Ponatinib

Systematic (IUPAC) name
3-(2-Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide
Clinical data
Trade names Iclusig
Licence data US FDA:link
  • US: D (Evidence of risk)
Oral
Identifiers
943319-70-8
L01XE24
PubChem CID 24826799
ChemSpider 24747381
UNII 4340891KFS
ChEBI CHEBI:78543
ChEMBL CHEMBL1171837
Synonyms AP24534
Chemical data
Formula C29H27F3N6O
532.56 g/mol

Ponatinib (trade name Iclusig, 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.[1] 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.[2]

Oncologists have complained, however, 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 far more expensive than what is needed to pay the development costs.[3][4]

The United States Food and Drug Administration approved the drug as a candidate in 2012, but temporarily suspended sales on 31 October 2013 because of "the risk of life-threatening blood clots and severe narrowing of blood vessels".[5][6] 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.

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's accelerated approval program the applicant will be required to carry out additional studies.

Adverse effects

The United States Food and Drug Administration issued a partial clinical hold on new trial enrollment for Iclusig on 9 October 2013 due to an increased number of blood clots observed in patients taking the drug.[8] The EPIC trial was later cancelled on 18 October.[9]

Clinical trials

The PACE (Ponatinb 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 Dec 2012.[7][10]

At the 2010 annual meeting of the American Society of Hematology, ARIAD announced 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 EPIC (Evaluation of Ponatinib versus Imatinib in CML) phase-III trial began in June 2012 [11] and was halted on 18 October 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.[12]

The road to discovery can be 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, on nanomolar scale, Src and Bcr-Abl kinases including many common imatinib resistant Bcr-Abl mutations. AP23464 does not inhibit the T315I mutation, however, whereas AP24534 (ponatinib) does.

See also

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ Pollack A (April 25, 2013). "Doctors Denounce Cancer Drug Prices of $100,000 a Year". New York Times.
  4. ↑ "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. PMID 23620577.
  5. ↑ "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.
  6. ↑ Grady D (2013-10-31). "Serious Danger of Blood Clots Halts Sale of Leukemia Drug". Business. New York Times.
  7. ↑ 7.0 7.1 Gever J (Dec 14, 2012). "Ponatinib Wins Early FDA Nod". Oncology/Hematology. MedPageToday.com.
  8. ↑ Carroll J. "UPDATED: Ariad hammered on toxicity concerns for leukemia drug Iclusig". FierceBiotech.
  9. ↑ "ARIAD Announces Discontinuation of the Phase 3 Epic Trial of Iclusig in Patients with Newly Diagnosed Chronic Myeloid Leukemia".
  10. ↑ Gever J (Dec 10, 2012). "Ponatinib Retains Luster in Leukemia". Oncology/Hematology. MedPageToday.com.
  11. ↑ "Ponatinib in Newly Diagnosed Chronic Myeloid Leukemia".
  12. ↑ 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.