Binimetinib

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Binimetinib
Names
Trade namesMektovi
Other namesMEK162, ARRY-162, ARRY-438162
  • 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzo[d]imidazole-6-carboxamide
Clinical data
Drug classAntineoplastic
Main usesMelanoma[1]
Side effectsTiredness, nausea, diarrhea, abdominal pain[2]
Typical dose45 mg BID[3]
External links
AHFS/Drugs.comMonograph
MedlinePlusa618041
Legal
License data
Legal status
Chemical and physical data
FormulaC17H15BrF2N4O3
Molar mass441.233 g·mol−1
3D model (JSmol)
  • CN1C=NC2=C1C=C(C(=C2F)NC3=C(C=C(C=C3)Br)F)C(=O)NOCCO
  • InChI=1S/C17H15BrF2N4O3/c1-24-8-21-16-13(24)7-10(17(26)23-27-5-4-25)15(14(16)20)22-12-3-2-9(18)6-11(12)19/h2-3,6-8,22,25H,4-5H2,1H3,(H,23,26)
  • Key:ACWZRVQXLIRSDF-UHFFFAOYSA-N

Binimetinib, sold under the brand name Mektovi, is as medication used to treat melanoma.[1] Specifically it is used with encorafenib for cases that are BRAF V600 positive and cannot be removed by surgery.[1] It is taken by mouth.[3]

Common side effects include tiredness, nausea, diarrhea, and abdominal pain.[2] Other side effects may include heart damage, blood clots, eye problems, interstitial lung disease, liver problems, muscle breakdown, and bleeding.[2] Use in pregnancy may harm the baby.[2] It works by blocking MEK, preventing its activation by BRAF, thereby slowing cancer growth.[1]

Binimetinib was approved for medication use in the United States and Europe in 2018.[2][1] In the United Kingdom 4 weeks of treatment costs the NHS about £4,500 as of 2021.[3] This amount in the United States costs about 12,800 USD.[4]

Medical uses

Dosage

It is typically taken as 45 mg twice per day.[3]

Mechanism of action

MAPK and PI3K/AKT/mTOR pathway[5]

Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor.[6] MEK is part of the RAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.[7] Binimetinib, uncompetitive with ATP, binds to and inhibits the activity of MEK1/2 kinase, which has been shown to regulate several key cellular activities including proliferation, survival, and angiogenesis.[8] MEK1/2 are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.[9] Inhibition of MEK1/2 prevents the activation of MEK1/2 dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling.[10] As demonstrated in preclinical studies, this may eventually lead to an inhibition of tumor cell proliferation and an inhibition in production of various inflammatory cytokines including interleukin-1, -6 and tumor necrosis factor.[10]

History

In 2015, it was in phase III clinical trials for ovarian cancer,[11] BRAF mutant melanoma,[12] and NRAS Q61 mutant melanoma.[13]

In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.[14] In the trial, those receiving binimetinib had a median progression-free survival of 2.8 months versus 1.5 months for those on the standard dacarbazine treatment.[15] NDA submitted Jun 2016,[16] and the FDA should decide by 30 June 2017.[17]

In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy.[18]

Binimetinib was studied for treatment of rheumatoid arthritis, but a phase II trial did not show benefit.[medical citation needed]

In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and the New Drug Application was withdrawn.[19]

