A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of NV-5138 in Adults With Treatment Resistant Depression

This study will evaluate the efficacy and safety of NV-5138 in adults with TRD

Start Date28 Feb 2022

Sponsor / Collaborator

Navitor Pharmaceuticals, Inc.

[+1]

NCT05384977 / CompletedPhase 1

An Open-label, Single Dose, Mass Balance Study to Assess the Disposition of [14C]-NV-5138 in Healthy Male Subjects

The objective of this study is to assess the mass balance and routes of excretion of total radioactivity after a single oral dose of 1600 mg [14C]-NV-5138.

Start Date11 Nov 2021

Sponsor / Collaborator

Supernus Pharmaceuticals, Inc.

100 Clinical Results associated with NV-5138

100 Translational Medicine associated with NV-5138

100 Patents (Medical) associated with NV-5138

Literatures (Medical) associated with NV-5138

01 Mar 2024·Clinical Therapeutics

Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers

Article

Author: Kosheleff, Alisa R ; Portelli, Jeanelle ; Gomeni, Roberto ; Nasser, Azmi ; Hughes, Thomas E ; Adeojo, Lilian W ; Randall Owen, J

PURPOSENV-5138 ([S]-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine).METHODSData were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2-6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations.FINDINGSTwenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in the PK parameter and pharmacodynamic (PD) analyses. A 2-compartment plasma and CSF PK parameter, with indirect PD effects, model was developed and validated. NV-5138 plasma concentrations were positively correlated with those in CSF, although CSF concentrations lagged slightly behind those in plasma, as indicated by a counterclockwise hysteresis effect. Similarly, the relationship between the PD measures of mTORC1 activation and NV-5138 was also characterized by counterclockwise hysteresis, when the increase in CSF biomarker concentrations lagged behind those of NV-5138, consistent with a signaling intermediary/cascade, such as mTORC1. Maximal biomarker activation was achieved at NV-5138 CSF concentrations of approximately 3 µg/mL, which were associated with daily doses of 1600 mg NV-5138. The safety profile analysis (n = 42) found that most of the reported adverse events were mild in severity, with no severe, serious, unusual, or unexpected adverse events or any dissociative effects; 2 subjects (400-mg cohort) discontinued due to adverse events that were judged to be unrelated to study medication.IMPLICATIONSThe 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.

01 Oct 2023·International Immunopharmacology

Targeting upregulation of the immunosuppressive activity of MDSCs with indirubin as a novel strategy to alleviate psoriasis

Article

Author: Jiang, Wencheng ; Li, Wen ; He, Xufeng ; Chen, Xi ; Su, Lin ; Xu, Zihang ; Shen, Fang ; Hou, Yifei ; Chen, Xiao ; Zhang, Huimin ; Zou, Chunpu ; Zhu, Yangzhuangzhuang ; Liu, Mingxi

BACKGROUNDPsoriasis is a chronic and incurable skin disorder that causes inflammation. There is an urgent clinical need for new treatments. We identified the natural compound indirubin as a potential potent agent for the treatment of psoriasis, but it's therapeutic effect and underlying mechanisms were not well understood.METHODSPeripheral blood and skin tissues from psoriasis patients and healthy individuals were collected. Bioinformatics analysis was performed to investigate LAT1 expression and associated signal pathways in psoriasis skin lesions. A mouse model of psoriasis was established. Indirubin was administered separately or in combination with MDSCs depletion or adoptively transferred MDSCs. JPH203, rapamycin, siRNA, and NV5138 were further used to investigate the potential mechanism by which indirubin regulates MDSCs.RESULTSPsoriasis patients had increased numbers of MDSCs in their blood and skin lesions, with high expression of Lat1. The upregulation of LAT1 expression and the arginine synthesis pathway was observed in psoriasis skin lesions. The number of MDSCs was increased, while their inhibitory effect on psoriatic T cells was decreased. Indirubin decreased Lat1 expression on the surface of MDSCs, inhibited mTOR pathway activation, upregulated Arg1 expression in MDSCs, and enhanced the immunosuppressive activity of MDSCs while inhibiting CD4⁺CCR6⁺ T cells.CONCLUSIONThis study demonstrates indirubin's pharmacological and therapeutic effects, providing a basis for future clinical application in treating psoriasis.

