NV-5138 · program

Mefluleucine (NV-5138) for Treatment-resistant depression

DiscontinuedDiscontinuedSupernus Pharmaceuticals, Inc. (SUPN)

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.

Data current as of

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.

Clinical trials in Treatment-resistant depression

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.

NCT03606395Phase 1Completedn=80

Safety, Tolerability, PK and Efficacy of Single Doses of NV-5138 in Healthy Volunteers and Subjects With Treatment-Resistant Depression

Started Jun 2018· Primary completion Jun 2019· 📍 9 sites across 1 country (United States)

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——

Mechanism of action (compound-wide)

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

TargetActionAffinity
mTORC1primaryMTORActivator—ⓘ
Sestrin2SESN2Modulator—ⓘ

← Full NV-5138 compound page (identity, identifiers, all indications)

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. clinicaltrials.gov — clinicaltrials.gov
  3. ir.supernus.com — Reference
  4. Mefluleucine — Wikipedia
  5. NV-5138 Phase 2b TRD (NCT05066672) — ClinicalTrials.gov
  6. Open-Label Study of SPN-820 in Adults With Major Depressive Disorder (NCT06235905) — ClinicalTrials.gov
  7. Supernus Phase 2b TRD topline (failed) — Supernus IR