Ponatinib

Ponatinib (trade name Iclusig /aɪˈkluːsɪɡ/ eye-KLOO-sig, previously AP24534) is an oral drug 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.[2] 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.[3]

Ponatinib
Clinical data
Pronunciation/poʊˈnætɪnɪb/ poh-NAT-i-nib
Trade namesIclusig
Other namesAP24534
License data
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    administration    		By mouth (tablets)
    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%)[1]
    Identifiers
    CAS Number
    PubChem CID
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    Chemical and physical data
    FormulaC29H27F3N6O
    Molar mass532.56 g/mol g·mol−1
    3D model (JSmol)

    The United States Food and Drug Administration approved the drug as a candidate in December 2012, but temporarily suspended sales on 31 October 2013 because of "the risk of life-threatening blood clots and severe narrowing of blood vessels".[4][5] This suspension was partially lifted on Dec. 20, 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.

    In the US it can cost $138,000 a year, which has been criticized.[6][7]

    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.[8] 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.[9]

    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.[10] The EPIC trial was later canceled on October 18.[11] 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.[12]

    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.

    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.[8][13]

    The EPIC (Evaluation of Ponatinib versus Imatinib in CML) phase-III trial began in June 2012 [14] and was halted[11] 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.

    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.

    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.[15]

    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.

    Cost, coverage and availability

    [US] 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.[6][7]

    In 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,[16] and has not been appraised by the National Institute for Health and Care Excellence (NICE), who noted the small expected patient population.[17] 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.

    See also

    References
    1. "Iclusig (ponatinib) Tablets, for Oral Use. Full Prescribing Information". ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street, Cambridge, MA 02139-4234. Retrieved 2 October 2016.
    2. 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 (June 2010). "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". J. Med. Chem. 53 (12): 4701–19. doi:10.1021/jm100395q. PMID 20513156.
    3. 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 (November 2009). "AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance". Cancer Cell. 16 (5): 401–12. doi:10.1016/j.ccr.2009.09.028. PMC 2804470. PMID 19878872.
    4. "FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales". FDA Drug Safety Communication. U.S. Food and Drug Administration. 2013-10-31.
    5. Grady D (2013-10-31). "Serious Danger of Blood Clots Halts Sale of Leukemia Drug". Business. New York Times.
    6. Pollack A (April 25, 2013). "Doctors Denounce Cancer Drug Prices of $100,000 a Year". New York Times.
    7. "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): 4439–42. May 2013. doi:10.1182/blood-2013-03-490003. PMC 4190613. PMID 23620577.
    8. Gever J (Dec 14, 2012). "Ponatinib Wins Early FDA Nod". Oncology/Hematology. MedPageToday.com.
    9. http://www.onclive.com/web-exclusives/fda-grants-ponatinib-full-approval-for-rare-leukemias
    10. Carroll J. "UPDATED: Ariad hammered on toxicity concerns for leukemia drug Iclusig". FierceBiotech.
    11. "ARIAD Announces Discontinuation of the Phase 3 Epic Trial of Iclusig in Patients with Newly Diagnosed Chronic Myeloid Leukemia".
    12. http://www.onclive.com/web-exclusives/fda-grants-ponatinib-full-approval-for-rare-leukemias
    13. Gever J (Dec 10, 2012). "Ponatinib Retains Luster in Leukemia". Oncology/Hematology. MedPageToday.com.
    14. "Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia".
    15. Zhou T, Commodore L, Huang WS, Wang Y, Thomas M, Keats J, Xu Q, Rivera VM, Shakespeare WC, Clackson T, Dalgarno DC, Zhu X (January 2011). "Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance". Chem Biol Drug Des. 77 (1): 1–11. doi:10.1111/j.1747-0285.2010.01054.x. PMID 21118377.
    16. NHS England. "National Cancer Drugs Fund list Ver4.3". Jun 5, 2015 (last retrieved Jul 20, 2015)
    17. National Institute for Health and Care Excellence. "Consultation on Batch 33 draft remits and draft scopes and summary of comments and discussions at scoping workshops". 2014 (last retrieved Jul 20, 2015)
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