NMRA 335140 for Depression

Recruiting at 35 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

383 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new treatment, NMRA-335140, to determine if it reduces symptoms of depression in individuals with Major Depressive Disorder (MDD). Participants will take either the experimental medication or a placebo (a pill with no active drug) once daily for six weeks. Those experiencing a depressive episode for more than four weeks but less than a year, with moderate to severe symptoms, might be suitable candidates. The study will assess whether NMRA-335140 effectively improves depression symptoms compared to no active treatment. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for this trial?

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

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

Research has shown that NMRA-335140 is generally safe and well-tolerated. In earlier studies, no serious side effects were reported. While some side effects might occur, they were not severe or life-threatening. Participants did not show signs of increased risk for major problems. This suggests that NMRA-335140 might be safe for use in human trials for depression. ^{1 2 3 4 5}

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

Researchers are excited about NMRA 335140 because it represents a fresh approach to treating depression. Unlike standard treatments, which often include selective serotonin reuptake inhibitors (SSRIs) and other antidepressants that primarily target serotonin levels, NMRA 335140 may work through a new mechanism of action that could offer benefits over existing therapies. This could mean an alternative for patients who do not respond well to current medications, potentially providing faster relief or different side effect profiles. Such innovations are crucial for advancing mental health treatment options.

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

Research has shown that NMRA-335140, also known as BTRX-335140, might help treat symptoms of major depressive disorder (MDD). In this trial, participants will receive either NMRA-335140 or a placebo. One study found that NMRA-335140 improved symptoms more than a placebo. However, another study did not find significant improvement in reducing depression symptoms using the MADRS measurement tool. Early research suggests that NMRA-335140 might help with depression, the inability to feel pleasure, and anxiety. Although initial results are mixed, researchers are studying the treatment further to understand its effectiveness. ^{1 2 3 4 5}

Are You a Good Fit for This Trial?

This trial is for individuals with Major Depressive Disorder (MDD) confirmed by a clinical interview, experiencing symptoms for more than 4 weeks but less than 12 months. Participants must have a significant level of depression severity and haven't had two or more failed antidepressant treatments for the current episode. Excluded are those with certain other mental disorders, recent substance abuse, or serious suicidal risk.

Inclusion Criteria

Have you been diagnosed with Major Depressive Disorder?

Exclusion Criteria

Do you struggle with substance or alcohol abuse?

Have you been diagnosed with an eating disorder?

Have you tried at least 2 antidepressants that haven't worked?

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 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 (optional)

Participants may opt into continuation of treatment long-term

52 weeks

What Are the Treatments Tested in This Trial?

Interventions

• NMRA 335140

Trial Overview The study tests NMRA 335140's impact on depression symptoms against a placebo over six weeks. It's randomized and double-blind, meaning neither participants nor researchers know who gets the real drug or placebo during the study. Those completing this phase may join an extension study.

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 once daily (QD)

Group II: Placebo Placebo Group 1 Intervention

Placebo participants will receive matching placebo tablet orally, once daily. Participants who complete the study may be eligible to participate in a separate 52-week open-label long term study.

Who Is Running the Clinical Trial?

Neumora Therapeutics, Inc.

Lead Sponsor

Trials

7

Recruited

2,100+

Published Research Related to This Trial

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]

Treatment-resistant depression (TRD) affects 15%-40% of patients and is linked to the glutamatergic system, particularly the NMDAR and AMPAR receptors, which are targeted by ketamine and esketamine.

The gene GRIN2B, which encodes a subunit of the NMDAR, along with other genes related to AMPARs, may help predict treatment responses and understand the mechanisms behind TRD, suggesting a path towards personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic variables of the glutamatergic system associated with treatment-resistant depression: A review of the literature. Saez, E., Erkoreka, L., Moreno-Calle, T., et al.[2022]

Levomilnacipran ER, approved by the FDA in 2013 for major depressive disorder, is generally well tolerated and shows significant efficacy compared to placebo in clinical trials.

Its unique mechanism as a serotonin-norepinephrine reuptake inhibitor, with a stronger effect on norepinephrine, may offer a new approach to treating depression, although further studies are needed to compare it with other antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levomilnacipran (Fetzima): A New Serotonin-Norepinephrine Reuptake Inhibitor for the Treatment of Major Depressive Disorder. Saraceni, MM., Venci, JV., Gandhi, MA.[2022]

Meranzin hydrate (MH) demonstrated a rapid antidepressant effect in rats, similar to ketamine, by acting on AMPA receptors, which was confirmed through various behavioral tests and blocked by an AMPA receptor antagonist.

