NMRA-335140 for Depression

Recruiting at 109 trial locations

Overseen By Study Contact

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Neumora Therapeutics, Inc.

Disqualifiers: Personality disorder, Bipolar, Schizophrenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 52 weeks

650 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new medication called NMRA-335140 to see if it helps people with major depressive disorder. It includes participants who have no safety concerns. The medication aims to improve mood by affecting brain chemicals.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that you must comply with medication restrictions from the parent study. It's best to discuss your current medications with the study team to understand any specific requirements.

What data supports the effectiveness of the drug NMRA-335140 for depression?

Research suggests that drugs targeting the glutamatergic system, like NMDA receptor antagonists, have shown antidepressant properties by promoting new synaptic connections and reversing stress-induced changes in the brain. This indicates potential effectiveness for NMRA-335140, which may work through similar mechanisms. ^{1 2 3 4 5}

What makes the drug NMRA-335140 unique for treating depression?

NMRA-335140, also known as Navacaprant, is unique because it may target the glutamatergic system, which is involved in rapid antidepressant effects, unlike traditional antidepressants that primarily affect monoamine neurotransmitters like serotonin and dopamine. ^{2 3 4 5 6}

Eligibility Criteria

This trial is for people who have major depressive disorder and completed a previous NMRA-335140 study. They must have signed an informed consent form, agree to follow medication restrictions, and comply with contraception requirements from the earlier study.

Inclusion Criteria

You have consented to participation in this study via the completion of an ICF.

You are willing to follow the associated medication/therapy rules outlined in the document.

You have successfully concluded a Phase 3 MDD study (NMRA-335140-301, NMRA-335140-302, or NMRA-335140-303) as dictated by the provisions of the source protocol.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NMRA-335140 at a dose of 80 mg once daily during a 52-week treatment period

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2-4 weeks

Open-label extension

Participants continue to receive NMRA-335140 to assess long-term safety and effectiveness

52 weeks

Treatment Details

Interventions

• NMRA-335140

Trial Overview The trial is testing the safety and effectiveness of a drug called NMRA-335140 over 52 weeks in participants with major depressive disorder who previously took part in related studies.

Participant Groups

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) during a 52-week treatment period.

Who Is Running the Clinical Trial?

Neumora Therapeutics, Inc.

Lead Sponsor

Trials

7

Recruited

2,100+

Findings from Research

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]

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]

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]

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 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]

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]

References

1. United States 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

New targets for rapid antidepressant action. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Role of calcium, glutamate and NMDA in major depression and therapeutic application. [2015]

4. Germany 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. [2018]

5. Netherlands 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. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Prolonged administration of antidepressant drugs leads to increased binding of [(3)H]MPEP to mGlu5 receptors. [2018]