01 May 2021·CNS DrugsQ2 · MEDICINE

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status

Q2 · MEDICINE

Review

Author: Henter, Ioline D ; Zarate, Carlos A ; Park, Lawrence T

The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. 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 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.

News (Medical) associated with NV-5138

18 Oct 2024

·endpts.com

Supernus’ depression drug shows ‘rapid’ onset in mid-stage test

Supernus Pharmaceuticals’ mTORC1 activator has cleared a small trial in patients with major depressive disorder, potentially bringing the biotech one step closer to offering a treatment that could be effective within hours. In the Phase 2a study’s primary endpoint, Supernus’ SPN-820 given every three days on top of baseline antidepressants achieved a 9.6-point reduction in the Hamilton Depression Rating Scale – 6 Items (HAM-D6) total score at 10 days, according to a Thursday release . Supernus said the effect was “rapid and substantial,” with a 6.1-point reduction seen at just two hours. Stifel analysts said the results moved patients from “high-to-moderate” or “low-to-severe” depression at baseline to “normal-to-mild” depression after treatment, which “far exceed[s] the meaningful clinical thresholds” for the scale. The drug’s rapid effect and convenient oral dosing is “highly valuable” because most antidepressants take at least a week before patients see an improvement, the analysts added. The open-label study enrolled 40 adults with major depressive disorder, all but two of whom finished the 10-day treatment period. The company said SPN-820 was well-tolerated in the study with adverse events including headache (20%), nausea (20%) and sleepiness (15%). But the analysts said the trial’s small patient numbers and open-label design mean conclusions on safety are limited. Elsewhere, Supernus is recruiting for a Phase 2b study of the same drug dosed daily in people with treatment-resistant depression. The biotech expects to complete enrollment of 236 participants in November, with topline data anticipated in the first half of next year. The primary endpoint is change in Montgomery-Asberg Depression Rating Scale total score at five weeks.

Phase 2Clinical Result

17 Oct 2024

·www.biospace.com

Supernus Announces Promising Data from Open-Label Phase 2a Study of SPN-820 in Adults with Major Depressive Disorder

