AVP-786 · program
AVP-786 (deudextromethorphan-quinidine) for Schizophrenia
Indications for AVP-786: Agitation in Alzheimer's disease · Discontinued Schizophrenia · Discontinued Treatment-resistant depression · Discontinued
AVP-786 (deudextromethorphan/ultra-low-dose quinidine) as adjunctive treatment for negative symptoms of schizophrenia in patients stable on an atypical antipsychotic - an NMDA-hypofunction play on residual negative symptoms. DISCONTINUED FOR FUTILITY. The Phase 2 study 202 (NCT02477670, 'residual schizophrenia', sequential parallel comparison design, 145 enrolled, completed July 2017) missed its NSA-16 total-score primary: the posted SPCD weighted analysis gives z = -1.79, p = 0.073 - a trend that Otsuka never announced by press release but that was evidently judged sufficient to fund a confirmatory study. The Phase 2/3 study 207 (NCT03896945, PANSS Marder negative factor score at week 15 primary, planned ~582) started February 2019, but at the pre-planned interim analysis the independent data monitoring committee recommended stopping for futility and Otsuka terminated the study (136 enrolled; trial completion 2023-05-23, per the ClinicalTrials.gov record - no press release was ever issued). No further schizophrenia development followed, and Otsuka terminated the AVP-786 molecule entirely in May 2024 after the Alzheimer's-agitation Phase 3 failures. A deliberately captured negative program: it is one of the cleanest recent tests - and failures - of adjunctive NMDA/sigma-1 modulation for negative symptoms.
Development timeline
- Study 207 terminated at the pre-planned interim analysis: 'Based on the Interim Analysis outcome and recommendation by the DMC, Otsuka approved termination of the study based on futility' (ClinicalTrials.gov whyStopped; 136 of a planned ~582 enrolled). The date is the trial's actual completion date on termination - Otsuka's internal decision date was never disclosed and no press release exists. This ended schizophrenia development; the molecule itself was terminated across all indications in May 2024.
- Trial terminatedPhase 2/3 negative-symptoms study 207 (NCT03896945) terminated for futility at interim
- missedPhase 2 study 202 results posted to ClinicalTrials.gov: adjunctive AVP-786 missed the NSA-16 primary in residual schizophrenia (SPCD weighted z -1.79, p=0.073) - a trend, never announced by the company.
- Phase 2/3 study 207 (NCT03896945) started per ClinicalTrials.gov: multicenter, randomized, double-blind, placebo-controlled, parallel-arm study of adjunctive AVP-786 for negative symptoms of schizophrenia; primary endpoint change from baseline to week 15 in the PANSS Marder negative factors score.
- Study 202 completed (145 enrolled). Posted results (first posted to ClinicalTrials.gov 2020-09-16) show the SPCD weighted primary analysis of NSA-16 change did not reach significance: weighted OLS z-statistic -1.79, p=0.073. No company announcement of these results was ever made.
- Phase 2 study 202 (NCT02477670) started per ClinicalTrials.gov (start date September 2015): a multicenter, randomized, double-blind, placebo-controlled SPCD study of AVP-786 as adjunctive therapy for negative symptoms in patients with residual schizophrenia on stable atypical antipsychotic treatment; primary endpoint NSA-16 total score at weeks 6 and 12.
Readouts
- 2020-09-16ReportedFull resultsmissedNCT02477670
Phase 2 study 202 results posted to ClinicalTrials.gov: adjunctive AVP-786 missed the NSA-16 primary in residual schizophrenia (SPCD weighted z -1.79, p=0.073) - a trend, never announced by the company.
Clinical trials in Schizophrenia
NCT0389694518-AVP-786-207Phase 2/3Discontinuedn=136
Phase 2/3 study of the efficacy, safety, and tolerability of adjunctive AVP-786 for the treatment of negative symptoms of schizophrenia
terminatedprimaryChange from baseline to week 15 in PANSS Marder negative factors score
Study terminated for futility at the pre-planned interim analysis on the recommendation of the independent data monitoring committee (136 of a planned ~582 enrolled). No efficacy results were disclosed or posted.
NCT0247767015-AVP-786-202Phase 2Completedn=145
Phase 2 SPCD study of adjunctive AVP-786 for the treatment of negative symptoms in patients with residual schizophrenia
missedprimaryChange from baseline in NSA-16 total score at week 6 and week 12 (SPCD weighted analysis) (0.073)
Primary not met: SPCD weighted ordinary-least-squares z-statistic -1.79, p=0.073 (posted ClinicalTrials.gov results, first posted 2020-09-16). A directional trend favoring AVP-786 that did not reach significance; never announced by the company.
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| AVP-786 oral capsule (d6-DM 18/28/42.63 mg + quinidine sulfate 4.9 mg) Capsules combining deudextromethorphan hydrobromide with ultra-low-dose quinidine sulfate 4.9 mg. The Phase 2 depression study administered AVP-786 (d6-dextromethorphan hydrobromide and quinidine sulfate combination) orally over a 10-week adjunctive, placebo-controlled design; the registry record does not disclose the mg strengths used. | Oral | Twice daily | — |
Mechanism of action
Deudextromethorphan (d6-DM) is deuterated dextromethorphan: selective replacement of six hydrogens with deuterium at the O- and N-methyl positions increases metabolic stability at CYP2D6 without altering the parent molecule's receptor pharmacology - uncompetitive NMDA receptor antagonism, sigma-1 receptor agonism, and inhibition of the serotonin and norepinephrine transporters. Ultra-low-dose quinidine sulfate (4.9 mg) is included purely as a CYP2D6 inhibitor to sustain plasma exposure of the active moiety. In treatment-resistant depression the rationale was the NMDA-antagonist antidepressant hypothesis (the same glutamatergic mechanism later validated by ketamine/esketamine and by dextromethorphan-bupropion): adjunctive rapid-acting glutamatergic modulation in patients with inadequate response to SSRIs/SNRIs.
| Target | Action | Affinity |
|---|---|---|
| NMDA receptorprimaryGRIN1 | Antagonist | —ⓘ |
| Norepinephrine transporter (NET)SLC6A2 | Reuptake inhibitor | —ⓘ |
| Serotonin transporter (SERT)SLC6A4 | Reuptake inhibitor | —ⓘ |
| Sigma-1 receptorSIGMAR1 | Agonist | —ⓘ |
← Full AVP-786 compound page (identity, identifiers, all indications)
Sources
- Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease (open-access review: AVP-786 composition, deuteration rationale, mechanism) — PubMed Central (NCBI)
- NCT02153502 (14-AVP-786-201) - Phase 2 study of AVP-786 in treatment-resistant depression: completed February 2016, no results ever posted (hasResults=false as of 2026-08-14) — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT02477670 (15-AVP-786-202) - Phase 2 SPCD study of adjunctive AVP-786 for negative symptoms in residual schizophrenia, with posted results (NSA-16 primary p=0.073) — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT03896945 (18-AVP-786-207) - Phase 2/3 study of adjunctive AVP-786 for negative symptoms of schizophrenia, terminated for futility on DMC recommendation — ClinicalTrials.gov (U.S. National Library of Medicine)