SPN-820 / Navitor Pharma, Supernus Pharma - LARVOL DELTA

Next-Generation Pharmacotherapies for Unipolar Mood Disorders: A Leading Article on Phase II/III Drug Development Across Diverse Mechanisms. (PubMed, CNS Drugs) - "Following the US Food and Drug Administration (FDA) approval of esketamine and brexanolone in 2019, industry investment in therapeutics with novel mechanisms for mood and anxiety disorders has expanded, catalyzing a new wave of innovative interventions...The drug names discussed are ALTO-100, ALTO-203, ALTO-207, ALTO-300, BHV-7000, BI-1569912, BPL-003, COMP360, DT120, ELE-101, GATE-251, GH001, GM-1020, GM-2505, HLP003, MK-1942, NBI-1065845, NBI-1070770, NV-5138, PIPE-307, SEP-363856, SPT-300, VLS-01, and XEN1101. The US Clinical Trials registry (clinicaltrials.gov), MEDLINE, conference proceedings, and company communications such as press releases were consulted to obtain up-to-date trial information and reported outcomes. Overall, the therapeutic landscape shows an expanding range of clinical compounds under active development; nonetheless, persistent challenges remain, including approaches to therapeutics where functional unblinding may occur, the ways in which to..."

Journal • P2/3 data • Review • CNS Disorders • Mood Disorders • Psychiatry

High-concentration hydrogen mitigates cognitive impairment in a murine model of Sepsis-associated encephalopathy by enhancing oligodendrocyte maturation and myelination in the mPFC. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "To verify the underlying mechanism, mTOR agonist NV-5138 and antagonist rapamycin were used for pathway validation. In summary, hydrogen promotes oligodendrocyte maturation and myelination by suppressing mTOR pathway activity and restoring cortical myelin plasticity, thereby ameliorating cognitive dysfunction in SAE. This work reveals a previously unrecognized neuroprotective mechanism of hydrogen and provides actionable therapeutic targets for SAE clinical intervention."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Infectious Disease • Septic Shock • Solid Tumor

Tankyrase-2 regulates adipocyte differentiation through AMPK/mTOR signaling. (PubMed, FEBS J) - "However, the lower differentiation rate of TNKS2 knockout cells was salvaged by pharmacological activation of autophagy (by NV-5138) and the pharmacological inhibition of LKB1 (by HY-10371), an upstream suppressor of the mTOR system. Finally, TNKS2 can ADP-ribosylate LKB1, rendering it susceptible for ubiquitinylation that appears to be a key step towards committing adipocytes to differentiation. Together this data validates the use of TNK inhibitors for managing metabolic diseases and raises the possibility that TNK inhibition can influence tumor or immunometabolism and amplify the effects of other treatments."

Journal • Metabolic Disorders • Oncology • Targeted Protein Degradation • STK11 • TNKS2

Phase 2 Study of NV-5138 in Adults With Treatment Resistant Depression (clinicaltrials.gov) - P2 | N=250 | Completed | Sponsor: Navitor Pharmaceuticals, Inc. | N=400 ➔ 250

Enrollment change • CNS Disorders • Depression • Mood Disorders • Psychiatry

A novel, experimental design to assess rapid antidepressant action: Results from a phase 1b randomized trial of NV-5138. (PubMed, J Psychiatr Res) - P1 | "The innovative design of this exploratory study facilitated appropriate participant selection and rapid antidepressant response detection. These features may be useful in other trials evaluating RAADs (ClinicalTrials.gov, NCT03606395)."

Clinical • First-in-human • Journal • P1 data • CNS Disorders • Depression • Psychiatry

Catalpol enhances mTORC1/HIF-1α/PDHK1-mediated oxidative metabolism that leads to promote the differentiation of Treg cells in RA. (PubMed, Mol Immunol) - "Treatment with NV5138 was observed to reduce Treg differentiation and oxidative metabolism, effects which were reversed by CAT. These findings demonstrate that CAT promotes Treg differentiation and exerts anti-RA effects through inhibition of the mTORC1/HIF-1α/PDHK1 signaling pathway and enhancement of pyruvate aerobic oxidation."

