Small Molecule · NV-5138

Mefluleucine (NV-5138)

DiscontinuedNavitor Pharmaceuticals, Inc.

Oral leucine-analogue that binds the leucine sensor sestrin2, relieving its inhibition of GATOR2 and directly activating mTORC1 — driving rapid synaptogenesis (a ketamine-like rationale without NMDA antagonism). Navitor Pharmaceuticals; optioned to Supernus as SPN-820. The lead TRD Phase 2b failed.

Also known as: NV-5138, SPN-820, Mefluleucine

Data current as of

Modality
Small molecule
Chemical class
Amino acid, Leucine analog, Organofluorine
Chemistry
Single enantiomer
Mechanism
mTORC1 activator
Highest phase
Discontinued
Lead indication
Treatment-resistant depression
Developer
Navitor Pharmaceuticals, Inc.
Trials
1 tracked · 1 sites

Mechanism of action

Binds sestrin2 (the intracellular leucine sensor), derepressing GATOR2/mTORC1 — selective direct mTORC1 activation driving synaptogenic signaling. No published binding affinity.

TargetActionAffinity
mTORC1primaryMTORActivator—ⓘ
Sestrin2SESN2Modulator—ⓘ

Formulations

FormulationRouteRegimenPharmacokinetics
NV-5138 oral once-daily
Oral doses of 400-3000 mg once daily studied in Phase 1 healthy volunteers; 800 and 1600 mg once daily in Phase 2 TRD
OralOnce daily—
SPN-820 oral intermittent (every 3 days)capsule (6 x 400 mg)
2400 mg orally (six 400 mg capsules) administered every 3 days in an open-label Phase 2a MDD study
Oral——

Development timeline

DiscontinuedFeb 2025
  1. Phase 2b TRD failed primary MADRS endpoint; program future under review with Navitor.↗
Phase 2Jan 2025
  1. Phase 2b TRD study (NCT05066672) reached primary completion.

Mefluleucine (NV-5138) for Treatment-resistant depression

DiscontinuedDiscontinuedTreatment-resistant depression indication →

NV-5138/SPN-820 for TRD. The Phase 2b study (NCT05066672, n=250) FAILED its primary endpoint — MADRS change at Week 4 (SPN-820 -12.3 vs placebo -11.9; not significant). Announced 18 Feb 2025; no path forward in TRD disclosed.

Clinical trials

NCT05066672SPN-820 Phase 2bPhase 2Completedn=250

Phase 2b Study of NV-5138 (SPN-820) in Adults With Treatment Resistant Depression

Started Jan 2022· Primary completion Jan 2025· 📍 1 site across 1 country (United States)

missedprimaryMADRS change at Week 4 — SPN-820 -12.3 vs placebo -11.9

Did not meet primary endpoint; no separation on secondary endpoints; safety clean. Announced 18 Feb 2025.

Identifiers

Sources

  1. Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers — Clinical Therapeutics
  2. ir.supernus.com — Reference
  3. Mefluleucine — Wikipedia
  4. NV-5138 Phase 2b TRD (NCT05066672) — ClinicalTrials.gov
  5. Open-Label Study of SPN-820 in Adults With Major Depressive Disorder (NCT06235905) — ClinicalTrials.gov
  6. Supernus Phase 2b TRD topline (failed) — Supernus IR