navacaprant (NMRA-140) / Neumora Therap - LARVOL DELTA

Navacaprant, a Novel and Highly Selective Kappa Opioid Receptor Antagonist, in Adults With Major Depressive Disorder: A Randomized, Double-Blind Phase 2 Clinical Trial. (PubMed, J Clin Psychopharmacol) - "Although the primary endpoint was not met in the efficacy population, which included participants with mild depression, statistically significant improvements with navacaprant on depressive symptoms including anhedonia in the moderate-to-severe MDD subgroup, along with a favorable safety profile, support further study of navacaprant for the treatment of MDD."

Clinical • Journal • P2 data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry

Study to Assess the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=332 | Recruiting | Sponsor: Neumora Therapeutics, Inc. | Trial completion date: May 2025 ➔ Jun 2026 | Trial primary completion date: Jan 2025 ➔ May 2026

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

Study to Assess the Safety and Effectiveness of NMRA-335140-501 (clinicaltrials.gov) - P3 | N=650 | Recruiting | Sponsor: Neumora Therapeutics, Inc. | Trial completion date: Sep 2026 ➔ Jun 2027 | Trial primary completion date: Mar 2026 ➔ Jun 2027

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

Study to Assess the Effects of Oral NMRA-335140 in Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=332 | Recruiting | Sponsor: Neumora Therapeutics, Inc. | Trial completion date: Jun 2025 ➔ Mar 2026 | Trial primary completion date: Mar 2025 ➔ Feb 2026

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

To Evaluate the Effects of NMRA-335140 on Symptoms of Major Depression in Participants With Bipolar II Disorder. (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Neumora Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Current evidence for the role of rapid-acting antidepressants (RAAD) in bipolar depression? A perspective and plan for action. (PubMed, Biol Psychiatry) - "The following RAAD substance classes have been or are currently investigated as possible treatments for bipolar depression: NMDA antagonists and indirect AMPA agonists (ketamine, esketamine, riluzole, felbamate), GABA-A activators or positive allosteric modulators (zuranolone, pregnenolone, PEA), psychedelics (psilocybin, 5-MeO-DMT), muscarine receptor antagonists (scopolamine), and kappa-opioid receptor antagonists (navacaprant). Recent research into RAADs demonstrates the growing field of novel mechanisms of action in the pharmacological treatment of bipolar depression. However, there is an urgent need for well-controlled clinical studies on RAADs in bipolar depression to expand treatment options and improve outcomes for millions of affected individuals worldwide."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

Navacaprant: Optimizing KOASTAL-2 and -3 Studies Based on Learnings from KOASTAL-1 (GlobeNewswire) - "Navacaprant...Neumora has paused KOASTAL-2 and -3 and plans to make the following changes to KOASTAL-2 and -3. The Company plans to resume the KOASTAL-2 and -3 studies in March 2025...The Company reduced the number of clinical sites and selected those sites that we believe have the greatest level of expertise in conducting MDD studies...Neumora plans to add the clinician-rated Massachusetts General Hospital Clinical Trials Network and Institute SAFER approach...For the ongoing studies, Neumora will add the Verified Clinical Trial (VCT) screening database to complement CTS, with the goal to identify and exclude participants enrolled in multiple clinical studies from enrolling in the KOASTAL studies...The Company expects to report topline data from KOASTAL-3 in the first quarter of 2026 and -2 in the second quarter of 2026."

Clinical protocol • P3 data: top line • Trial status • Major Depressive Disorder

Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=383 | Completed | Sponsor: Neumora Therapeutics, Inc. | Active, not recruiting ➔ Completed

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

Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=332 | Active, not recruiting | Sponsor: Neumora Therapeutics, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2025 ➔ Jan 2025

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

Preclinical and clinical efficacy of kappa opioid receptor antagonists for depression: A systematic review. (PubMed, J Affect Disord) - "Kappa opioid receptor antagonists may serve as mechanistically-novel treatments for MDD and persons who inadequately respond to index conventional antidepressants. Anhedonia is debilitating and insufficiently treated with conventional antidepressants. Future research vistas should establish the efficacy and safety of KORAs in phase 3 studies in both acute and maintenance paradigms."

Journal • Preclinical • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Navacaprant, a novel and selective kappa opioid receptor antagonist with no agonist properties implicated in opioid-related abuse. (PubMed, Neuropharmacology) - "Importantly, navacaprant did not alter extracellular dopamine concentrations in the nucleus accumbens shell of freely-moving rats following doses ≤ 100 mg/kg, p.o., whereas morphine (10, 20 mg/kg, i.p.) significantly increased dopamine levels. These results demonstrate that navacaprant is a KOR-selective antagonist with no pharmacological properties implicated in opioid-related abuse."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry

To Evaluate the Effects of NMRA-335140 on Symptoms of Major Depression in Participants With Bipolar II Disorder. (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Neumora Therapeutics, Inc.

