Otsuka Drug Candidate Fails Phase III Alzheimer’s Agitation Study

elderly woman and brain scan_iStock, peakSTOCK

Pictured: Doctor holding a brain scan with an elderly woman patient in the background/iStock, peakSTOCK

Otsuka Pharmaceuticals on Monday announced that its investigational drug candidate AVP-786 fell short of its primary efficacy endpoint in a Phase III trial evaluating its effects as a treatment for agitation in Alzheimer’s disease.

The Japanese multinational provided only sparse efficacy data in its announcement but said that at 12 weeks, AVP-786 was unable to significantly differentiate itself from placebo in terms of total score on the Cohen-Mansfield Agitation Inventory—a validated 29-item tool used to systematically assess levels of agitation.

Full results and analyses of the trial were not yet available, the company said. However, Otsuka did reveal that there were four deaths in the study, only one of which occurred in an AVP-786-treated arm. The study also detected one treatment-emergent adverse event—a fall—that occurred at a frequency of over 5% in patients treated with Otsuka’s candidate.

CMO John Kraus in a statement called the results of the study “disappointing,” adding that Otsuka will continue to evaluate the trial’s results “to determine the future potential of AVP-786 in the treatment of agitation associated with dementia due to Alzheimer’s disease.” The company will also submit these data for publication.

Originally developed by Avanir Pharmaceuticals, AVP-786 consists of two drugs: ultra-low dose quinidine, an inhibitor of the CYP2D6 enzyme, plus deuterium-modified dextromethorphan, which is an agonist of the NMDA receptor and the sigma-1 receptor as well as an inhibitor of the SERT and NET transporters. The drug combo, particularly the deuterium alteration, makes AVP-786 less susceptible to metabolism and boosts its bioavailability. 

Otsuka acquired Avanir in December 2014 for $3.5 billion.

Avanir had previously been testing AVP-786 in major depressive disorder (MDD) but Otsuka is now only assessing the candidate in agitation in Alzheimer’s disease.

Otsuka has an FDA-approved asset for this indication: Rexulti (brexpiprazole), which is an atypical antipsychotic agent approved in May 2023 for the treatment of agitation in Alzheimer’s disease. Rexulti, which Otsuka developed in collaboration with Lundbeck, is also approved as an adjunctive therapy for MDD and as a monotherapy for schizophrenia.

Prior to the FDA’s approval, the pharma partners in June 2022 touted strong Phase III data for Rexulti, showing a significant reduction in agitation in treated patients. These findings paved the way for a favorable vote by the FDA’s Pharmacologic Drugs Advisory Committee and its Peripheral and Central Nervous System Drugs Advisory Committee in April 2023, recommending the approval of Rexulti in this indication.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at or

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