Acalabrutinib

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Acalabrutinib
Acalabrutinib.svg
Clinical data
Trade names Calquence
Other namesACP-196
AHFS/Drugs.com Monograph
MedlinePlus a618004
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
ChEBI
ChEMBL
PDB ligand
ECHA InfoCard 100.247.121 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C26H23N7O2
Molar mass 465.517 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, 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 Lymphoma (CLL/SLL). [7] It may be used both in relapsed as well as in treatment-naive settings. [8]

Contents

Common side effects include headaches, feeling tired, low red blood cells, low platelets, and low white blood cells. [7] It is a second generation Bruton's tyrosine kinase inhibitor. [9] [10] Acalabrutinib blocks an enzyme called Bruton's tyrosine kinase, which helps B cells to survive and grow. [5] 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. [5]

Acalabrutinib was approved for medical use in the United States in 2017, [7] and in the European Union in November 2020. [5]

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). [5] It is also indicated for the treatment of adults with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy. [5]

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). [4]

Side effects

The most common adverse events were headache, diarrhea and weight gain. [10] 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. [10]

Society and culture

Acalabrutinib was approved for medical use in the United States in 2017, [7] and in the European Union in November 2020. [5]

As of February 2016, acalabrutinib had received orphan drug designation in the United States for mantle cell lymphoma and chronic lymphocytic leukemia (CLL), [11] [12] 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). [13] [14] [15] [16] Approval would result in a 10-year period of market exclusivity for the stated indications within Europe. [17]

Economics

It was developed by Acerta Pharma. [18] After promising results for CLL in initial clinical trials, [9] 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. [19]

Names

Acalabrutinib is the international nonproprietary name (INN), [20] and the United States Adopted Name (USAN). [21]

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. [10] 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. [10] These findings strongly suggest an improved safety profile of acalabrutinib with minimized adverse effects relative to ibrutinib. [10] In pre-clinical studies, it was shown to be more potent and selective than ibrutinib, the first-in-class BTK inhibitor. [9] [10]

The interim results of the still on-going[ when? ] 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. [9] 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. [10]

Related Research Articles

<span class="mw-page-title-main">Chronic lymphocytic leukemia</span> Bone marrow cancer in which lymphocytes are overproduced

Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes. Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years.

<span class="mw-page-title-main">Bruton's tyrosine kinase</span> Kinase that plays a role in B cell development

Bruton's tyrosine kinase, also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.

<span class="mw-page-title-main">Ofatumumab</span> Medication

Ofatumumab is a fully human monoclonal antibody to CD20, which appears to provide rapid B-cell depletion. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the European Union and other regions. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. It is sold by Novartis under license from Genmab.

Richter's transformation (RT), also known as Richter's syndrome, is the conversion of chronic lymphocytic leukemia (CLL) or its variant, small lymphocytic lymphoma (SLL), into a new and more aggressively malignant disease. CLL is the circulation of malignant B lymphocytes with or without the infiltration of these cells into lymphatic or other tissues while SLL is the infiltration of these malignant B lymphocytes into lymphatic and/or other tissues with little or no circulation of these cells in the blood. CLL along with its SLL variant are grouped together in the term CLL/SLL.

<span class="mw-page-title-main">Mantle cell lymphoma</span> Type of blood cancer

Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffeld and Jaffe in 1991.

<span class="mw-page-title-main">Bendamustine</span> Chemical compound

Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein.

Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody used as a treatment for cancer. It was originated by GlycArt Biotechnology AG and developed by Roche.

Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti-CD22 immunotoxin medication for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Moxetumomab pasudotox is a CD22-directed cytotoxin and is the first of this type of treatment for adults with HCL. The drug consists of the binding fragment (Fv) of an anti-CD22 antibody fused to a toxin called PE38. This toxin is a 38 kDa fragment of Pseudomonas exotoxin A.

<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

<span class="mw-page-title-main">Idelalisib</span> Chemical compound

Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers. Idelalisib acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase. It was developed by Gilead Sciences. It is taken orally.

<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

<span class="mw-page-title-main">Duvelisib</span> PI3K inhibitor

Duvelisib, sold under the brand name Copiktra, is a medication used to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma after other treatments have failed. It is taken by mouth. It is a PI3 kinase inhibitor.

<span class="mw-page-title-main">Umbralisib</span> Chemical compound

Umbralisib, sold under the brand name Ukoniq, is an anti-cancer medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). It is taken by mouth.

