Acalabrutinib

Acalabrutinib, sold under the brand name Calquence, is a medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL).[5] It may be used both in relapsed as well as in treatment-naive settings.[6]

Acalabrutinib
Clinical data
Trade namesCalquence
Other namesACP-196
AHFS/Drugs.comMonograph
MedlinePlusa618004
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • 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
ChEBI
ChEMBL
ECHA InfoCard100.247.121
Chemical and physical data
FormulaC26H23N7O2
Molar mass465.517 g·mol−1
3D model (JSmol)
SMILES
  • CC#CC(=O)N1CCC[C@H]1c2nc(c3n2ccnc3N)c4ccc(cc4)C(=O)Nc5ccccn5
InChI
  • 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

Common side effects include headaches, feeling tired, low red blood cells, low platelets, and low white blood cells.[5] It is a second generation Bruton's tyrosine kinase inhibitor.[7][8] Acalabrutinib blocks an enzyme called Bruton's tyrosine kinase, which helps B cells to survive and grow.[4] By blocking this enzyme, acalabrutinib is expected to slow down the build-up of cancerous B cells in CLL, thereby delaying progression of the cancer.[4]

Acalabrutinib was approved for medical use in the United States in 2017,[5] and in the European Union in November 2020.[4]

Medical uses

In the European Union, acalabrutinib as monotherapy or in combination with obinutuzumab is indicated for the treatment of adults with previously untreated chronic lymphocytic leukaemia (CLL).[4] It is also indicated for the treatment of adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy.[4]

In the United States, acalabrutinib is indicated for the treatment of adults with mantle cell lymphoma (MCL) who have received at least one prior therapy, and for the treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).[3]

Side effects

The most common adverse events were headache, diarrhea and weight gain.[8] 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.[8]

Society and culture

Acalabrutinib was approved for medical use in the United States in 2017,[5] and in the European Union in November 2020.[4]

As of February 2016, acalabrutinib had received orphan drug designation in the United States for mantle cell lymphoma and chronic lymphocytic leukemia (CLL),[9] [10] 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).[11][12][13][14] Approval would result in a 10-year period of market exclusivity for the stated indications within Europe.[15]

Economics

It was developed by Acerta Pharma.[16] After promising results for CLL in initial clinical trials,[7] 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.[17]

Names

Acalabrutinib is the international nonproprietary name (INN),[18] and the United States Adopted Name (USAN).[19]

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.[8] 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.[8] These findings strongly suggest an improved safety profile of acalabrutinib with minimized adverse effects relative to ibrutinib.[8] In pre-clinical studies, it was shown to be more potent and selective than ibrutinib, the first-in-class BTK inhibitor.[7][8][20]

The interim results of the still on-going first human phase I/II 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.[7] 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.[8]

References
  1. "Acalabrutinib (Calquence) Use During Pregnancy". Drugs.com. 23 October 2019. Retrieved 28 March 2020.
  2. "Summary Basis of Decision (SBD) for Calquence". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  3. "Calquence- acalabrutinib capsule, gelatin coated". DailyMed. 22 November 2019. Retrieved 11 November 2020.
  4. "Calquence EPAR". European Medicines Agency. 20 July 2020. Retrieved 11 November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. "Acalabrutinib Monograph for Professionals". Drugs.com. Retrieved 16 March 2019.
  6. "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.
  7. 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.
  8. 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.
  9. "Acalabrutinib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 15 April 2020.
  10. "Acalabrutinib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 15 April 2020.
  11. "EU/3/16/1624". European Medicines Agency (EMA). 2 May 2016. Retrieved 15 April 2020.
  12. "EU/3/16/1625". European Medicines Agency (EMA). 4 May 2016. Retrieved 15 April 2020.
  13. "EU/3/16/1626". European Medicines Agency (EMA). 4 May 2016. Retrieved 15 April 2020.
  14. "azn201602256k.htm". www.sec.gov. Retrieved 2016-11-21.
  15. House DW (2016-02-25). "AstraZeneca and Acerta Pharma's acalabrutinib tagged an Orphan Drug in Europe for three indications". Seeking Alpha. Retrieved 2016-11-21.
  16. "AstraZeneca to buy Acerta for blood cancer drug". www.rsc.org. Chemistry World - Royal Society of Chemistry. Retrieved 24 December 2015.
  17. Walker I, Roland D (2015-12-17). "AstraZeneca to Buy Stake in Acerta Pharma". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-11-19.
  18. World Health Organization (2016). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75". WHO Drug Information. 30 (1): 94. hdl:10665/331046.
  19. "Acalabrutinib" (PDF). 27 January 2016.
  20. 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.
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