Chemistry:Brigatinib
 | |
| Clinical data | |
|---|---|
| Trade names | Alunbrig, others |
| Other names | AP26113 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a617016 |
| License data |
|
| Pregnancy category |
|
| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| ChemSpider | |
| UNII | |
| KEGG | |
| PDB ligand | |
| Chemical and physical data | |
| Formula | C29H39ClN7O2P |
| Molar mass | 584.10 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
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 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.[citation needed]
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
References
- ↑ "Summary Basis of Decision (SBD) for Alunbrig". 23 October 2014. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00415&lang=en.
- ↑ 2.0 2.1 "Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase". Journal of Medicinal Chemistry 59 (10): 4948–4964. May 2016. doi:10.1021/acs.jmedchem.6b00306. PMID 27144831.
- ↑ "Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer". Nature Communications 8: 14768. March 2017. doi:10.1038/ncomms14768. PMID 28287083. Bibcode: 2017NatCo...814768U.
- ↑ 4.0 4.1 "Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors". Science Translational Medicine 3 (75): 75ra26. March 2011. doi:10.1126/scitranslmed.3002003. PMID 21430269.
- ↑ 5.0 5.1 "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. February 2022. doi:10.17305/bjbms.2021.5859. PMID 34082691.
- ↑ "NDA 208772 Multidisciplinary Review and Evaluation Alunbrig (brigatinib)". 29 August 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208772Orig1s000MultidisciplineR.pdf.
- ↑ "About Brigatinib". ARIAD Pharmaceuticals, Inc. http://www.ariad.com/research-development/brigatinib/.
- ↑ "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. https://www.cancer.gov/news-events/cancer-currents-blog/2017/brigatinib-fda-lung-cancer.
- ↑ "Takeda Announces FDA Accelerated Approval of Alunbrig (brigatinib)". Takeda Pharmaceuticals. https://www.takeda.com/newsroom/newsreleases/2017/alunbrig-fda-approval/.
- ↑ "Phosphorous derivatives as kinase inhibitors". 9 July 2023. https://patents.google.com/patent/US9012462B2/en.
- ↑ "Takeda Completes Acquisition of Ariad Pharmaceuticals, Inc.". 26 February 2017. https://www.takeda.com/newsroom/newsreleases/2017/Takeda-Completes-Acquisition-of-ARIAD-Pharmaceuticals-Inc/.
- ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75". World Health Organization. 2016. p. 104. https://www.who.int/medicines/publications/druginformation/innlists/RL75.pdf.
External links
- "Brigatinib". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/brigatinib.
 |  |
