NMRA-335140 for Depression

Recruiting at 46 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Neumora Therapeutics, Inc.

Disqualifiers: Personality disorder, Bipolar, Schizophrenia, Substance use, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

332 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called NMRA-335140 to determine its effectiveness in reducing symptoms of depression in individuals with Major Depressive Disorder (MDD). Participants will receive either the actual treatment or a placebo (a pill with no active ingredients) for six weeks. The trial suits those who have experienced symptoms of depression for more than four weeks but less than a year, without other major mental health or substance use issues. As a Phase 3 trial, it represents the final step before FDA approval, allowing participants to contribute to a potentially groundbreaking treatment for depression.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that NMRA-335140 is likely to be safe for humans?

Research has shown that NMRA-335140 was tested in earlier studies for treating major depressive disorder (MDD). In one study, adults with MDD used this treatment and reported their experiences over time. The results indicated that participants generally tolerated NMRA-335140 well.

Some participants experienced side effects, but these were not serious enough to discontinue treatment. The side effects resembled those seen with other depression medications, suggesting that NMRA-335140 has a safety profile similar to other treatments for depression.

This treatment is now being tested in a more advanced phase of clinical trials, indicating it has already passed earlier safety tests and is currently being evaluated for effectiveness and any additional safety information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

NMRA-335140 is unique because it offers a novel approach to treating depression by potentially targeting different pathways than traditional antidepressants like SSRIs or SNRIs. Researchers are particularly excited about its new active ingredient, which could provide relief for patients who haven't responded well to existing treatments. Unlike the standard options, NMRA-335140 might offer faster results with fewer side effects, making it a promising candidate for those struggling with depression.

What evidence suggests that NMRA-335140 might be an effective treatment for depression?

Research has shown mixed results for NMRA-335140 in treating Major Depressive Disorder (MDD). A previous study found no significant difference between NMRA-335140 and a placebo in reducing symptoms of depression, as both groups showed similar improvements in their depression scores. This suggests NMRA-335140 may not be more effective than a placebo for MDD. These findings are important when considering treatment options. Participants in this trial will receive either NMRA-335140 or a placebo to further evaluate its effectiveness. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with Major Depressive Disorder (MDD) confirmed by a specific interview, experiencing symptoms for more than 4 weeks but less than 12 months. They must have moderate to severe depression scores and stable symptoms between screening and baseline. People with psychotic features or unstable conditions are excluded.

Inclusion Criteria

Are you between the ages of 18 and 65?

Do you have a primary diagnosis of major depressive disorder?

Are you currently experiencing symptoms of depression?

Exclusion Criteria

Are you pregnant or breastfeeding?

Have you ever been diagnosed with bipolar disorder, schizophrenia, obsessive-compulsive disorder or post-traumatic stress disorder (PTSD)?

Do you have a history of HIV?

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

5 weeks

Treatment

Participants receive either NMRA-335140 or placebo for 6 weeks

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants may opt into continuation of treatment with NMRA-335140 long-term

What Are the Treatments Tested in This Trial?

Interventions

• NMRA-335140

Trial Overview The study tests the effects of NMRA-335140 on depression symptoms compared to a placebo over six weeks. Participants will be randomly assigned to either the test drug or placebo without knowing which one they receive, in multiple centers.

How Is the Trial Designed?

Group I: NMRA-335140 80 milligrams (mg) once daily (QD) Experimental Treatment 1 Intervention

Participants will receive a NMRA-335140 tablet at a dose of 80 mg QD

Group II: Placebo Placebo Group 1 Intervention

Placebo participants will receive matching placebo tablet once daily

Who Is Running the Clinical Trial?

Neumora Therapeutics, Inc.

Lead Sponsor

Trials

7

Recruited

2,100+

Published Research Related to This Trial

Prolonged treatment with various antidepressants and the mGlu5 negative allosteric modulator MTEP resulted in significant increases in mGlu5 receptor binding in the rat brain, suggesting enhanced receptor availability.

The study indicates that adaptive up-regulation of mGlu5 receptors may be a common response to different antidepressant treatments, which could play a role in their therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged administration of antidepressant drugs leads to increased binding of [(3)H]MPEP to mGlu5 receptors. Nowak, G., Pomierny-Chamioło, L., Siwek, A., et al.[2018]

In two Phase III studies involving 614 patients with major depressive disorder, TC-5214 (dexmecamylamine) did not show significant antidepressant effects compared to placebo, as measured by the Montgomery Åsberg Depression Rating Scale (MADRS).

