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

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

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

Clinical • New P2 trial • CNS Disorders • Depression • Mood Disorders • Psychiatry

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status. (PubMed, CNS Drugs) - "This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1..."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Gastrointestinal Disorder • Major Depressive Disorder • Mood Disorders • Psychiatry

Supernus Announces First Quarter 2021 Financial Results (GlobeNewswire) - P1, N=NA; "SPN-820 has advanced to a Phase II clinical program in treatment-resistant depression following the successful completion of a multiple-ascending dose (MAD) study in healthy volunteers. In the MAD study, SPN-820 exhibited a favorable safety and tolerability profile across a broad range of potentially therapeutic doses. The Company expects to initiate a randomized Phase II clinical study in treatment-resistant depression by the end of 2021."

New P2 trial • P1 data • Trial completion • CNS Disorders • Depression

[VIRTUAL] Randomized Double-Blind, Placebo Controlled Study to Evaluate NV-5138/SPN-820 (NV-5138), an mTORC1 activator, by Quantitative Eeg (qEEG) in Healthy Volunteers, Supports Target Engagement and Translational Strategy (ASCP 2021) - "Introduction: NV-5138, a direct mTORC1 activator demonstrates rapid and long-lasting 'antidepressant' effects comparable to ketamine in pre-clinical models. NV-5138 was generally safe, well tolerated. NV-5138 actively modulated neural activity as measured by qEEG band amplitudes and coherences. The pattern of electrophysiology changes on drug was consistent with desired antidepressant effects."

Clinical • CNS Disorders • Depression • Psychiatry

Supernus Announces Fourth Quarter and Full Year 2020 Financial Results (Streetinsider.com) - "SPN-820 - Novel first-in-class activator of mTORC1: Development activities are ongoing, including a multiple-ascending dose study in healthy volunteers, with the goal of initiating a Phase II clinical program in treatment-resistant depression by the end of 2021."

New P2 trial • Trial status • CNS Disorders • Depression

Supernus Announces Third Quarter 2020 Financial Results (GlobeNewswire) - "Commercial Update: Third quarter 2020 net product sales were $152.1 million, 52% higher than the same period in 2019, driven by the addition of $40.9 million of net product sales from the acquired commercial products...Net Product Sales ($ in millions): APOKYN: 34.5...XADAGO: 2.3....SPN-820 - Novel first-in-class activator of mTORC1: Preclinical and development activities are ongoing, with the goal of initiating a Phase II clinical program in treatment-resistant depression by the end of 2021."

New P2 trial • Sales • CNS Disorders • Depression • Multiple System Atrophy • Parkinson's Disease

Discovery of NV-5138, the first selective Brain mTORC1 activator. (PubMed, Sci Rep) - "The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1."

Journal • Psychiatry