Efficacy and Safety of SPN-820 for Adults with Major Depressive Disorder: Primary Results from a Phase 2, Open-label Trial
Introduction: SPN-820 (oral formulation of NV-5138), is a first-in-class, rapid-acting antidepressant (RAAD) drug candidate that acts intracellularly to increase mechanistic target of rapamycin complex 1 (mTORC1) activity, a neuronal signaling protein that enhances neuroplasticity. A single dose (2400 mg) pilot study in participants with treatment resistant depression (Nf32) showed SPN-820 rapidly and significantly improved Hamilton Depression Rating Scale-6 (HAM-D6) scores vs. placebo. This open-label Phase 2 study [NCT06235905] evaluates potential for early and continued response to SPN-820 in adults with depression.
Methods: Participants maintained on stable dose (≥6 weeks) antidepressant therapy, with Montgomery-Åsberg Depression Rating Scale (MADRS) scores ≥22 and CGI-S ≥4, received 2400mg SPN-820 once every 3 days for 3 doses. Efficacy (HAM-D6) was evaluated at 2-, 4-, 8-, 24-, and 48 hours following each dose and 72 hours following last dose.
Results: Treated participants (Nf40; mean±SD 44.7±15.39 years; 67.5% female, HAM-D6 13.6±1.69, MADRS 33.1±5.41at Baseline) showed early, marked HAM-D6 and MADRS improvement (-7.2±3.96, -16.6±10.06 points respectively) at Day 1 (4-hours), that further improved through Day 10 (Nf38, -9.6±3.18, -22.9±9.98, respectively). Rapid MADRS response (50% reduction) and remission (MADRS≤10) were also observed, reaching 50.0% and 35.0% of participants, respectively, on Day 1 (4-hours) and 84.2% and 63.2%, respectively, on Day 10. Common AEs included headache (20.0%), nausea (20.0%), somnolence (15.0%), and dizziness (10.0%). Adverse events led to withdrawal in 1 (2.5%) participant. Dissociative effects were not reported.
Conclusions: Adjunctive SPN-820 rapidly and substantially improved depressive symptoms. Effects persisted 3-days following last dose. Treatment appeared well tolerated.
