Brigatinib

Brigatinib, sold under the brand name Alunbrig among others, is a small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc.[2] Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.

Brigatinib
Clinical data
Trade namesAlunbrig, others
Other namesAP26113
AHFS/Drugs.comMonograph
MedlinePlusa617016
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • 5-Chloro-2-N-{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-4-N-[2-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
PDB ligand
Chemical and physical data
FormulaC29H39ClN7O2P
Molar mass584.10 g·mol−1
3D model (JSmol)
SMILES
  • COc1cc(ccc1Nc1ncc(Cl)c(Nc2ccccc2P(C)(C)=O)n1)N1CCC(CC1)N1CCN(C)CC1
InChI
  • 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

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.[3]

Mechanism of action

Brigatinib is an inhibitor of ALK[2] and mutated EGFR.[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.[5]

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.[4] 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.[6]

In 2016, brigatinib was granted orphan drug status by the FDA for treatment of NSCLC.[7]

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);[8][9] as a 2nd-line therapy for ALK-positive NSCLC.

In 2020, it was approved as first-line treatment for ALK-positive metastatic NSCLC patients.[5]

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."[10]

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.[11]

Names

Brigatinib is the INN.[12]

References
  1. "Summary Basis of Decision (SBD) for Alunbrig". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  2. 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): 4948–64. doi:10.1021/acs.jmedchem.6b00306. PMID 27144831.
  3. 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.
  4. 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.
  5. Patcas, Adela; Chis, Ana Florica; Militaru, Claudia Florentina; Bordea, Ioana Roxana; Rajnoveanu, Ruxandra; Coza, Ovidiu Florin; Hanna, Reem; Tiberiu, Tamas; Todea, Doina Adina (2022-02-01). "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. ISSN 1840-4812. PMC 8860314. PMID 34082691.
  6. "NDA 208772 Multidisciplinary Review and Evaluation Alunbrig (brigatinib)" (PDF). FDA.gov. 29 August 2016. Retrieved 31 October 2017.
  7. "Takeda Oncology".
  8. FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer
  9. Takeda Announces FDA Accelerated Approval of Alunbrig (brigatinib)
  10. "Ariad Announces Issuance of Key U.S. Patent on Brigatinib". Ariad. 22 April 2015. Retrieved 31 October 2017.
  11. "Takeda Completes Acquisition of Ariad Pharmaceuticals, Inc". takeda.com. 26 February 2017. Retrieved 31 October 2017.
  12. "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75" (PDF). World Health Organization. 2016. p. 104. Retrieved 14 February 2017.
  • "Brigatinib". Drug Information Portal. U.S. National Library of Medicine.
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