MH treatment increased levels of BDNF and activated the ERK1/2 signaling pathway in the hippocampus, suggesting a mechanism that underlies its fast-acting antidepressant properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The involvement of AMPA-ERK1/2-BDNF pathway in the mechanism of new antidepressant action of prokinetic meranzin hydrate. Xie, Y., Huang, X., Hu, SY., et al.[2013]

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]

Current antidepressants primarily target monoamines, but many patients experience limited efficacy and delayed onset of relief from major depressive disorder (MDD).

Glutamate receptor modulators, particularly NMDA antagonists like ketamine, show rapid antidepressant effects and may offer advantages such as oral administration and reduced side effects, making them promising alternatives in treating MDD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Modulation of Glutamate Receptors in Major Depressive Disorder. Jaso, BA., Niciu, MJ., Iadarola, ND., et al.[2023]

Ketamine acts as a fast-acting antidepressant by blocking NMDA receptors, which are linked to glutamatergic transmission dysfunction in depression, offering a new treatment avenue for those with treatment-resistant depression.

The review highlights various mechanisms by which ketamine exerts its effects, including its action on GABAergic interneurons and different NMDA receptor subunits, suggesting that future antidepressants could be developed using advanced technologies like cryo-EM and AI-based drug design.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NMDA receptors as therapeutic targets for depression treatment: Evidence from clinical to basic research. Lv, S., Yao, K., Zhang, Y., et al.[2023]

The study established that a loading dose of 250 mg of AR-R15896AR is the maximum tolerated dose in acute ischemic stroke patients, with subsequent maintenance doses of 120 mg every 8 hours also being well tolerated.

Safety profiles showed similar rates of mortality and serious adverse events between AR-R15896AR and placebo groups, indicating that while the drug is neuroprotective in animal models, its efficacy in humans requires further investigation as no significant differences in clinical outcomes were observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability of the low-affinity, use-dependent NMDA antagonist AR-R15896AR in stroke patients: a dose-ranging study. Lees, KR., Dyker, AG., Sharma, A., et al.[2019]

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]

In a blinded, placebo-controlled trial with 20 patients suffering from treatment-resistant depression, nitrous oxide inhalation showed significant improvement in depressive symptoms at both 2 hours and 24 hours after treatment compared to placebo.

Nitrous oxide treatment resulted in a 20% response rate and a 15% remission rate, with no serious adverse events reported, indicating it may be a safe and effective rapid treatment option for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial. Nagele, P., Duma, A., Kopec, M., 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]

In a study involving rats, both memantine and amantadine effectively protected cholinergic cells from loss due to NMDA-induced damage, with memantine showing the highest potency at a low dose (ED50 of 2.81 mg/kg).

Memantine and amantadine demonstrated neuroprotective effects with fewer side effects compared to (+)-MK-801, suggesting they could be safer options for therapeutic use in conditions involving glutamate receptor activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MK-801, memantine and amantadine show neuroprotective activity in the nucleus basalis magnocellularis. Wenk, GL., Danysz, W., Mobley, SL.[2019]

Dextromethorphan (DM) can be safely administered to neurosurgical patients, with serum levels correlating well with cerebrospinal fluid (CSF) and brain levels, indicating potential neuroprotective effects similar to those seen in animal studies.

While some patients experienced mild and reversible side effects like nystagmus and nausea, no severe adverse reactions were reported, suggesting that DM could be a viable treatment for patients at risk of cerebral injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose escalation safety and tolerance study of the N-methyl-D-aspartate antagonist dextromethorphan in neurosurgery patients. Steinberg, GK., Bell, TE., Yenari, MA.[2013]

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]

Citations

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

Navacaprant (NMRA-140), A Novel and Highly Selective ... results from preclinical studies support its potential to modulate depression, anhedonia, and anxiety6 (Figure 1). Ȳ Navacaprant (NMRA-140, BTRX-335140) is a ...

2. clinicaltrials.eu clinicaltrials.eu/inn/nmra-335140/

Nmra-335140 – Application in Therapy and Current ... These trials aim to evaluate the safety, effectiveness, and potential benefits of NMRA-335140 in improving symptoms of depression and anhedonia (the inability ...

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. 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 ...

5. 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 ...