AVP-786 · program

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

DiscontinuedDiscontinuedOtsuka Pharmaceutical Co., Ltd. (4578)
  • FDA Fast Track (Agitation Associated With Dementia Of The Alzheimer'S Type; November 2015)

Indications for AVP-786: Agitation in Alzheimer's disease · Discontinued Schizophrenia · Discontinued Treatment-resistant depression · Discontinued

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.

Data current as of

Development timeline

DiscontinuedMay 2024 – Sept 2024
  1. Trial terminatedLong-term extension study 303 (NCT02446132) terminated, closing out the AVP-786 agitation program
  2. Trial terminatedPhase 3 study 307 (NCT04464564) terminated - AVP-786 program discontinued
  3. Trial terminatedPhase 3 study 306 (NCT04408755) terminated - AVP-786 program discontinued
  4. Otsuka announced termination of AVP-786 development for agitation associated with dementia due to Alzheimer's disease after detailed analysis of the failed study 305. The ongoing Phase 3 studies 306 (NCT04408755) and 307 (NCT04464564) were terminated in June 2024 and the long-term extension 303 (NCT02446132) in September 2024, each with the ClinicalTrials.gov reason 'The AVP-786 program was discontinued'.↗
Phase 3Jul 2015 – Feb 2024
  1. missedStudy 305 topline (2024-02-13): no statistically significant difference vs placebo on the CMAI primary; falls 8.6%/9.1% on AVP-786 vs 2.8% on placebo. The result that triggered termination of the AVP-786 program on 2024-05-22.↗
  2. missedTRIAD-2 topline (2019-09-27): primary and key secondary endpoints not met - neither AVP-786 dose separated from placebo on CMAI change to week 12 (posted results p=0.789 and p=0.200).↗
  3. mixedTRIAD-1 topline (2019-03-25): mixed - the SPCD-combined CMAI primary was met on the higher AVP-786 dose (42.63 mg d6-DM/4.9 mg Q; posted-results p=0.008) but not the lower 28 mg dose (p=0.208).↗
  4. Fast TrackFDA grants Fast Track designation to AVP-786 for agitation in Alzheimer's dementia↗
  5. TRIAD-1 (NCT02442765, 15-AVP-786-301), the first Phase 3, started per ClinicalTrials.gov; TRIAD-2 (NCT02442778) followed 2015-11-11 and the long-term extension 303 (NCT02446132) 2015-11-13. FDA Fast Track for agitation in Alzheimer's dementia was granted in November 2015. The program went straight to Phase 3 on the strength of the parent AVP-923 (dextromethorphan/quinidine) Phase 2 agitation signal plus Phase 1 PK bridging of the deuterated form.

Readouts

  • 2024-02-13ReportedTopline datamissedNCT03393520

    Study 305 topline (2024-02-13): no statistically significant difference vs placebo on the CMAI primary; falls 8.6%/9.1% on AVP-786 vs 2.8% on placebo. The result that triggered termination of the AVP-786 program on 2024-05-22. ↗

  • 2019-09-27ReportedTopline datamissedNCT02442778

    TRIAD-2 topline (2019-09-27): primary and key secondary endpoints not met - neither AVP-786 dose separated from placebo on CMAI change to week 12 (posted results p=0.789 and p=0.200). ↗

  • 2019-03-25ReportedTopline datamixedNCT02442765

    TRIAD-1 topline (2019-03-25): mixed - the SPCD-combined CMAI primary was met on the higher AVP-786 dose (42.63 mg d6-DM/4.9 mg Q; posted-results p=0.008) but not the lower 28 mg dose (p=0.208). ↗

Clinical trials in Agitation in Alzheimer's disease

NCT0446456420-AVP-786-307Phase 3Discontinuedn=241

Study 307: Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type

Started Sept 2020· Primary completion Jun 2024· 📍 106 sites across 13 countries (United States, Mexico, Slovakia, Chile)

NCT0440875520-AVP-786-306Phase 3Discontinuedn=184

Study 306: Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type

Started Jul 2020· Primary completion Jun 2024· 📍 95 sites across 11 countries (United States, Poland, Bulgaria, United Kingdom)

NCT0339352017-AVP-786-305Phase 3Completedn=601

Assessment of the Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type (worldwide study 305)

Started Oct 2017· Primary completion Nov 2023· 📍 211 sites across 11 countries (United States, Spain, Poland, Czechia)

missedprimaryChange from baseline to week 12 in CMAI composite score

Topline 2024-02-13: no statistically significant difference vs placebo on the CMAI primary for either dose. Falls in 8.6% (high dose) and 9.1% (low dose) vs 2.8% (placebo); four deaths (1 low dose, 3 placebo). No numeric p-value disclosed and no results posted to CT.gov as of 2026-08-14.