Journal • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CD4 • EIF4EBP1 • FOXP3 • HIF1A • IL10 • PDK1

Phase 2 Study of NV-5138 in Adults With Treatment Resistant Depression (clinicaltrials.gov) - P2 | N=400 | Completed | Sponsor: Navitor Pharmaceuticals, Inc. | Recruiting ➔ Completed

Trial completion • CNS Disorders • Depression • Mood Disorders • Psychiatry

Bulky substrates of isoleucine 2-epimerase: α-Neopentylglycine and NV-5138. (PubMed, Bioorg Med Chem Lett) - "NV-5138 is a ligand of the leucine-binding site of Sestrin2, which activates the mechanistic target of rapamycin complex1 (mTORC1) and is structurally similar to α-neopentylglycine. Our demonstration that LbIleE catalyzes the racemization of l-NV-5138 (kcat/Km = 2.2 ± 0.2 s-1 M-1), along with the fact that L. buchneri can be present in the human gut microbiome, suggests that formation of d-NV-5138 could occur in humans when l-NV-5138 is used as a pharmacological intervention for depression."

Journal • CNS Disorders • Depression • Psychiatry

NAV-17A-008: Open-Label of SPN-820 in Adults With Major Depressive Disorder (clinicaltrials.gov) - P2 | N=40 | Completed | Sponsor: Navitor Pharmaceuticals, Inc. | Recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Aug 2024 | Trial primary completion date: Dec 2024 ➔ Aug 2024

Trial completion • Trial completion date • Trial primary completion date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Supernus Announces Topline Results from Phase 2b Study in Adults with Treatment Resistant Depression (GlobeNewswire) - P2b | N=400 | NCT05066672 | Sponsor: Navitor Pharmaceuticals, Inc. | "Supernus Pharmaceuticals...announced today that the Phase 2b study of SPN-820 in adults with treatment-resistant depression (TRD) did not demonstrate a statistically significant improvement on the primary endpoint of change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score to Week 4 (SPN-820 [LS mean ± Standard Error]: -12.3 ± 0.96 vs. placebo: -11.9 ± 0.96; p = not significant). There was no treatment difference between SPN-820 and placebo in the change from baseline to Week 4 for the secondary endpoints. The safety profile of SPN-820 was consistent with previous clinical trials, showing few adverse events....The study examined the efficacy and safety of SPN-820 over a course of four weeks of treatment and then a week of blinded placebo-washout in approximately 250 patients from approximately 40 clinical sites."

P2b data • Depression

Supernus Presents Promising Data from Open-Label Phase 2a Study of SPN-820 Data in Major Depressive Disorder at Psych Congress 2024 (GlobeNewswire) - P2 | N=50 | NCT06235905 | Sponsor: Navitor Pharmaceuticals, Inc. | “In the Phase 2a study, SPN-820 demonstrated a clinically meaningful improvement of -6.1 at two hours and -9.6 at Day 10 on the Hamilton Depression Rating Scale-6 items (HAM-D6), as well as a clinically meaningful improvement of -16.6 at four hours and -22.9 at Day 10 on the Montgomery Åsberg Depression Rating Scale (MADRS). New data from the Phase 2a study presented at Psych Congress 2024 demonstrate a rapid MADRS response rate (≥50% reduction) and remission (MADRS ≤10), reaching 50.0% and 35.0% of participants, respectively, at 4 hours, with additional improvement to 84.2% and 63.2% by Day 10.”

P2 data • Major Depressive Disorder

NV-5138, an Orally-Administered Investigational Rapid-Acting Antidepressant, Acutely Alters Prefrontal Cortical Neuronal Responses in Mice: Comparison to Ketamine and Rapastinel (SOBP 2024) - "Background: NV-5138, a Phase-2, rapid-acting antidepressant (RAAD) candidate, activates mechanistic target of rapamycin complex 1 (mTORC1) through a novel intracellular mechanism and without psychotomimetic effects. NV-5138 (160-mg/kg) and ketamine (10-mg/kg) moderately increased locomotor activity (p<0.05), whereas ketamine (30-mg/kg) produced strong hyperlocomotion (consistent with psychotomimetic effects). NV 5138 increased average spike rate (p=0.05) without changing the number of active cells; both metrics were reduced by ketamine (10, 30-mg/kg, p<0.05). NV 5138 increased the proportion of up-modulated neurons (p<0.05) without impacting the proportion of down-modulated neurons, whereas ketamine conferred opposite effects, increasing the proportion of down-modulated neurons (p<0.01) without impacting the proportion of up modulated neurons."

Late-breaking abstract • Preclinical • CNS Disorders

Advanced Model-Based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers. (PubMed, Clin Ther) - "The model will be used for designing future efficacy and tolerability studies. Consecutive daily doses of NV-5138 were well tolerated in this healthy volunteer study."

Biomarker • Clinical • Journal • Metastases • CNS Disorders • Depression • Psychiatry

Dr. Vince Clinical Research Announces First Dosing in a Phase II Study in Patients With Depression (Businesswire) - "Dr. Vince Clinical Research (DVCR), a contract research organization (CRO) specializing in early phase trials, announced the first dosing in a Phase II multicenter trial of SPN-820 in adults with major depressive disorder (MDD)....The Phase II study is being conducted at six U.S. sites and is expected to enroll approximately 50 adult MDD patients."

