Brigatinib Explained

Width:275
Tradename:Alunbrig, others
Dailymedid:Brigatinib
Pregnancy Au:D
Routes Of Administration:By mouth
Atc Prefix:L01
Atc Suffix:ED04
Legal Au:S4
Legal Ca:Rx-only
Legal Ca Comment:[1] [2]
Legal Uk:POM
Legal Us:Rx-only
Legal Eu:Rx-only
Cas Number:1197953-54-0
Pubchem:68165256
Iuphar Ligand:7741
Chemspiderid:34982928
Unii:HYW8DB273J
Kegg:D10866
Pdb Ligand:6GY
Synonyms:AP26113
Iupac Name:5-Chloro-2-N--4-N-[2-(dimethylphosphoryl)phenyl]pyrimidine-2,4-diamine
C:29
Cl:1
H:39
N:7
O:2
P:1
Smiles:COc1cc(ccc1Nc1ncc(Cl)c(Nc2ccccc2P(C)(C)=O)n1)N1CCC(CC1)N1CCN(C)CC1
Stdinchi: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)
Stdinchikey: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.

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.

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.[6] 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.

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."[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]

Names

Brigatinib is the INN.[13]

Notes and References

  1. Web site: Summary Basis of Decision (SBD) for Alunbrig . . 23 October 2014 . 29 May 2022.
  2. Web site: Drug and medical device highlights 2018: Helping you maintain and improve your health . . 14 October 2020 . 17 April 2024.
  3. Huang WS, Liu S, Zou D, Thomas M, Wang Y, Zhou T, Romero J, Kohlmann A, Li F, Qi J, Cai L, Dwight TA, Xu Y, Xu R, Dodd R, Toms A, Parillon L, Lu X, Anjum R, Zhang S, Wang F, Keats J, Wardwell SD, Ning Y, Xu Q, Moran LE, Mohemmad QK, Jang HG, Clackson T, Narasimhan NI, Rivera VM, Zhu X, Dalgarno D, Shakespeare WC . 6 . 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 . 27144831 . 10.1021/acs.jmedchem.6b00306 .
  4. Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, Fujita N, Katayama R . 6 . Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer . Nature Communications . 8 . 14768 . March 2017 . 28287083 . 5355811 . 10.1038/ncomms14768 . 2017NatCo...814768U .
  5. Patcas A, Chis AF, Militaru CF, Bordea IR, Rajnoveanu R, Coza OF, Hanna R, Tiberiu T, Todea DA . 6 . 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 . 34082691 . 8860314 . 10.17305/bjbms.2021.5859 .
  6. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, Christensen JG, Wain JC, Lynch TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Mino-Kenudson M, Engelman JA . 6 . Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors . Science Translational Medicine . 3 . 75 . 75ra26 . March 2011 . 21430269 . 3132801 . 10.1126/scitranslmed.3002003 .
  7. Web site: NDA 208772 Multidisciplinary Review and Evaluation Alunbrig (brigatinib) . 29 August 2016 . FDA.gov. 31 October 2017.
  8. Web site: About Brigatinib . https://web.archive.org/web/20161230023339/http://www.ariad.com/research-development/brigatinib/ . 30 December 2016 . ARIAD Pharmaceuticals, Inc .
  9. Web site: FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer . National Cancer Institute . 19 May 2017 . U.S. Department of Health and Human Services .
  10. Web site: Takeda Announces FDA Accelerated Approval of Alunbrig (brigatinib) . Takeda Pharmaceuticals .
  11. Web site: Phosphorous derivatives as kinase inhibitors . 9 July 2023 . 7 July 2023 .
  12. Web site: Takeda Completes Acquisition of Ariad Pharmaceuticals, Inc. . 26 February 2017 . takeda.com . 31 October 2017.
  13. Web site: International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75 . World Health Organization . 14 February 2017 . 104 . 2016.