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BINIMETINIB* (MEK162)
Phase 2, N/A, Phase 3, Phase 1/Phase 2
MEK Inhibitor
Hemat
MEK162 is an orally bioavailable, selective allosteric MAPK kinase (MEK) inhibitor. Areas of Research: Melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, and pancreatic cancer.

Compound DescriptionOral, selective allosteric MAPK kinase (MEK) inhibitor

Areas of ResearchMelanoma, non-small cell lung cancer (NSCLC), ovarian cancer, and pancreatic cancer

Proposed Mechanism of ActionBinimetinib (MEK162, Arry-162) is an oral, selective allosteric MEK inhibitor.1 MEK1 and MEK2 play an important role in cancer cell proliferation, differentiation, apoptosis, and metastasis. Both MEK1 and MEK2 are key components of the Ras-Raf-MEK-extracellular regulated signal kinases (ERK) signaling pathway (or MAPK signaling pathway).2,3 Hyperactivation of this signaling pathway through K-Ras, B-Raf, and receptor tyrosine kinase mutations is closely associated with the development of human tumors, such as melanoma, pancreatic, CRC, lung, and thyroid cancers and increases the sensitivity of tumor cells to MEK inhibitors.3,4

Key Preclinical DataBinimetinib is a small molecule inhibitor of MEK1 and MEK2 that binds to a pocket adjacent to the adenosine triphosphate (ATP) binding pocket in the kinase domain and is not competitive with ATP.1 Binimetinib inhibits MEK1/MEK2 in cell lines, which results in reduced phosphorylation of the MEK1/MEK2 substrates, pERK1 and pERK2, and reduced expression of downstream target genes.1,4

Binimetinib inhibits proliferation in a large number of cancer cell lines, especially cell lines with B-Raf and N-Ras mutations, and to a lesser degree K-Ras, all of which are components of the Raf-MEK-ERK intracellular pathway.4

In xenograft models, MEK162 demonstrated activity in K-Ras and B-Raf mutant tumors in CRC, NSCLC, and pancreatic cancer.4

Clinical StatusBinimetinib is currently being studied in various advanced or metastatic solid tumors including malignant. Phase Ib studies are ongoing in patients with various solid tumors in patients harboring B-Raf/Ras dependent disease, and in combination with phosphatidylinositol 3-kinase (PI3K) inhibitor (BKM120).5,6,8 In malignant melanoma, the NEMO (NRAS Melanoma and MEK inhibitor study) and COLUMBUS (Combined encorafenib (LGX818) plus binimetinib) Phase III trials in patients with NRAS and BRAF mutant melanoma are actively recruiting (NCT01763164).

MOA data is based on in vitro/in vivo data. Clinical benefit is unknown.
Binimetinib (MEK162) is an investigational compound. Efficacy and safety have not been established.
There is no guarantee binimetinib (MEK162) will become commercially available.
*MEK162 (also known as ARRY-162) is licensed from Array BioPharma Inc.
References
  1. Novartis, data on file, 2014.
  2. Sturgill TW. MAP kinase: it’s been longer than fifteen minutes. Biochem Biophys Res Commun. 2008;371:1–4.
  3. Fremin C, Meloche S. From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. J Hematol Oncol. 2010;3:8–11.
  4. Lee P, Wallace E, Marlow A, et al. Preclinical development of ARRY-162, a potent and selective MEK 1/2 inhibitor. Presented at: 101st Annual Meeting of the American Association for Cancer Research (AACR); April 17–21, 2010; Washington, DC. Abstract 2515.
  5. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrial.gov/ct2/show/NCT01543698. Updated November 18, 2013. Accessed January 13, 2014.
  6. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrial.gov/ct2/show/NCT01363232. Updated December 19, 2013. Accessed January 13, 2014.
  7. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrial.gov/ct2/show/NCT01337765. Updated December 24, 2013. Accessed January 13, 2014.
  8. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01320085. Updated January 6, 2014. Accessed January 16, 2014.
  9. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01763164. Updated January 14, 2014. Accessed January 16, 2014.
  10. http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70024-X/abstract
  11. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01927341. Updated October 17, 2013. Accessed January 16, 2014.
  12. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01449058. Updated December 4, 2013. Accessed January 16, 2014.
  13. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01828034. Updated January 20, 2014. Accessed January 27, 2014.
  14. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01801358. Updated December 10, 2013. Accessed January 16, 2014.
  15. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01781572. Updated July 22, 2013. Accessed January 13, 2014.
  16. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01909453. Updated September 26, 2013. Accessed January 13, 2014.
  17. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01763164. Updated January 14, 2014. Accessed January 16, 2014.
  18. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01885195. Updated January 22, 2014. Accessed January 27, 2014.
  19. National Institutes of Health (NIH). ClinicalTrials.gov. www.clinicaltrials.gov/ct2/show/NCT01849874. Updated February 3, 2014. Accessed February 19, 2014.

The information contained herein was last updated on April 12, 2013.

All Compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available.

The search results, details, and descriptions of clinical trials viewed in this app are supplied by ClinicalTrials.gov and EUtrialregistry.com. This information is maintained by a third party over whom Novartis Pharmaceuticals Corporation has no control. As such, Novartis Pharmaceuticals Corporation does not guarantee the accuracy, completeness, adequacy, or any other aspect of the information contained on this site.