Phase 2a study demonstrated rapid and substantial decrease in depressive symptoms SPN-820 was well-tolerated with few adverse events SPN-820 is a novel, first-in-class intracellular modulator of mTORC1 for the treatment of depression Company to host webcast today at 4:30 p.m. ET to discuss the topline data Topline results from Phase 2b randomized double-blind placebo-controlled study of SPN-820 in adults with treatment-resistant depression expected first-half 2025 ROCKVILLE, Md., Oct. 17, 2024 (GLOBE NEWSWIRE) -- Supernus Pharmaceuticals, Inc. (Nasdaq: SUPN), a biopharmaceutical company focused on developing and commercializing products for the treatment of central nervous system (CNS) diseases, today announced data from its exploratory open-label Phase 2a clinical study of SPN-820 in adults with major depressive disorder. The study examined the safety and tolerability of SPN-820 2400 mg given once every 3 days as an adjunctive treatment to the current baseline antidepressant therapy, as well as assessed the rapid onset of improvement in depressive symptoms. The analysis is based on 40 enrolled subjects, of which 38 completed the 10-day treatment period. Summary of the Data 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) total score. Clinically meaningful improvement of –16.6 at four hours and –22.9 at Day 10 on the Montgomery Åsberg Depression Rating Scale (MADRS) total score. Suicidal ideation decreased by 80% (12.5% with suicidal ideation at baseline decreased to 2.6% with suicidal ideation at Day 10). SPN-820 was well-tolerated with few adverse events (AEs) and had acceptable tolerability with a discontinuation rate of 2.5% due to AEs. Most common AEs related to the drug included headache, nausea, somnolence, and dizziness. Additional AEs such as cognitive disorder, dry mouth, fatigue, nasal decongestion, and paresthesia oral were observed. “These Phase 2a data underscore our belief that SPN-820 has the potential as a novel treatment option for patients with depression, with the opportunity to decrease symptoms quickly and without certain burdensome side effects,” said Jack Khattar, President and CEO of Supernus. “We expect to complete enrollment in the Phase 2b randomized double-blind placebo-controlled study of SPN-820 in adults with treatment-resistant depression in November of this year, with topline results expected in the first half of 2025.” Webcast Details Supernus will host a conference call and webcast today, October 17, 2024, at 4:30 p.m. ET to discuss these topline results. A live webcast with presentation slides will be available via this webcast link or in the Events & Presentations section of the Company’s Investor Relations website at . Following management’s prepared remarks and discussion of the interim trial results, the call will open for questions. Participants may also pre-register any time before the call here . Once registration is completed, participants will be provided a dial-in number with a personalized conference code to access the call. Please dial in 15 minutes prior to the start time. Following the live call, a replay will be available on the Company’s Investor Relations website at . The webcast will be available on the Company’s website for 60 days following the live call. About SPN-820 SPN-820 is a first-in-class, orally active small molecule that increases the brain mechanistic target of rapamycin complex 1 (mTORC1) mediated synaptic function intracellularly. SPN-820 is being developed to provide a rapid-onset antidepressant response via oral administration for adult patients with depression. The compound has a novel mechanism of action that enhances synaptic activity and cellular metabolism in the brain and has demonstrated a rapid onset of action (signal at two hours) in early clinical studies. SPN-820 is expected to provide rapid antidepressant efficacy without potential dissociative side effects. A Phase 2b clinical study of SPN-820 in approximately 227 adult patients with treatment-resistant depression is ongoing. About the SPN-820 Phase 2a Clinical Study The study is a Phase 2a open-label study in 40 subjects with major depressive disorder (MDD). The primary objective of the study is to assess efficacy in MDD, as well as onset of efficacy and safety. About Supernus Pharmaceuticals, Inc. Supernus Pharmaceuticals is a biopharmaceutical company focused on developing and commercializing products for the treatment of central nervous system (CNS) diseases. Our diverse neuroscience portfolio includes approved treatments for epilepsy, migraine, ADHD, hypomobility in Parkinson’s disease (PD), cervical dystonia, chronic sialorrhea, and dyskinesia in PD patients receiving levodopa-based therapy. We are developing a broad range of novel CNS product candidates including new potential treatments for hypomobility in PD, epilepsy, depression, and other CNS disorders. For more information, please visit . Forward Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements do not convey historical information but relate to predicted or potential future events that are based upon management’s current expectations. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. In addition to the factors mentioned in this press release, such risks and uncertainties include, but are not limited to, the Company’s reporting on preliminary and exploratory open label clinical study on SPN-820, the Company’s ability to sustain and increase its profitability; the Company’s ability to raise sufficient capital to fully implement its corporate strategy; the implementation of the Company’s corporate strategy; the Company’s future financial performance and projected expenditures; the Company’s ability to increase the number of prescriptions written for each of its products and the products of its subsidiaries; the Company’s ability to increase net revenue; the Company’s ability to commercialize its products and the products of its subsidiaries; the Company’s ability to enter into future collaborations with pharmaceutical companies and academic institutions or to obtain funding from government agencies; the Company’s ability to conduct and progress product research and development activities, including the timing and progress of the Company’s clinical trials, and projected expenditures; the Company’s ability to receive, and the timing of any receipt of, regulatory approvals to develop and commercialize the Company’s product candidates including SPN-820; the Company’s ability to protect its intellectual property and the intellectual property of its subsidiaries and operate its business without infringing upon the intellectual property rights of others; the Company’s expectations regarding federal, state and foreign regulatory requirements; the therapeutic benefits, effectiveness and safety of the Company’s product candidates including SPN-820; the accuracy of the Company’s estimates of the size and characteristics of the markets that may be addressed by its product candidates; the Company’s ability to increase its manufacturing capabilities for its products and product candidates including SPN-820; the Company’s projected markets and growth in markets; the Company’s product formulations and patient needs and potential funding sources; the Company’s staffing needs; and other risk factors set forth from time to time in the Company’s filings with the Securities and Exchange Commission made pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934, as amended. The Company undertakes no obligation to update the information in this press release to reflect events or circumstances after the date hereof or to reflect the occurrence of anticipated or unanticipated events. CONTACTS: Jack A. Khattar, President and CEO Timothy C. Dec, Senior Vice President and CFO Supernus Pharmaceuticals, Inc. (301) 838-2591 or INVESTOR CONTACT: Peter Vozzo ICR Westwicke (443) 213-0505 peter.vozzo@westwicke.com

Phase 2Clinical Result

10 Oct 2024

·www.biospace.com

Supernus Pharmaceuticals to Host Webcast to Review Open-Label Phase 2a Study of SPN-820 for the Treatment of Major Depressive Disorder