NCT0244613215-AVP-786-303Phase 3Discontinuedn=1197

Long Term, Extension Study of the Safety and Efficacy of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type

Started Nov 2015· Primary completion Sept 2024· 📍 227 sites across 10 countries (United States, Poland, Czechia, Spain)

NCT0244277815-AVP-786-302Phase 3Completedn=522

TRIAD-2: Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Agitation in Participants With Dementia of the Alzheimer's Type (parallel design)

Started Nov 2015· Primary completion Aug 2019· 📍 83 sites across 2 countries (United States, Canada)

missedprimaryChange from baseline to week 12 in CMAI composite score (0.2)

Neither dose separated from placebo (posted results: one comparison p=0.789 LS mean difference +0.4, the other p=0.200 LS mean difference -2.0). Primary and key secondary endpoints not met per the 2019-09-27 Avanir announcement.

NCT0244276515-AVP-786-301Phase 3Completedn=387

TRIAD-1: Efficacy, Safety and Tolerability of AVP-786 for the Treatment of Agitation in Patients With Dementia of the Alzheimer's Type (SPCD)

Started Jul 2015· Primary completion Jan 2019· 📍 126 sites across 6 countries (United States, Poland, Estonia, Puerto Rico)

mixedprimaryChange from baseline in CMAI composite score (SPCD stages 1+2 combined) (0.008)

Mixed result. SPCD-combined weighted analysis significant for AVP-786-42.63 vs placebo (MMRM weighted z -2.65, p=0.008; stage 1 LS mean difference -4.0, p=0.021) but not for AVP-786-28 (weighted z -1.26, p=0.208). Values from the posted ClinicalTrials.gov results section.

Formulations

FormulationRouteRegimenPharmacokinetics
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.
OralTwice daily—

Mechanism of action (compound-wide)

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.

TargetActionAffinity
NMDA receptorprimaryGRIN1Antagonist—ⓘ
Norepinephrine transporter (NET)SLC6A2Reuptake inhibitor—ⓘ
Serotonin transporter (SERT)SLC6A4Reuptake inhibitor—ⓘ
Sigma-1 receptorSIGMAR1Agonist—ⓘ

← Full AVP-786 compound page (identity, identifiers, all indications)

Sources

  1. Avanir Pharmaceuticals, Inc. Reports Data from the Second Phase 3 Study (TRIAD-2) Evaluating Investigational AVP-786 (2019-09-27) — Avanir Pharmaceuticals, Inc.
  2. Avanir Pharmaceuticals, Inc. Reports Phase 3 Data Evaluating Investigational AVP-786 for the Treatment of Moderate-to-Severe Agitation in Patients with Alzheimer's Dementia (TRIAD-1 topline, 2019-03-25) — Avanir Pharmaceuticals, Inc. (via PR Newswire)
  3. AVP-786 - Therapeutics entry (cross-indication development timeline including the completed, undisclosed treatment-resistant depression trial) — Alzforum (FBRI / Biomedical Research Forum)
  4. Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease (open-access review: AVP-786 composition, deuteration rationale, mechanism) — PubMed Central (NCBI)
  5. 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)
  6. NCT02442765 (15-AVP-786-301, TRIAD-1) - Phase 3 SPCD study of AVP-786 in agitation in Alzheimer's dementia, with posted results — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT02442778 (15-AVP-786-302, TRIAD-2) - Phase 3 parallel-design study of AVP-786 in agitation in Alzheimer's dementia, with posted results and dose strengths (18/28/42.63 mg d6-DM + 4.9 mg Q) — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT02446132 (15-AVP-786-303) - Long-term extension study of AVP-786 in agitation in Alzheimer's dementia, terminated: program discontinued — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT03393520 (17-AVP-786-305) - Phase 3 worldwide study of AVP-786 in agitation in Alzheimer's dementia — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. NCT04408755 (20-AVP-786-306) - Phase 3 study of AVP-786 in agitation in Alzheimer's dementia, terminated: program discontinued — ClinicalTrials.gov (U.S. National Library of Medicine)
  11. NCT04464564 (20-AVP-786-307) - Phase 3 study of AVP-786 in agitation in Alzheimer's dementia, terminated: program discontinued — ClinicalTrials.gov (U.S. National Library of Medicine)
  12. Otsuka Announces Phase 3 Topline Results of AVP-786 in the Treatment of Agitation Associated with Dementia due to Alzheimer's Disease (2024-02-13) — Otsuka Pharmaceutical Co., Ltd.
  13. Otsuka to Terminate Development of AVP-786 (2024-05-22) - the molecule-wide termination used as the citable terminal anchor for this silently abandoned program — Otsuka Pharmaceutical Co., Ltd. / Otsuka America