Brigatinib, sold under the brand name Alunbrig among others, is a
small-molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
targeted cancer therapy being
developed by
Ariad Pharmaceuticals
ARIAD Pharmaceuticals, Inc. was an American oncology company, now part of Takeda Oncology, which was founded in 1991 by Harvey J. Berger, M.D. and headquartered in Cambridge, Massachusetts. ARIAD engaged in the discovery, development, and commer ...
, Inc.
Brigatinib acts as both an
anaplastic lymphoma kinase
Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ''ALK'' gene.
Identification
Anaplastic lymphoma kinase (ALK) was originally dis ...
(ALK) and
epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor recept ...
(EGFR) inhibitor.
Brigatinib could overcome resistance to
osimertinib
Osimertinib, sold under the brand name Tagrisso, is a medication used to treat non-small-cell lung carcinomas with specific mutations. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor.
The most common side eff ...
conferred by the EGFR C797S mutation if it is combined with an anti-EGFR antibody such as
cetuximab
Cetuximab, sold under the brand name Erbitux, is an epidermal growth factor receptor (EGFR) inhibitor medication used for the treatment of metastatic colorectal cancer and head and neck cancer. Cetuximab is a chimeric (mouse/human) monoclonal an ...
or
panitumumab
Panitumumab, sold under the brand name Vectibix, is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as ''EGF receptor'', ''EGFR'', ''ErbB-1'' and ''HER1'' in humans).
Panitumumab is manufactured by ...
.
Mechanism of action
Brigatinib is an inhibitor of ALK
[ and mutated EGFR.][
ALK was first identified as a chromosomal rearrangement in ]anaplastic large cell lymphoma
Anaplastic large cell lymphoma (ALCL) refers to a group of non-Hodgkin lymphomas in which aberrant T cells proliferate uncontrollably. Considered as a single entity, ALCL is the most common type of peripheral lymphoma and represents ~10% of all per ...
(ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to sm ...
(NSCLC) and neuroblastoma
Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the ...
s, 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
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor recept ...
(EGFR) is another validated target in NSCLC. Additionally, the T790M
T790M, also known as Thr790Met, is a gatekeeper mutation of the epidermal growth factor receptor (EGFR). The mutation substitutes a threonine (T) with a methionine (M) at position 790 of exon 20, affecting the ATP binding pocket of the EGFR k ...
"gatekeeper" mutation is linked in approximately 50 percent of patients who grow resistant to first-generation EGFR inhibitors. While second-generation EGFR inhibitor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor recep ...
s 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
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment o ...
by the FDA for treatment of NSCLC.
On 28 April 2017, it was granted an accelerated approval The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endp ...
from the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) for metastatic non-small cell lung cancer
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to sm ...
(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
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
.
References
External links
*
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