In June 2018, it was approved for the treatment of certain melanomas by the U.S. Food and Drug Administration (FDA) in combination with encorafenib.[20] The FDA approved binimetinib based primarily on evidence from one clinical trial (NCT01909453) of 383 patients with BRAF V600 mutation-positive melanoma that was advanced or could not be removed by surgery.[21] The trial was conducted at 162 sites in Europe, North America, and various countries around the world.[21]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Mektovi". Archived from the original on 6 October 2021. Retrieved 10 January 2022.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "DailyMed - MEKTOVI- binimetinib tablet, film coated". dailymed.nlm.nih.gov. Archived from the original on 6 April 2021. Retrieved 10 January 2022.
  3. ↑ 3.0 3.1 3.2 3.3 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1014. ISBN 978-0857114105.
  4. ↑ "Mektovi Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 22 January 2021. Retrieved 10 January 2022.
  5. ↑ Guerrero, Patricia; Albarrán, Víctor; San Román, María; González-Merino, Carlos; García de Quevedo, Coral; Moreno, Jaime; Calvo, Juan Carlos; González, Guillermo; Orejana, Inmaculada; Chamorro, Jesús; Martínez-Delfrade, Íñigo; Morón, Blanca; de Frutos, Belén; Ferreiro, María Reyes (January 2023). "BRAF Inhibitors in Metastatic Colorectal Cancer and Mechanisms of Resistance: A Review of the Literature". Cancers. 15 (21): 5243. doi:10.3390/cancers15215243. ISSN 2072-6694.
  6. ↑ Wu PK, Park JI (December 2015). "MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms". Seminars in Oncology. 42 (6): 849–62. doi:10.1053/j.seminoncol.2015.09.023. PMC 4663016. PMID 26615130.
  7. ↑ "Binimetinib". PubChem. Archived from the original on 6 January 2021. Retrieved 31 May 2021.
  8. ↑ Ascierto PA, Schadendorf D, Berking C, et al. (March 2013). "MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study". The Lancet. Oncology. 14 (3): 249–56. doi:10.1016/S1470-2045(13)70024-X. PMID 23414587.
  9. ↑ Mehdizadeh A, Somi MH, Darabi M, et al. (February 2016). "Extracellular signal-regulated kinase 1 and 2 in cancer therapy: a focus on hepatocellular carcinoma". Molecular Biology Reports. 43 (2): 107–16. doi:10.1007/s11033-016-3943-9. PMID 26767647. S2CID 15113957.
  10. ↑ 10.0 10.1 Woodfield SE, Zhang L, Scorsone KA, et al. (March 2016). "Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression". BMC Cancer. 16: 172. doi:10.1186/s12885-016-2199-z. PMC 4772351. PMID 26925841.
  11. ↑ Clinical trial number NCT01849874 for "A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer" at ClinicalTrials.gov
  12. ↑ Clinical trial number NCT01909453 for "Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)" at ClinicalTrials.gov
  13. ↑ Clinical trial number NCT01763164 for "Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma" at ClinicalTrials.gov
  14. ↑ Hufford A (December 2015). "Array BioPharma Has Successful Trial for Cancer Drug Binimetinib". Wall Street Journal. Archived from the original on 6 January 2021. Retrieved 31 May 2021.
  15. ↑ "Array BioPharma announces Phase 3 binimetinib trial meets primary endpoint for NRAS-mutant melanoma". Metro Denver. December 2015. Archived from the original on 7 January 2021. Retrieved 31 May 2021.
  16. ↑ "Array Bio submits marketing application in U.S. for lead product candidate in certain type of melanoma. June 2016". Archived from the original on 15 August 2016. Retrieved 31 May 2021.
  17. ↑ House DW (1 September 2016). "FDA accepts Array Bio's NDA for binimetinib, action date June 30". Seeking Alpha. Archived from the original on 19 September 2016. Retrieved 31 May 2021.
  18. ↑ House DW (1 April 2016). "Array bags Phase 3 study of binimetinib in ovarian cancer; shares down 4%". Seeking Alpha. Archived from the original on 6 December 2016. Retrieved 31 May 2021.
  19. ↑ Adams B (20 March 2017). "Losing Nemo: Array pulls skin cancer NDA for binimetinib". Fierce Biotech. Archived from the original on 6 January 2021. Retrieved 31 May 2021.
  20. ↑ "FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations" (Press release). U.S. Food and Drug Administration (FDA). 27 June 2018. Archived from the original on 19 December 2019. Retrieved 17 July 2018. Public Domain This article incorporates text from this source, which is in the public domain.
  21. ↑ 21.0 21.1 "Drug Trial Snapshot: Mektovi". U.S. Food and Drug Administration (FDA). 19 December 2019. Archived from the original on 19 December 2019. Retrieved 19 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.

External links

External sites:
Identifiers:
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