Brigatinib

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Brigatinib
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Clinical data
Trade namesAlunbrig, others
Other namesAP26113
AHFS/Drugs.comMonograph
MedlinePlusa617016
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Pregnancy
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  • AU: D
Routes of
administration		By mouth
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Identifiers
  • 5-Chloro-2-N-{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-4-N-[2-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine
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Chemical and physical data
FormulaC29H39ClN7O2P
Molar mass584.10 g·mol−1
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  • COc1cc(ccc1Nc1ncc(Cl)c(Nc2ccccc2P(C)(C)=O)n1)N1CCC(CC1)N1CCN(C)CC1
  • InChI=1S/C29H39ClN7O2P/c1-35-15-17-37(18-16-35)21-11-13-36(14-12-21)22-9-10-24(26(19-22)39-2)33-29-31-20-23(30)28(34-29)32-25-7-5-6-8-27(25)40(3,4)38/h5-10,19-21H,11-18H2,1-4H3,(H2,31,32,33,34)
  • Key:AILRADAXUVEEIR-UHFFFAOYSA-N
Data page
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Brigatinib, sold under the brand name Alunbrig among others, is a small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc.[3] Brigatinib acts as an inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR), as well as several nonreceptor tyrosine kinases such as FAK, FAK2, and FER.[4] It shows activity against ALK-positive non–small cell lung cancer, ALK-positive anaplastic large cell lymphoma (ALCL),[5] and NF2-related schwannomatosis.[6]

Brigatinib could overcome resistance to osimertinib conferred by the EGFR C797S mutation if it is combined with an anti-EGFR antibody such as cetuximab or panitumumab.[7]

Mechanism of action

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Brigatinib acts as an inhibitor of the ALK[3] and mutated EGFR,[8] as well as several nonreceptor tyrosine kinases such as FAK, FAK2, and FER.[4]

ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.

Brigatinib inhibits ROS proto-oncogene-1 fusions and EGFR mutations and has a remarkable effect on the central nervous system.[9]

Epidermal growth factor receptor (EGFR) is another validated target in NSCLC. Additionally, the T790M "gatekeeper" mutation is linked in approximately 50 percent of patients who grow resistant to first-generation EGFR inhibitors.[8] While second-generation EGFR inhibitors are in development, clinical efficacy has been limited due to toxicity thought to be associated with inhibiting the native (endogenous or unmutated) EGFR. A therapy designed to target EGFR, the T790M mutation but avoiding inhibition of native EGFR is another promising molecular target for cancer therapy.

History

Regulatory approval

Ariad Pharmaceuticals, Inc. filed an investigational new drug (IND) application to the US FDA on August 29, 2016.[10]

In 2016, brigatinib was granted orphan drug status by the FDA for treatment of NSCLC.[11]

On 28 April 2017, it was granted an accelerated approval from the U.S. Food and Drug Administration (FDA) for metastatic non-small cell lung cancer (NSCLC);[12][13] as a 2nd-line therapy for ALK-positive NSCLC.[citation needed]

In 2020, it was approved as first-line treatment for ALK-positive metastatic NSCLC patients.[9]

Intellectual property

On 22 April 2015, Ariad Pharmaceuticals, Inc. announced the issuance of its first U.S. patent on brigatinib, the protection is through December 30, 2030. The United States Patent and Trademark Office granted U.S. Patent No. 9,012,462 under the title, "Phosphorous Derivatives as Kinase Inhibitors."[14]

Commercialization

Brigatinib is manufactured by Ariad Pharmaceuticals, Inc. (NASDAQ: ARIA) which is focused on rare cancers. Ariad then was acquired by Takeda Pharmaceutical Company Limited (TSE: 4502) in February 2017 through a tender offer (for $24.00 per share in cash) and subsequent merger of Ariad with Kiku Merger Co., Inc., a wholly owned subsidiary of Takeda Pharmaceuticals U.S.A. Ariad is an indirect wholly owned subsidiary of Takeda.[15]

