AVP-786 (deudextromethorphan-quinidine)

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.

Formulations#

AVP-786 (deudextromethorphan-quinidine) for Agitation in Alzheimer's disease#

DiscontinuedDiscontinuedAgitation in Alzheimer's disease indication →

AVP-786 (deudextromethorphan/ultra-low-dose quinidine) for moderate-to-severe agitation associated with dementia of the Alzheimer's type - the compound's lead indication and one of the largest Phase 3 programs ever run in this indication. FAILED AND DISCONTINUED. Built on a positive Phase 2 signal with the non-deuterated parent AVP-923 (NUEDEXTA) and FDA Fast Track (November 2015), the program comprised five Phase 3 efficacy studies plus a long-term extension, all on the Cohen-Mansfield Agitation Inventory (CMAI) primary. Results were mixed, then repeatedly negative: TRIAD-1 (NCT02442765, 387 randomized, sequential parallel comparison design) reported 2019-03-25 with the higher dose (d6-DM 42.63 mg/Q 4.9 mg BID) significant on the SPCD-combined CMAI analysis (weighted z p=0.008 per posted results) but the lower 28 mg dose not (p=0.208); TRIAD-2 (NCT02442778, 522 randomized, conventional parallel design) reported 2019-09-27 with neither dose separating from placebo (p=0.789 and p=0.200); the worldwide study 305 (NCT03393520, 601 randomized) reported 2024-02-13 with no significant difference on CMAI and more falls on drug (8.6% high dose, 9.1% low dose vs 2.8% placebo). Otsuka announced termination of AVP-786 development on 2024-05-22 after detailed analysis of study 305; the still-running studies 306 (NCT04408755) and 307 (NCT04464564) were terminated in June 2024 and the long-term extension 303 (NCT02446132, 1,197 enrolled) in September 2024, each with the registry reason 'The AVP-786 program was discontinued'. The negative arc contrasts with the same mechanism's later success by another sponsor: dextromethorphan-bupropion (AXS-05, a different, separately tracked product) went on to FDA approval in this indication.

AVP-786 (deudextromethorphan-quinidine) for Schizophrenia#

DiscontinuedDiscontinuedSchizophrenia indication →

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.

AVP-786 (deudextromethorphan-quinidine) for Treatment-resistant depression#

DiscontinuedDiscontinuedTreatment-resistant depression indication →

AVP-786 (deudextromethorphan/ultra-low-dose quinidine) as adjunctive treatment for major depressive disorder with inadequate response to standard antidepressants (SSRIs/SNRIs) - treatment-resistant depression. DISCONTINUED, SILENTLY, WITH RESULTS NEVER DISCLOSED. The single Phase 2 study (14-AVP-786-201, NCT02153502) was a 10-week, multicenter, randomized, double-blind, placebo-controlled proof-of-concept study using the sequential parallel comparison design (SPCD, the Fava/Schoenfeld anti-placebo-response design), primary endpoint MADRS total score, 206 enrolled at ~30 US sites; it started July 2014 - announced by Avanir shortly before Otsuka's acquisition closed - and completed February 2016. No topline was ever announced, no publication has been found, and no results were posted to ClinicalTrials.gov in the ten years since (still hasResults=false as of 2026-08-14). No further depression study of AVP-786 was ever registered, and Otsuka terminated the molecule across all indications in May 2024. Historically notable as one of the first oral dextromethorphan-based products taken into depression - the concept that later succeeded as Axsome's dextromethorphan-bupropion (AXS-05/AUVELITY, FDA-approved for MDD in 2022, tracked separately) - and as a deliberately captured example of a silently abandoned program: the absence of any disclosure after a completed 206-patient study is itself competitive intelligence.

Clinical trials#