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Acalabrutinib

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Acalabrutinib
Clinical data
Trade namesCalquence
Other namesACP-196
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
  • 4-{8-Amino-3-[(2S)-1-(2-butynoyl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl}-N-(2-pyridinyl)benzamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard100.247.121 Edit this at Wikidata
Chemical and physical data
FormulaC26H23N7O2
Molar mass465.517 g·mol−1
3D model (JSmol)
  • CC#CC(=O)N1CCC[C@H]1c2nc(c3n2ccnc3N)c4ccc(cc4)C(=O)Nc5ccccn5
  • InChI=1S/C26H23N7O2/c1-2-6-21(34)32-15-5-7-19(32)25-31-22(23-24(27)29-14-16-33(23)25)17-9-11-18(12-10-17)26(35)30-20-8-3-4-13-28-20/h3-4,8-14,16,19H,5,7,15H2,1H3,(H2,27,29)(H,28,30,35)/t19-/m0/s1
  • Key:WDENQIQQYWYTPO-IBGZPJMESA-N

Acalabrutinib (trade name Calquence) is a medication used to treat a type of non-Hodgkin lymphoma known as mantle cell lymphoma.[2] Specifically it is for people who had previously been treated with another therapy.[3] As of 2019, it was unclear whether it improved outcomes.[2]

Common side effects include headaches, feeling tired, low red blood cells, low platelets, and low white blood cells.[2] It is a second generation Bruton's tyrosine kinase inhibitor.[4][5]

Acalabrutinib was approved for medical use in the United States in 2017.[2] The wholesale cost as of 2018 in the United States is US$14,064 per month.[6]

Medical uses

It is used to treat a type of non-Hodgkin lymphoma known as mantle cell lymphoma.[2] It is unclear if it results in improved outcomes as of 2019.[2]

Side effects

The most common adverse events were headache, diarrhea and weight gain.[5] Despite the appearance of a greater occurrence of transient headaches, data suggest a preferred advantage of acalabrutinib over ibrutinib due to expected reduced adverse events of skin rash, severe diarrhea, and bleeding risk.[5]

Society and culture

Names

Acalabrutinib is the INN.[7]

Regulatory

As of February 2016, acalabrutinib had received orphan drug designation in the United States for mantle cell lymphoma and chronic lymphocytic leukemia (CLL),[8] [9] and was similarly designated as an orphan medicinal product by the European Medicines Agency (EMA) Committee for Orphan Medicinal Products (COMP) for treatment of three indications - CLL/ small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and lymphoplasmacytic lymphoma (Waldenström's macroglobulinaemia, WM).[10][11][12][13] Approval would result in a 10-year period of market exclusivity for the stated indications within Europe.[14]

Economics

It was developed by Acerta Pharma.[15] After promising results for CLL in initial clinical trials,[4] Astra Zeneca purchased a 55% stake in Acerta Pharma for $4 billion in December 2015, with an option to acquire the remaining 45% stake for an additional $3 billion, conditional on approval in both the US and Europe and the establishment of commercial opportunity.[16]

Research

Relative to ibrutinib, acalabrutinib demonstrated higher selectivity and inhibition of the targeted activity of BTK, while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1.[5] In addition, in platelets treated with ibrutinib, thrombus formation was clearly inhibited while no impact to thrombus formation was identified relative to controls for those treated with acalabrutinib.[5] These findings strongly suggest an improved safety profile of acalabrutinib with minimized adverse effects relative to ibrutinib.[5] In pre-clinical studies, it was shown to be more potent and selective than ibrutinib, the first-in-class BTK inhibitor.[4][5][17]

The interim results of the still on-going[when?] first human phase 1/2 clinical trial (NCT02029443) with 61 patients for the treatment of relapsed chronic lymphocytic leukemia (CLL) are encouraging, with a 95% overall response rate demonstrating potential to become a best-in-class treatment for CLL.[4] Notably, a 100% response rate was achieved for those people which were positive for the 17p13.1 gene deletion - a subgroup that typically results in a poor response to therapy and expected outcomes.[5]

References

  1. ^ a b "Acalabrutinib (Calquence) Use During Pregnancy". Drugs.com. 23 October 2019. Retrieved 28 March 2020.
  2. ^ a b c d e f "Acalabrutinib Monograph for Professionals". Drugs.com. Retrieved 16 March 2019.
  3. ^ "FDA approves new treatment for adults with mantle cell lymphoma". U.S. Food and Drug Administration (FDA) (Press release). 31 October 2017. Retrieved 28 March 2020.
  4. ^ a b c d Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, et al. (January 2016). "Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia". The New England Journal of Medicine. 374 (4): 323–32. doi:10.1056/NEJMoa1509981. PMC 4862586. PMID 26641137.
  5. ^ a b c d e f g h Wu J, Zhang M, Liu D (March 2016). "Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor". Journal of Hematology & Oncology. 9: 21. doi:10.1186/s13045-016-0250-9. PMC 4784459. PMID 26957112.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ "In Brief: Acalabrutinib (Calquence) for Mantle Cell Lymphoma (online only)". The Medical Letter. Retrieved 16 March 2019.
  7. ^ "WHO Drug Information - recommended INN" (PDF). WHO Drug Information. World Health Oorganisation. Retrieved 24 December 2015.
  8. ^ "Acalabrutinib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 15 April 2020.
  9. ^ "Acalabrutinib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 15 April 2020.
  10. ^ "EU/3/16/1624". European Medicines Agency (EMA). 2 May 2016. Retrieved 15 April 2020.
  11. ^ "EU/3/16/1625". European Medicines Agency (EMA). 4 May 2016. Retrieved 15 April 2020.
  12. ^ "EU/3/16/1626". European Medicines Agency (EMA). 4 May 2016. Retrieved 15 April 2020.
  13. ^ "azn201602256k.htm". www.sec.gov. Retrieved 2016-11-21.
  14. ^ House, Douglas W. (2016-02-25). "AstraZeneca and Acerta Pharma's acalabrutinib tagged an Orphan Drug in Europe for three indications". Seeking Alpha. Retrieved 2016-11-21. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  15. ^ "AstraZeneca to buy Acerta for blood cancer drug". www.rsc.org. Chemistry World - Royal Society of Chemistry. Retrieved 24 December 2015.
  16. ^ Walker, Ian; Roland, Denise (2015-12-17). "AstraZeneca to Buy Stake in Acerta Pharma". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-11-19. {{cite news}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  17. ^ Wu J, Zhang M, Liu D (March 2016). "Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor". Journal of Hematology & Oncology. 9 (1): 21. doi:10.1186/s13045-016-0250-9. PMC 4784459. PMID 26957112.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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