<span class="mw-page-title-main">Zanubrutinib</span> Chemical compound

Zanubrutinib, sold under the brand name Brukinsa, is an anticancer medication used for the treatment of mantle cell lymphoma (MCL), Waldenström's macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL). Zanubrutinib is classified as a Bruton's tyrosine kinase (BTK) inhibitor. It is given by mouth.

Brexucabtagene autoleucel, sold under the brand name Tecartus, is a cell-based gene therapy medication for the treatment of mantle cell lymphoma (MCL) and acute lymphoblastic leukemia (ALL).

BeiGene, Ltd. is a China-based drug developer. It specializes in the development of drugs for cancer treatment. Founded in 2010 by chief executive officer John V. Oyler and Xiaodong Wang, the multinational company headquartered in Cambridge, Massachusetts has offices in North America, Europe, South America, Asia and Australia. BeiGene has a large presence in Chinese market. BeiGene has developed several pharmaceuticals, including tislelizumab, a checkpoint inhibitor, and zanubrutinib, a Bruton's tyrosine kinase inhibitor.

Mosunetuzumab, sold under the brand name Lunsumio, is a monoclonal antibody used for the treatment of follicular lymphoma. It bispecifically binds CD20 and CD3 to engage T-cells. It was developed by Genentech.

<span class="mw-page-title-main">Pirtobrutinib</span> Chemical compound

Pirtobrutinib, sold under the brand name Jaypirca, is an anticancer medication that is used to treat mantle cell lymphoma. It inhibits B cell lymphocyte proliferation and survival by binding and inhibiting Bruton's tyrosine kinase (BTK). It is taken by mouth.

<span class="mw-page-title-main">Nemtabrutinib</span> Chemical compound

Nemtabrutinib is a small molecule drug that works as a reversible Bruton's tyrosine kinase (BTK) inhibitor; unlike other BTK inhibitors it also works against some mutated forms of BTK. Merck paid $2.7 billion to acquire the company ArQule and the drug, which is being investigated as a cancer treatment.

<span class="mw-page-title-main">Orelabrutinib</span> Drug for treatment of cancer

Orelabrutinib is a drug for the treatment of cancer.

References

  1. ↑ "Acalabrutinib (Calquence) Use During Pregnancy". Drugs.com. 23 October 2019. Retrieved 28 March 2020.
  2. ↑ https://www.tga.gov.au/resources/auspmd/calquence [ bare URL ]
  3. ↑ "Summary Basis of Decision (SBD) for Calquence". Health Canada . 23 October 2014. Retrieved 29 May 2022.
  4. 1 2 "Calquence- acalabrutinib capsule, gelatin coated". DailyMed. 22 November 2019. Retrieved 11 November 2020.
  5. 1 2 3 4 5 6 7 "Calquence EPAR". European Medicines Agency . 20 July 2020. Retrieved 11 November 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ↑ "Calquence Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  7. 1 2 3 4 "Acalabrutinib Monograph for Professionals". Drugs.com. Retrieved 16 March 2019.
  8. ↑ "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.
  9. 1 2 3 4 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): 323–332. doi:10.1056/NEJMoa1509981. PMC   4862586 . PMID   26641137.
  10. 1 2 3 4 5 6 7 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.
  11. ↑ "Acalabrutinib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 15 April 2020.
  12. ↑ "Acalabrutinib Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). Retrieved 15 April 2020.
  13. ↑ "EU/3/16/1624". European Medicines Agency (EMA). 2 May 2016. Retrieved 15 April 2020.
  14. ↑ "EU/3/16/1625". European Medicines Agency (EMA). 4 May 2016. Retrieved 15 April 2020.
  15. ↑ "EU/3/16/1626". European Medicines Agency (EMA). 4 May 2016. Retrieved 15 April 2020.
  16. ↑ "azn201602256k.htm". www.sec.gov. Retrieved 21 November 2016.
  17. ↑ House DW (25 February 2016). "AstraZeneca and Acerta Pharma's acalabrutinib tagged an Orphan Drug in Europe for three indications". Seeking Alpha. Retrieved 21 November 2016.
  18. ↑ "AstraZeneca to buy Acerta for blood cancer drug". www.rsc.org. Chemistry World - Royal Society of Chemistry. Retrieved 24 December 2015.
  19. ↑ Walker I, Roland D (17 December 2015). "AstraZeneca to Buy Stake in Acerta Pharma". Wall Street Journal. ISSN   0099-9660 . Retrieved 19 November 2016.
  20. ↑ World Health Organization (2016). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75". WHO Drug Information. 30 (1): 94. hdl: 10665/331046 .
  21. ↑ "Acalabrutinib" (PDF). 27 January 2016.
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