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

Navacaprant, a Novel and Selective Kappa Opioid Receptor Antagonist, Improves Symptoms of Major Depressive Disorder in a Phase 2 Trial, including in Participants with Comorbid Anxiety at Baseline (ASCP 2024) - "Navacaprant was associated with statistically significant improvements compared to placebo in symptoms of depression, including anhedonia, following 8 weeks of treatment in participants with moderate-to-severe anxiety at baseline, a population that often experiences poorer acute outcomes. These findings support the further development of navacaprant as an antidepressant monotherapy."

P2 data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry

A Randomized Placebo-Controlled Phase 2 Trial of Navacaprant, a Novel and Selective Kappa Opioid Receptor Antagonist, in Major Depressive Disorder (ASCP 2024) - "Navacaprant was associated with statistically significant reductions in depressive symptoms including anhedonia in participants with moderate-to-severe MDD and a favorable safety profile. The clinical relevance of the efficacy findings is underscored by the superior response and remission rates observed with navacaprant. These data support the further development of navacaprant as monotherapy in MDD."

Clinical • P2 data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Navacaprant, a Novel Kappa Opioid Receptor Antagonist for Major Depressive Disorder: A Randomized Placebo-Controlled Phase 2 Trial (SOBP 2024) - "Navacaprant resulted in statistically and clinically significant reductions in symptoms of depression and anhedonia compared with placebo in patients with moderate-to-severe MDD. Navacaprant was generally safe and well tolerated. These findings support the further development of navacaprant as an antidepressant monotherapy."

Clinical • P2 data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry

Navacaprant (NMRA-140): A Novel and Highly Selective Kappa Opioid Receptor Antagonist Evaluated in a Randomized Placebo-Controlled Phase 2 Trial in Patients with Major Depressive Disorder (ADAA 2024) - "Statistically significant reductions in depressive symptoms including anhedonia with navacaprant in a moderate-to-severe MDD population, along with a favorable safety profile, support its further study as monotherapy for the treatment of MDD. Does this session relate to the conference theme: "Sex and Gender: Navigating the Biological and Social Constructs in Depression and Anxiety Disorders"? Yes Please explain how."

Clinical • P2 data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Study to Assess the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=332 | Recruiting | Sponsor: Neumora Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

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

Study to Assess the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=332 | Not yet recruiting | Sponsor: Neumora Therapeutics, Inc.

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

Study to Assess the Effects of Oral NMRA-335140 in Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=332 | Recruiting | Sponsor: Neumora Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

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

Study to Assess the Safety and Effectiveness of NMRA-335140-501 (clinicaltrials.gov) - P3 | N=650 | Recruiting | Sponsor: Neumora Therapeutics, Inc.

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

Study to Evaluate the Effects of Oral NMRA 335140 Versus Placebo in Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=332 | Recruiting | Sponsor: Neumora Therapeutics, Inc.

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

Microdosing Partial Agonists Inactivates Kappa Opioid Receptors - An Alternative Strategy for Human Trials (ACNP 2023) - "Two pharmacological types of selective KOR antagonists have been described – reversible competitive (e.g. Aticaprant and NMRA-140) and KOR-inactivating antagonists (e.g. norBNI and JDTic); however, which type would be more effective is not yet clear. Low, repeated doses of nalmefene and nalfurafine inactivated KOR by the established JNK mechanism. We show that ROS generation via KOR agonism with nalfurafine was dependent on estrus cycle stage, with high estradiol during proestrus (like the estrogen spike before ovulation in human females) blocking generation of ROS. This presents a unique problem when examining long-lasting inactivation in women."

Addiction (Opioid and Alcohol) • CNS Disorders • Cognitive Disorders • Pain • NR3C1 • PRDX6

Navacaprant (NMRA-140), A Novel and Highly Selective Kappa Opioid Receptor Antagonist, in Patients With Major Depressive Disorder: A Randomized Placebo-Controlled Phase 2 Trial (ACNP 2023) - "Navacaprant resulted in statistically and clinically significant reductions in symptoms of depression and anhedonia compared with placebo following 8 weeks of treatment in patients with moderate-to-severe MDD. Navacaprant was generally safe and well tolerated, with low rates of discontinuation due to TEAEs. These findings support the further development of navacaprant as an antidepressant monotherapy."

Clinical • P2 data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry

Navacaprant (NMRA-140), A Novel and Highly Selective Kappa Opioid Receptor Antagonist, in Patients With Major Depressive Disorder: A Randomized Placebo-Controlled Phase 2 Trial (ACNP 2023) - "Navacaprant resulted in statistically and clinically significant reductions in symptoms of depression and anhedonia compared with placebo following 8 weeks of treatment in patients with moderate-to-severe MDD. Navacaprant was generally safe and well tolerated, with low rates of discontinuation due to TEAEs. These findings support the further development of navacaprant as an antidepressant monotherapy."

Clinical • P2 data • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Pain • Psychiatry

Study to Assess the Safety and Effectiveness of NMRA-335140-501 (clinicaltrials.gov) - P3 | N=650 | Recruiting | Sponsor: Neumora Therapeutics, Inc. | Not yet recruiting ➔ Recruiting

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