Names

Brigatinib is the INN.[16]

References

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  1. ^ Page Module:Citation/CS1/styles.css has no content."Summary Basis of Decision (SBD) for Alunbrig". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  2. ^ Page Module:Citation/CS1/styles.css has no content."Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada. 14 October 2020. Retrieved 17 April 2024.
  3. ^ a b Page Module:Citation/CS1/styles.css has no content.Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, et al. (May 2016). "Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase". Journal of Medicinal Chemistry. 59 (10): 4948–4964. doi:10.1021/acs.jmedchem.6b00306. PMID 27144831.
  4. ^ a b Page Module:Citation/CS1/styles.css has no content.Chang LS, Oblinger JL, Smith AE, Ferrer M, Angus SP, Hawley E, et al. (2021). "Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK". PLOS ONE. 16 (7) e0252048. Bibcode:2021PLoSO..1652048C. doi:10.1371/journal.pone.0252048. PMC 8282008. PMID 34264955.
  5. ^ Page Module:Citation/CS1/styles.css has no content.Veleanu L, Lamant L, Sibon D (June 2024). "Brigatinib in ALK-Positive ALCL after Failure of Brentuximab Vedotin". The New England Journal of Medicine. 390 (22): 2129–2130. doi:10.1056/NEJMc2402419. PMID 38865667.
  6. ^ Page Module:Citation/CS1/styles.css has no content.Plotkin SR, Yohay KH, Nghiemphu PL, Dinh CT, Babovic-Vuksanovic D, Merker VL, et al. (June 2024). "Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors". The New England Journal of Medicine. 390 (24): 2284–2294. doi:10.1056/NEJMoa2400985. PMID 38904277.
  7. ^ Page Module:Citation/CS1/styles.css has no content.Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, et al. (March 2017). "Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer". Nature Communications. 8 14768. Bibcode:2017NatCo...814768U. doi:10.1038/ncomms14768. PMC 5355811. PMID 28287083.
  8. ^ a b Page Module:Citation/CS1/styles.css has no content.Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. (March 2011). "Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors". Science Translational Medicine. 3 (75): 75ra26. doi:10.1126/scitranslmed.3002003. PMC 3132801. PMID 21430269.
  9. ^ a b Page Module:Citation/CS1/styles.css has no content.Patcas A, Chis AF, Militaru CF, Bordea IR, Rajnoveanu R, Coza OF, et al. (February 2022). "An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance". Bosnian Journal of Basic Medical Sciences. 22 (1): 1–13. doi:10.17305/bjbms.2021.5859. PMC 8860314. PMID 34082691.
  10. ^ Page Module:Citation/CS1/styles.css has no content."NDA 208772 Multidisciplinary Review and Evaluation Alunbrig (brigatinib)" (PDF). FDA.gov. 29 August 2016. Archived from the original (PDF) on December 23, 2019. Retrieved 31 October 2017.
  11. ^ Page Module:Citation/CS1/styles.css has no content."About Brigatinib". ARIAD Pharmaceuticals, Inc. Archived from the original on 30 December 2016.
  12. ^ Page Module:Citation/CS1/styles.css has no content."FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer". National Cancer Institute. U.S. Department of Health and Human Services. 19 May 2017.
  13. ^ Page Module:Citation/CS1/styles.css has no content."Takeda Announces FDA Accelerated Approval of Alunbrig (brigatinib)". Takeda Pharmaceuticals.
  14. ^ Page Module:Citation/CS1/styles.css has no content."Phosphorous derivatives as kinase inhibitors". 9 July 2023. Retrieved 7 July 2023.
  15. ^ Page Module:Citation/CS1/styles.css has no content."Takeda Completes Acquisition of Ariad Pharmaceuticals, Inc". takeda.com. 26 February 2017. Retrieved 31 October 2017.
  16. ^ Page Module:Citation/CS1/styles.css has no content."International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75" (PDF). World Health Organization. 2016. p. 104. Retrieved 14 February 2017.

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