Trial status • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders

Open-Label of SPN-820 in Adults With Major Depressive Disorder (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Navitor Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Open-Label of SPN-820 in Adults With Major Depressive Disorder (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Navitor Pharmaceuticals, Inc.

New P2 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Phase 2 Study of NV-5138 in Adults With Treatment Resistant Depression (clinicaltrials.gov) - P2 | N=400 | Recruiting | Sponsor: Navitor Pharmaceuticals, Inc. | Trial completion date: May 2023 ➔ Dec 2024 | Trial primary completion date: May 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • CNS Disorders • Depression • Mood Disorders • Psychiatry

Nv-5138, A Selective Brain Mtorc1 Activator, Reduced Infarct Size In Early Cerebral Ischemia-reperfusion With Decreased Bbb Disruption (ASA 2023) - "Background Mechanistic target of rapamycin (mTOR) is a protein kinase and is an integral regulator of cellular survival and metabolism (1)...Methods A left middle cerebral artery occlusion (MCAO) was performed in rats under isoflurane anesthesia with controlled ventilation...Decreased BBB disruption could be one of the contributing factors. The major mechanism of neuroprotection by NV-5138 may be related to the mTOR signaling but additional roles of NV-5138 in decreasing BBB disruption during early ischemia-reperfusion could be considered."

Anesthesia • Cardiovascular • Reperfusion Injury

Targeting upregulation of the immunosuppressive activity of MDSCs with indirubin as a novel strategy to alleviate psoriasis. (PubMed, Int Immunopharmacol) - "This study demonstrates indirubin's pharmacological and therapeutic effects, providing a basis for future clinical application in treating psoriasis."

Journal • Review • Dermatology • Immunology • Inflammation • Psoriasis • ARG1 • CCR6

Mass Balance Study of NV-5138 in Healthy Male Subjects (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: Supernus Pharmaceuticals, Inc.

New P1 trial

Phase 2 Study of NV-5138 in Adults With Treatment Resistant Depression (clinicaltrials.gov) - P2 | N=400 | Recruiting | Sponsor: Navitor Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Depression • Mood Disorders • Psychiatry

Mass Balance Study of NV-5138 in Healthy Male Subjects. (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: Navitor Pharmaceuticals, Inc. | Recruiting ➔ Completed

Trial completion

Mass Balance Study of NV-5138 in Healthy Male Subjects. (clinicaltrials.gov) - P1; N=6; Recruiting; Sponsor: Navitor Pharmaceuticals, Inc.

Clinical • New P1 trial

Clinical Data Analyses Using Model-Based Approach: The Relationship Between mTORC1 Activation Biomarkers and NV-5138/SPN 820 Concentration in the Human Plasma and CSF (ACNP 2021) - "NV-5138 plasma and CSF concentrations were significantly linearly correlated and therefore CSF concentrations can be robustly predicted from plasma concentrations in future studies. Increases in NV-5138 plasma and CSF concentrations were associated with increases in orotic acid, N-acetyl methionine, and N-formyl methionine CSF concentrations, indicating that plasma and CSF concentrations of NV-5138 are predictors of the CSF biomarker changes and activation of mTORC1. This NV-5138 CSF/biomarker correlation is consistent with results from the prior study of NV-5138 2400 mg conducted in healthy subjects."

Biomarker • Clinical data • Alzheimer's Disease • Back Pain • CNS Disorders • Depression • Musculoskeletal Pain • Pain • Psychiatry

Clinical Data Analyses Using Model-Based Approach: The Relationship Between mTORC1 Activation Biomarkers and NV-5138/SPN 820 Concentration in the Human Plasma and CSF (ACNP 2021) - "NV-5138 plasma and CSF concentrations were significantly linearly correlated and therefore CSF concentrations can be robustly predicted from plasma concentrations in future studies. Increases in NV-5138 plasma and CSF concentrations were associated with increases in orotic acid, N-acetyl methionine, and N-formyl methionine CSF concentrations, indicating that plasma and CSF concentrations of NV-5138 are predictors of the CSF biomarker changes and activation of mTORC1. This NV-5138 CSF/biomarker correlation is consistent with results from the prior study of NV-5138 2400 mg conducted in healthy subjects."

Biomarker • Clinical data • Alzheimer's Disease • Back Pain • CNS Disorders • Depression • Musculoskeletal Pain • Pain • Psychiatry