Brigatinib

Mechanism of action

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

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.

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. 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.

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

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); as a 2nd-line therapy for ALK-positive NSCLC.

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

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."

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.

Names

Brigatinib is the INN.

References

References

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6. (June 2024). "Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors". The New England Journal of Medicine.
7. (March 2017). "Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer". Nature Communications.
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11. "About Brigatinib". ARIAD Pharmaceuticals, Inc.
12. (19 May 2017). "FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer". U.S. Department of Health and Human Services.
13. "Takeda Announces FDA Accelerated Approval of Alunbrig (brigatinib)". Takeda Pharmaceuticals.
14. (9 July 2023). "Phosphorous derivatives as kinase inhibitors".
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16. (2016). "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75". World Health Organization.