Almorexant Explained

Almorexant (INN), also known by its development code ACT-078573, is an orexin antagonist, acting as a competitive antagonist of the OX1 and OX2 orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the treatment of insomnia.[1] Development of the drug was abandoned in January 2011 due to concerns over the hepatic safety of almorexant after transient increases in liver enzymes were observed in trials.[2] [3]

Pharmacology

Pharmacodynamics

Almorexant is a competitive, dual OX1 and OX2 receptor antagonist and selectively inhibits the functional consequences of OX1 and OX2 receptor activation, such as intracellular Ca2+ mobilization. It dissociates very slowly from the orexin receptors and this may prolong its duration of action.[4]

History

Originally developed by Actelion, from 2007 almorexant was being reported as a potential blockbuster drug, as its novel mechanism of action (orexin receptor antagonism) was thought to produce better quality sleep and fewer side effects than the traditional benzodiazepines and Z-drugs which dominated the multibillion-dollar insomnia medication market.[5]

In 2008, GlaxoSmithKline bought the development and marketing rights for almorexant from Actelion for an initial payment of $147 million.[6] The deal would have been worth an estimated $3.2 billion if the drug had successfully completed clinical development and obtained FDA approval.[7] GSK and Actelion continued to develop the drug together, and completed a Phase III clinical trial in November 2009.

However, in January 2011 Actelion and GSK announced they were abandoning the development of almorexant because of its side effect profile.[8]

In 2014 researchers from Actelion published work indicating that almorexant had mild abuse potential but significantly less abuse potential than zolpidem.[9]

External links

Notes and References

  1. Neubauer DN . Almorexant, a dual orexin receptor antagonist for the treatment of insomnia . Current Opinion in Investigational Drugs . 11 . 1 . 101–110 . January 2010 . 20047164 .
  2. Web site: GSK and Actelion discontinue clinical development of almorexant . https://web.archive.org/web/20110704194943/http://www.gsk.com/media/pressreleases/2011/2011_pressrelease_10019.htm . 2011-07-04 . GSK press release . 28 January 2011 .
  3. Hoch M, van Gorsel H, van Gerven J, Dingemanse J . Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant . Journal of Clinical Pharmacology . 54 . 9 . 979–986 . September 2014 . 24691844 . 10.1002/jcph.297 . 40714628 .
  4. Jacobson LH, Hoyer D, de Lecea L . Hypocretins (orexins): The ultimate translational neuropeptides . Journal of Internal Medicine . 291 . 5 . 533–556 . May 2022 . 35043499 . 10.1111/joim.13406 . 248119793 .
  5. Web site: Sleeping Beautifully . CBS Business Network . 24 September 2007 .
  6. Web site: Actelion Sells Glaxo Almorexant Sleep Medicine Rights . Bloomberg . 14 July 2008 .
  7. Web site: Actelion's top dollar deal leaves doubts, and little on the horizon . EP Vantage . 14 July 2008 .
  8. Web site: Actelion and GSK Discontinue Clinical Development of Almorexant . https://web.archive.org/web/20110303032221/http://www1.actelion.com/en/our-company/news-and-events/index.page?newsId=1483135 . 2011-03-03 . Actelion press release . 28 January 2011 .
  9. Cruz HG, Hoever P, Chakraborty B, Schoedel K, Sellers EM, Dingemanse J . Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users . CNS Drugs . 28 . 4 . 361–372 . April 2014 . 24627301 . 10.1007/s40263-014-0150-x .

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