↑ 2.0 2.1 "Iclusig- ponatinib hydrochloride tablet, film coated". 10 November 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=16d804b6-4957-43ee-b18c-3b36ec37c5ac. 
  3. ↑ "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. 
  4. ↑ "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. 
  5. ↑ "FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales". U.S. Food and Drug Administration. 2013-10-31. https://www.fda.gov/Drugs/DrugSafety/ucm373040.htm. 
  6. ↑ Grady D (2013-10-31). "Serious Danger of Blood Clots Halts Sale of Leukemia Drug". The New York Times. https://www.nytimes.com/2013/11/01/business/serious-danger-of-blood-clots-halts-sale-of-leukemia-drug.html. 
  7. ↑ 7.0 7.1 Gever J (Dec 14, 2012). "Ponatinib Wins Early FDA Nod". Oncology/Hematology. MedPageToday.com. http://www.medpagetoday.com/HematologyOncology/Leukemia/36462. 
  8. ↑ 8.0 8.1 "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. 
  9. ↑ 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. 
  10. ↑ 10.0 10.1 "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=. 
  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. ↑ Gever J (Dec 10, 2012). "Ponatinib Retains Luster in Leukemia". Oncology/Hematology. MedPageToday.com. http://www.medpagetoday.com/MeetingCoverage/ASHHematology/36368. 
  13. ↑ "Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia". 5 November 2014. http://clinicaltrials.gov/ct2/show/NCT01650805. 
  14. ↑ "Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance". Chemical Biology & Drug Design 77 (1): 1–11. January 2011. doi:10.1111/j.1747-0285.2010.01054.x. PMID 21118377. 
  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. https://www.webarchive.org.uk/wayback/archive/20150718154202/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. 



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