Chemistry:Mefluleucine

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Mefluleucine (INN;[1] developmental code names NV-5138, SPN-820) is an investigational new drug that is being evaluated by Navitor Pharmaceuticals and Supernus Pharmaceuticals[2] for the treatment of major depressive disorder (MDD).[3][4][5][6]

Mefluleucine is an analogue of the amino acid leucine and works by binding to and modulating sestrin2, a cellular sensor protein for leucine, which is a natural activator of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway.[4][5][7] The mTORC1 pathway is the same signaling pathway that the NMDA receptor antagonist ketamine activates in the medial prefrontal cortex (mPFC) and which may mediate its rapid-acting antidepressant effects.[4][5]

Pharmacology

Mefluleucine has been found to increase mTORC1 signaling within physiologic range and to stimulate synaptogenesis in the mPFC, and further to induce rapid antidepressant effects in multiple animal models of depression.[4][5] Like those of ketamine, these actions were demonstrated to require the signaling of brain-derived neurotrophic factor (BDNF).[4] The antidepressant effects following a single dose of mefluleucine are long-lasting, with a duration of up to 7 days, and are similar to those of ketamine.[4][5]

Clinical trials

Mefluleucine has undergone several clinical trials to assess its potential as a treatment for depression, with a particular focus on treatment-resistant depression (TRD). The clinical development program for mefluleucine began with a Phase 1 trial initiated by Navitor Pharmaceuticals in 2018.[4][8] This initial study was designed to evaluate the safety, tolerability, and pharmacokinetics of the compound in both healthy volunteers and patients diagnosed with TRD.[9]

Following the Phase 1 trial, larger Phase 2 studies were launched to further investigate the efficacy and safety of mefluleucine as an adjunctive treatment for adults with TRD.[10][11][3] These more extensive trials involved a larger number of participants and was structured to provide more comprehensive data on the compound's potential therapeutic benefits.[12]

See also

References

  1. ↑ "Archived copy". https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl133.pdf. 
  2. ↑ "Supernus and Navitor Announce Development and Option Agreement for Orally Active mTORC1 Activator NV-5138". April 21, 2020. https://ir.supernus.com/news-releases/news-release-details/supernus-and-navitor-announce-development-and-option-agreement. 
  3. ↑ 3.0 3.1 "NV 5138". 20 May 2025. https://adisinsight.springer.com/drugs/800052663. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide". F1000Research 7: 659. 2018. doi:10.12688/f1000research.14344.1. PMID 29899972. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Sestrin 2 Modulator NV-5138 Shows Ketamine-Like Rapid Antidepressant Effects via Direct Activation of mTORC1 Signaling". Neuropsychopharmacology 42 (1): S111–S293. November 2017. doi:10.1038/npp.2017.264. ACNP 56th Annual Meeting: Poster Session I, December 4, 2017. 
  6. ↑ "Discovery of NV-5138, the first selective Brain mTORC1 activator". Scientific Reports 9 (1): 4107. March 2019. doi:10.1038/s41598-019-40693-5. PMID 30858438. Bibcode: 2019NatSR...9.4107S. 
  7. ↑ "Sestrin2 is a leucine sensor for the mTORC1 pathway". Science 351 (6268): 43–48. January 2016. doi:10.1126/science.aab2674. PMID 26449471. Bibcode: 2016Sci...351...43W. 
  8. ↑ Clinical trial number NCT03606395 for "Safety, Tolerability, PK and Efficacy of Single Doses of NV-5138 in Healthy Volunteers and Subjects With Treatment-Resistant Depression" at ClinicalTrials.gov
  9. ↑ "Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers" (in English). Clinical Therapeutics 46 (3): 217–227. March 2024. doi:10.1016/j.clinthera.2023.12.015. PMID 38485588. 
  10. ↑ Clinical trial number NCT05066672 for "Phase 2 Study of NV-5138 in Adults With Treatment Resistant Depression" at ClinicalTrials.gov
  11. ↑ Clinical trial number NCT06235905 for "Open-Label of SPN-820 in Adults With Major Depressive Disorder" at ClinicalTrials.gov
  12. ↑ "Navitor's Three Phase 1 Studies for NV-5138 Show Antidepressant Effects and Biomarker Impact, Supporting Further Development of Direct Activator of mTORC1 in Depression". https://www.biospace.com/article/releases/navitor-s-three-phase-1-studies-for-nv-5138-show-antidepressant-effects-and-biomarker-impact-supporting-further-development-of-direct-activator-of-mtorc1-in-depression/. 



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