Brigatinib

Brigatinib
Clinical data
Trade names	Alunbrig, others
Other names	AP26113
AHFS/Drugs.com	Monograph
MedlinePlus	a617016
License data	US DailyMed: Brigatinib;
Pregnancy; category	AU: D; ;
Routes of; administration	By mouth
ATC code	L01ED04 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only; EU: Rx-only;
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	1197953-54-0;
PubChem CID	68165256;
IUPHAR/BPS	7741;
ChemSpider	34982928;
UNII	HYW8DB273J;
KEGG	D10866;
PDB ligand	6GY (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID501027929 ;
Chemical and physical data
Formula	C29H39ClN7O2P
Molar mass	584.10 g·mol−1
3D model (JSmol)	Interactive image;
	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 small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc.^[3] Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.^{[medical citation needed]}

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.^[4]

Mechanism of action

Brigatinib is an inhibitor of ALK^[3] and mutated EGFR.^[5]

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.^[6]

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.^[5] 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.^[7]

In 2016, brigatinib was granted orphan drug status by the FDA for treatment of NSCLC.^[8]

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);^[9]^[10] 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.^[6]

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."^[11]

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.^[12]