Brigatinib

Brigatinib
Clinical data
Trade names Alunbrig
Synonyms AP26113
AHFS/Drugs.com alunbrig
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
3D model (JSmol)

Brigatinib (INN;[1] marketed as Alunbrig) is an investigational small-molecule targeted cancer therapy being developed by ARIAD Pharmaceuticals, Inc.[2] Brigatinib acts as both a 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 a 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.

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.

Pre-clinical results

In 2010, ARIAD announced results of preclinical studies on brigatinib showing potent inhibition of the target protein and of mutant forms that are resistant to the first-generation ALK inhibitor, which currently is in clinical trials in patients with cancer.[5] Brigatinib potently inhibits activated EGFR or its T790M mutant, both in cell culture and in mouse tumor models following once daily oral dosing. The effective oral doses in these preclinical models were similar to those previously shown to be effective in resistant ALK models. When tested against the native form of EGFR, brigatinib lacked activity, indicating a favorable selectivity for activated EGFR.[6]

History

Clinical study

In September 2011 ARIAD Pharmaceuticals, Inc. initiated Phase 1/2 clinical trial of brigatinib (AP26113) conducted in patients with advanced malignancies, including anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). [7] Beginning in March 2014, the global Phase 2 ALTA study was conducted in patients with locally advanced or metastatic NSCLC who test positive for the ALK oncogene and were previously treated with crizotinib. This registration study enrolled approximately 220 patients at approximately 75 sites in North America, Europe and Asia. The primary endpoint of the Phase 2 trial is objective response rate as measured by RECIST criteria. Brigatinib received Breakthrough Therapy designation from the U.S. Food and Drug Administration in 2014. [8] In March 2016, The Phase 3 Multicenter Open-label Study of brigatinib was initiated in adult patients with ALK-positive locally advanced or metastatic NSCLC who have not previously been treated with an ALK inhibitor, which is designed to assess the efficacy of brigatinib in comparison to crizotinib based on evaluation of the primary endpoint of progression free survival. Research data from Phase 3 trial suggested that in the ALK TKI-naive group, it could potentially change patients’ natural history by better suppressing ALK+ disease from the beginning.[9]On 15 April 2016, ARIAD reported their updated results from the Phase ½ trial, a one year overall survival rate of 100 percent in crizotinib-naive patients, and 81 percent in patients with prior crizotinib treatment, as well as predictable pharmacokinetic data. .[10] An Expanded Access Study was further evaluated in May 2016. [11]

Regulatory approval

Ariad Pharmaceuticals, Inc. filed an investigational new drug (IND) application to the US FDA on August 29, 2016. [12]

In 2016, brigatinib was granted orphan drug status by the FDA for treatment of NSCLC.[13]

In 28 April 2017, it was granted an Accelerated Approval from the US FDA for metastatic non-small cell lung cancer (NSCLC);[14][15] as a 2nd-line therapy for ALK-positive NSCLC.[16]

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.” [17]

Commercialization

Alunbrig (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 now an indirect wholly owned subsidiary of Takeda. [18]

References

  1. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75" (PDF). World Health Organization. 2016. p. 104. Retrieved 14 February 2017.
  2. 1 2 Huang, Wei-Sheng; Liu, Shuangying; Zou, Dong; Thomas, Mathew; Wang, Yihan; Zhou, Tianjun; Romero, Jan; Kohlmann, Anna; Li, Feng. "Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase". Journal of Medicinal Chemistry. 59: 4948–64. doi:10.1021/acs.jmedchem.6b00306. PMID 27144831.
  3. ↑ Uchibori, Ken; Inase, Naohiko; Araki, Mitsugu; Kamada, Mayumi; Sato, Shigeo; Okuno, Yasushi; Fujita, Naoya; Katayama, Ryohei (2017-03-13). "Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer". Nature Communications. 8. doi:10.1038/ncomms14768. ISSN 2041-1723.
  4. 1 2 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 (23 March 2011). "Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors". Science Translational Medicine. 3 (75): 75ra26. doi:10.1126/scitranslmed.3002003. PMC 3132801.
  5. ↑ "ARIAD Presents Preclinical Data on Its Investigational ALK Inhibitor, AP26113, Demonstrating That It Can Overcome Mutation-Based Drug Resistance in Cancer Models".
  6. ↑ "ARIAD Announces Presentation on Its Investigational Lung Cancer Drug Candidate, AP26113, a Dual Inhibitor of ALK and EGFR, at World Conference on Lung Cancer".
  7. ↑ "A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral Anaplastic Lymphoma Kinase (ALK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Brigatinib (AP26113)". clinicaltrials.gov. 10 October 2011. Retrieved 31 October 2017.
  8. ↑ "A Study to Evaluate the Efficacy of Brigatinib (AP26113) in Participants With Anaplastic Lymphoma Kinase (ALK)-Positive, Non-small Cell Lung Cancer (NSCLC) Previously Treated With Crizotinib". clinicaltrials.gov. 24 March 2014. Retrieved 31 October 2017.
  9. ↑ "ALTA-1L Study: A Phase 3 Study of Brigatinib Versus Crizotinib in ALK-positive Advanced Non-Small Cell Lung Cancer Patients (ALTA-1L)". clinicaltrials.gov. 14 April 2016. Retrieved 31 October 2017.
  10. ↑ "ARIAD Presents Updated Phase 1/2 Clinical Data on Brigatinib in Patients with ALK+ Non-Small Cell Lung Cancer". Ariad.com. 15 April 2016. Retrieved 31 October 2017.
  11. ↑ "An Expanded Access Study of Brigatinib for Patients With ALK-positive Advanced Non-Small Cell Lung Cancer". clinicaltrials.gov. 26 May 2016. Retrieved 31 October 2017.
  12. ↑ "NDA 208772 Multidisciplinary Review and Evaluation ALUNBRIG (brigatinib)" (PDF). FDA.gov. 29 August 2016. Retrieved 31 October 2017.
  13. ↑ http://www.ariad.com/research-development/brigatinib/
  14. ↑ FDA Grants Brigatinib Accelerated Approval for Metastatic Non-Small Cell Lung Cancer
  15. ↑ Takeda Announces FDA Accelerated Approval of ALUNBRIGTM (brigatinib)
  16. ↑
  17. ↑ "ARIAD Announces Issuance of Key U.S. Patent on Brigatinib". ariad.com. 22 April 2015. Retrieved 31 October 2017.
  18. ↑ "Takeda Completes Acquisition of ARIAD Pharmaceuticals, Inc". takeda.com. 26 February 2017. Retrieved 31 October 2017.
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