ROCKVILLE, Md., Oct. 10, 2024 (GLOBE NEWSWIRE) -- Supernus Pharmaceuticals, Inc. (Nasdaq: SUPN), a biopharmaceutical company focused on developing and commercializing products for the treatment of central nervous system (CNS) diseases, today announced that the Company will hold a webcast and conference call on Thursday, October 17, 2024, at 4:30 p.m. ET to review data from the open-label Phase 2a study of SPN-820 for the treatment of major depressive disorder. A live webcast with presentation slides will be available via this webcast link or in the Events & Presentations section of the Company’s Investor Relations website at . Following management’s prepared remarks and discussion of the interim trial results, the call will open for questions. Participants may also pre-register any time before the call here . Once registration is completed, participants will be provided a dial-in number with a personalized conference code to access the call. Please dial in 15 minutes prior to the start time. Following the live call, a replay will be available on the Company’s Investor Relations website at . The webcast will be available on the Company’s website for 60 days following the live call. About Supernus Pharmaceuticals, Inc. Supernus Pharmaceuticals is a biopharmaceutical company focused on developing and commercializing products for the treatment of central nervous system (CNS) diseases. Our diverse neuroscience portfolio includes approved treatments for epilepsy, migraine, ADHD, hypomobility in Parkinson’s disease (PD), cervical dystonia, chronic sialorrhea, and dyskinesia in PD patients receiving levodopa-based therapy. We are developing a broad range of novel CNS product candidates including new potential treatments for hypomobility in PD, epilepsy, depression, and other CNS disorders. For more information, please visit . Forward Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements do not convey historical information but relate to predicted or potential future events that are based upon management’s current expectations. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. In addition to the factors mentioned in this press release, such risks and uncertainties include, but are not limited to, the Company’s ability to sustain and increase its profitability; the Company’s ability to raise sufficient capital to fully implement its corporate strategy; the implementation of the Company’s corporate strategy; the Company’s future financial performance and projected expenditures; the Company’s ability to increase the number of prescriptions written for each of its products and the products of its subsidiaries; the Company’s ability to increase its net revenue from its products and the products of its subsidiaries; the Company’s ability to commercialize its products and the products of its subsidiaries; the Company’s ability to enter into future collaborations with pharmaceutical companies and academic institutions or to obtain funding from government agencies; the Company’s product research and development activities, including the timing and progress of the Company’s clinical trials, and projected expenditures; the Company’s ability to receive, and the timing of any receipt of, regulatory approvals to develop and commercialize the Company’s product candidates; the Company’s ability to protect its intellectual property and the intellectual property of its subsidiaries and operate its business without infringing upon the intellectual property rights of others; the Company’s expectations regarding federal, state and foreign regulatory requirements; the therapeutic benefits, effectiveness and safety of the Company’s product candidates; the accuracy of the Company’s estimates of the size and characteristics of the markets that may be addressed by its product candidates; the Company’s ability to increase its manufacturing capabilities for its products and product candidates; the Company’s projected markets and growth in markets; the Company’s product formulations and patient needs and potential funding sources; the Company’s staffing needs; and other risk factors set forth from time to time in the Company’s filings with the Securities and Exchange Commission made pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934, as amended. The Company undertakes no obligation to update the information in this press release to reflect events or circumstances after the date hereof or to reflect the occurrence of anticipated or unanticipated events. CONTACTS: Jack A. Khattar, President and CEO Timothy C. Dec, Senior Vice President and CFO Supernus Pharmaceuticals, Inc. (301) 838-2591 or INVESTOR CONTACT: Peter Vozzo ICR Westwicke (443) 213-0505 peter.vozzo@westwicke.com

Phase 2

100 Deals associated with NV-5138

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 2	US	Navitor Pharmaceuticals, Inc.	15 Feb 2024
Depressive Disorder, Major	Phase 2	US	Supernus Pharmaceuticals, Inc.	15 Feb 2024
Depressive Disorder, Treatment-Resistant	Phase 2	US	Navitor Pharmaceuticals, Inc.	28 Feb 2022
Depressive Disorder, Treatment-Resistant	Phase 2	US	Supernus Pharmaceuticals, Inc.	28 Feb 2022

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT06235905 (Biospace) Manual	Phase 2	Depressive Disorder, Major	40	SPN-820 2400 mg	zawmhhnffn(taryraguhd) = yvkgnyihwc nuguhkljor (rlxnfalkhu ) View more	Positive	17 Oct 2024

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