While TC-5214 was generally well tolerated, the most common side effects reported were constipation and headache, indicating that while it may not be effective, it does not pose significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and tolerability of flexibly-dosed adjunct TC-5214 (dexmecamylamine) in patients with major depressive disorder and inadequate response to prior antidepressant. Vieta, E., Thase, ME., Naber, D., et al.[2022]

Current antidepressant treatments for major depressive disorder (MDD) and bipolar disorder (BD) often have delayed effects and limited efficacy, primarily targeting monoamine systems, while novel glutamate receptor modulators show promise for faster-acting antidepressant effects.

Ketamine, a non-competitive NMDA receptor antagonist, has demonstrated rapid and robust antidepressant effects, leading to the exploration of other NMDA antagonists and glutamate modulators, which may offer similar or improved therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New targets for rapid antidepressant action. Machado-Vieira, R., Henter, ID., Zarate, CA.[2022]

In a 52-week study involving 813 patients with major depressive disorder who had inadequate responses to previous treatments, dexmecamylamine was found to be generally safe and tolerable when used alongside SSRIs/SNRIs.

While 82.4% of patients on dexmecamylamine experienced adverse events, the most common were mild, such as constipation and dizziness, and overall safety profiles were consistent with earlier studies, indicating it may be a viable adjunct treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of dexmecamylamine (TC-5214) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to antidepressant therapy: results of a long-term study. Tummala, R., Desai, D., Szamosi, J., et al.[2022]

The combination of brexpiprazole and fluoxetine significantly alters amino acid levels in the brain, which may contribute to its antidepressant effects, as shown in a study measuring tissue levels after single and repeated doses.

Specifically, the combination increased GABA levels and affected the D-serine/L-serine and glycine/L-serine ratios in various brain regions, indicating a potential mechanism of action related to NMDAR neurotransmission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine. Ma, M., Ren, Q., Fujita, Y., et al.[2018]

Ketamine has shown a unique fast-acting neuroprotective and antidepressant effect by targeting the glutamatergic system, suggesting that glutamate plays a significant role in treating major depression.

Emerging treatments, including NMDA receptor antagonists and AMPA agonists, have demonstrated the ability to promote new synaptic connections and reverse stress-induced neuronal changes, indicating a promising direction for future antidepressant drug development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of calcium, glutamate and NMDA in major depression and therapeutic application. Deutschenbaur, L., Beck, J., Kiyhankhadiv, A., et al.[2015]

Citations

1. ir.neumoratx.com ir.neumoratx.com/news-releases/news-release-details/neumora-therapeutics-reports-data-koastal-1-study-navacaprant

Neumora Therapeutics Reports Data from KOASTAL-1 Study ... Study did not demonstrate statistically significant improvement on primary endpoint of reduction in depressive symptoms as measured by MADRS ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40199329/

A Randomized, Double-Blind Phase 2 Clinical Trial This phase 2a randomized, double-blind, placebo-controlled, 8-week trial assessed the efficacy and safety of navacaprant, a highly selective kappa opioid ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04221230

Study in Major Depressive Disorder With NMRA-335140 ... A proof of concept (POC) study evaluating the impact of NMRA-335140 (BTRX-335140) relative to placebo on symptoms of major depressive disorder (MDD) in ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032724010863

Preclinical and clinical efficacy of kappa opioid receptor ... Approximately 30 % of persons with Major Depressive Disorder (MDD) inadequately respond to conventional antidepressants.

5. psychiatrictimes.com psychiatrictimes.com/view/navacaprant-for-major-depressive-disorder-fails-in-late-stage-study

Navacaprant for Major Depressive Disorder Fails in Late- ... According to topline results, both navacaprant and placebo led to a 12.5-point improvement from baseline in the Montgomery-Åsberg Depression ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06429722

NCT06429722 | To Evaluate the Effects of NMRA-335140 ... This is a randomized, double-blind, placebo-controlled pilot study aiming to evaluate the effects of NMRA-335140 on symptoms of major depression in adults ...

7. neumoratx.com neumoratx.com/wp-content/uploads/2024/08/ACNP23_Ph2_Poster_Final.pdf

Navacaprant (NMRA-140), A Novel and Highly Selective ... 2022.963691. OBJECTIVE. This Phase 2 randomized clinical trial was designed to assess the efficacy and safety of navacaprant monotherapy in adults ...