Brigatinib

Brigatinib
Names
Trade namesAlunbrig, others
Other namesAP26113
IUPAC name
  • 5-Chloro-2-N-{4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl}-4-N-[2-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine
Clinical data
Drug classTyrosine kinase inhibitor[1]
Main usesNon-small cell lung cancer (NSCLC)[2]
Side effectsDiarrhea, tiredness, nausea, rash, muscle pain, headache, high blood pressure, shortness of breath[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
    Routes of
    use
    By mouth
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa617016
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    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, sold under the brand name Alunbrig among others, is a medication used to treat non-small cell lung cancer (NSCLC).[2] Specifically it is used for metastatic cases that are ALK-positive.[2] It is taken by mouth.[2]

    Common side effects include diarrhea, tiredness, nausea, rash, muscle pain, headache, high blood pressure, and shortness of breath.[2] Other side effects may include pneumonitis, vision problems, muscle breakdown, pancreatitis, high blood sugar, and sunburns.[2] Use in pregnancy may harm the baby.[2] It is a tyrosine kinase inhibitor that blocks ALK.[1]

    Brigatinib was approved for medical use in the United States in 2017 and Europe in 2018.[2][3] In the United Kingdom 4 weeks of medication costs the NHS about £4,900 as of 2021.[4] This amount in the United States is about 17,400 USD.[5]

    Medical uses

    Dosage

    It is taken at a dose of 90 mg once per day for 7 days and than increased to 180 mg once per day.[2]

    Mechanism of action

    Brigatinib is an inhibitor of ALK[6] and mutated EGFR.[7]

    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.

    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.[7] 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.[8]

    In 2016, brigatinib was granted orphan drug status by the FDA for treatment of NSCLC.[9]

    In 28 April 2017, it was granted an Accelerated Approval from the US FDA for metastatic non-small cell lung cancer (NSCLC);[10][11] as a 2nd-line therapy for ALK-positive NSCLC.[12]

    Society and culture

    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.” [13]

    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 now an indirect wholly owned subsidiary of Takeda.[14]

    Names

    Brigatinib is the INN.[15]

    References

    1. 1 2 "Brigatinib Monograph for Professionals". Drugs.com. Retrieved 11 January 2022.
    2. 1 2 3 4 5 6 7 8 9 10 "DailyMed - ALUNBRIG- brigatinib tablet, film coated ALUNBRIG- brigatinib kit". dailymed.nlm.nih.gov. Archived from the original on 12 May 2021. Retrieved 11 January 2022.
    3. "Alunbrig". Archived from the original on 11 November 2021. Retrieved 11 January 2022.
    4. BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1016. ISBN 978-0857114105.
    5. "Alunbrig Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 11 January 2022.
    6. 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.
    7. 1 2 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.
    8. "NDA 208772 Multidisciplinary Review and Evaluation Alunbrig (brigatinib)" (PDF). FDA.gov. 29 August 2016. Archived (PDF) from the original on 23 December 2019. Retrieved 31 October 2017.
    9. "Takeda Oncology". Archived from the original on 2017-04-30. Retrieved 2021-06-30.
    10. "FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer". Archived from the original on 2021-07-11. Retrieved 2021-06-30.
    11. "Takeda Announces FDA Accelerated Approval of Alunbrig (brigatinib)". Archived from the original on 2021-06-03. Retrieved 2021-06-30.
    12. "Archive copy". Archived from the original on 2020-01-26. Retrieved 2021-06-30.{{cite web}}: CS1 maint: archived copy as title (link)
    13. "ARIAD Announces Issuance of Key U.S. Patent on Brigatinib". ariad.com. 22 April 2015. Retrieved 31 October 2017.
    14. "Takeda Completes Acquisition of ARIAD Pharmaceuticals, Inc". takeda.com. 26 February 2017. Archived from the original on 7 November 2017. Retrieved 31 October 2017.
    15. "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75" (PDF). World Health Organization. 2016. p. 104. Archived (PDF) from the original on 2 February 2017. Retrieved 14 February 2017.
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