AVP-786 Falls Short in Phase 3 Study of Alzheimer Disease Agitation

John Kraus, MD, PHD

Newly announced topline results of a phase 3 trial (NCT03393520) assessing AVP-786 (Otsuka Pharmaceutical), a CYP2D6 inhibitor, showed that the treatment failed to distinguish itself from placebo in treating patients with Alzheimer disease (AD) agitation. The company plans to analyzed additional prespecified and exploratory analyses of the data set to determine the full potential of the agent.¹

The study comprised of 550 participants across 90 centers worldwide who received 1 of 2 doses of AVP-786 or placebo, for a 12-week period. Following the conclusion of the treatment period, data indicated that treatment with AVP-786 did not result in a statistically significant difference vs placebo on the primary efficacy end point, mean change in Cohen-Mansfield Agitation Inventory (CMAI) total score. Otsuka intends to submit the trial results for scientific publication at a later date.

In terms of the reported safety, fall was the only treatment-emergent adverse event (TEAE) that appeared in more than 5% of AVP-786-treated patients and had a greater incidence rate than placebo. In total, falls were found in 8.6% (n = 16), 9.1% (n = 18), and 2.8% (n = 6) of those in the AVP-786 high dose, AVP-786 low dose, and placebo groups, respectively. There were 4 deaths reported in the trial; 1 (0.5%) in the AVP-786 low dose group and 3 (1.4%) in the placebo group.

"While the result of this trial is disappointing, we plan to analyze the full data set to determine the future potential of AVP-786 in the treatment of agitation associated with dementia due to Alzheimer’s disease,” John Kraus, MD, PHD, executive vice president and chief medical officer at Otsuka, said in a statement.¹ "In 2023, Otsuka became the first company to get a drug approved for this patient population and we are committed to expanding and innovating in this area."

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In March 2019, Avanir, a subsidiary of Otsuka, announced topline data from TRIAD-1, a phase 3 trial (NCT02442765) comprised of 410 patients aged 50 to 90 with moderate-to-severe agitation and probable AD. Results demonstrated a significant improvement on the primary end point—change in CMAI—for 1 of the 2 doses being studied. In terms of safety, the most common AEs occurring in patients treated with AVP-786 were falls, urinary tract infection, headache, and diarrhea.²

Months later, the company reported data from the second study of its phase 3 clinical development program of AVP-786. Otherwise known as TRIAD-2, results showed that the agent did not meet its primary and key secondary end points. All told, patients treated with AVP-786 did not experience a statistically significant improvement in agitation compared with placebo, as measured by the CMAI, the trial’s primary end point.

There is currently 1 FDA-approved therapy for AD agitation: Otsuka’s brexpiprazole (Rexulti). Originally approved in 2015 as an adjunctive therapy to antidepressants in adults with major depressive disorder, the treatment had its indication expanded in 2023 based on data from 2 positive phase 3 studies, Study 331-12-283 (NCT01862640) and Study 331-14-213 (NCT03548584).^3,4

In Study 331-12-213, also known as Trial 213, 345 individuals with AD agitation who received brexpiprazole 2- or 3-mg/day doses demonstrated statistically greater improvements from baseline to week 12 in the primary end point of CMAI total scores compared with those on placebo (P = .0026). In study 283, brexpiprazole 2 mg/day demonstrated statistically significant greater improvements in CMAI total score from baseline to week 12 than placebo (adjusted mean difference, –3.77; confidence limits, –7.38 to –0.17; t(316) = –2.06; P = .040). Individuals in the 1-mg/day group did not show meaningful separation from placebo (adjusted mean difference, 0.23; confidence limits, –3.40 to 3.86; t(314) = 0.12; P = .90).

REFERENCES
1. Otsuka announces phase 3 topline results of AVP-786 in the treatment of agitation associated with dementia due to Alzheimer’s disease. Otsuka Pharmaceutical. February 12, 2024. Accessed February 13, 2024. https://www.biospace.com/article/releases/otsuka-announces-phase-3-topline-results-of-avp-786-in-the-treatment-of-agitation-associated-with-dementia-due-to-alzheimer-s-disease/
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. news release. Avanir Pharmaceuticals; March 25, 2019. Accessed February 13, 2024. prnmedia.prnewswire.com/news-releases/avanir-pharmaceuticals-inc-reports-phase-3-data-evaluating-investigational-avp-786-for-the-treatment-of-moderate-to-severe-agitation-in-patients-with-alzheimers-dementia-300817513.html.
3. Otsuka and Lundbeck announce US Food and Drug Administration (FDA) approval of supplemental new drug application (sNDA) for Rexulti (brexpiprazole) for the treatment of agitation associated with dementia due to Alzheimer’s disease. News release. Otsuka / Lundbeck. May 10, 2023. Accessed February 13, 2024. https://otsuka-us.com/news/otsuka-and-lundbeck-announce-us-food-and-drug-administration-fda-approval-supplemental-new
4. Grossberg GT, Kohegyi E, Mergel V, et al. Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer’s dementia: two 12-week, randomized, double-blind, placebo-controlled trials. Am J Geriatr Psychiatry. 2020;28(4):383-400. doi:10.1016/j.jagp.2019.09.009