Dr Sanjay Dube
Sanjay Dube, MD
Avanir Pharmaceuticals has released topline results from TRIAD-1 (NCT02442765), the first of 2 phase 3 studies of the investigational therapy AVP-786 for the treatment of moderate-to-severe agitation in patients with Alzheimer-related dementia. Results demonstrated a significant improvement on the primary endpoint -- change in the Cohen-Mansfield Agitation Inventory -- for 1 of the 2 doses being studied.
 
This is the first study in the TRIAD phase 3 clinical development program investigating the efficacy, safety, and tolerability of AVP-786. Improvements were observed for both doses from baseline to week 12, though the change in Cohen-Mansfield Agitation Inventory was only statistically significant for the one. Similar improvements were reported on the key secondary endpoint, as well.1

“If approved, AVP-786 would offer patients and their care communities the first FDA-approved treatment option for moderate-to-severe agitation in patients with Alzheimer dementia, bridging a significant gap in treatment for these patients,” Sanjay Dubé, MD, vice president research and development, head of clinical development and scientific strategy, Avanir Pharmaceuticals, Inc., told NeurologyLive. “We continue to investigate AVP-786 for the treatment of moderate-to-severe agitation in patients with Alzheimer’s dementia in 2 other ongoing phase 3 clinical studies (15-AVP-786-302 and 17-AVP-786-305), which use a conventional parallel-arm design, as opposed to the SPCD design. In addition, a long-term extension study (15-AVP-786-303) is also being conducted. We will report these results once they are available.”

The 12-week, phase 3, double-blind, placebo-controlled study enrolled 410 U.S. patients aged 50 to 90 with moderate-to-severe agitation and probable Alzheimer disease dementia living in either community or institutional care settings.

In the 6 week, stage 1 treatment period, study participants were randomly assigned to 1 of 2 doses of AVP-786 or placebo. Those participants assigned to AVP-786 in stage 1 continued with their assigned treatment in stage 2 for the next 6 weeks, while those who received placebo in stage 1 were re-randomized (1:1:1) to either dose of AVP-786 or placebo. Only placebo non-responders were used in the Sequential Parallel Comparison Design analysis in order to mitigate against placebo response.

The reported safety data showed that the most common adverse effects occurring in patients who received AVP-786 with greater than 5% incidence in either of the 2 doses were falls, urinary tract infection, headache, and diarrhea. There was an overall low mortality rate and none of the deaths were considered treatment-related.

“Currently, there is no FDA-approved treatment for agitation in patients with Alzheimer’s dementia,” Dubé concluded. “This research milestone is an important one, as any advancement in our clinical understanding of this patient population is important in helping bridge the treatment gap for patients with agitation in Alzheimer dementia and their care communities. We are confident in the development of AVP-786 for the treatment of moderate-to-severe agitation in patients with Alzheimer’s dementia and look forward to continuing to evaluate its potential in other studies across multiple doses.”

TRIAD-1 was completed in February 2019 and Avanir reported that the full dataset will be published in the future. TRIAD-2 (NCT02442778) is expected to be completed December 2019 with 470 participants enrolled in 75 centers. In 2015, AVP-786 was granted a fast track designation by the FDA for treatment of agitation in patients with Alzheimer disease.

In addition to the 2 phase 3 U.S.-based trials, additional global trials will be conducted as part of the TRIAD program. A long-term phase 3 extension study (NCT02446132) of AVP-786 is currently recruiting participants who have successfully completed TRIAD-1 (NCT02442765), TRIAD-2 (NCT02442778), or an earlier phase 2 study of AVP-923 (NCT01584440). Approximately 700 participants will be enrolled at 135 centers in North America for roughly 56 weeks total; however, those who have a follow-up visit 3 months after their last dose will be enrolled for 64 weeks total. Participants will receive either a low or high dose of AVP-786.

AVP-786 is also being investigated in patients with negative symptoms of schizophrenia and neurobehavioral disinhibition in traumatic brain injury.
REFERENCE
1. 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]. Aliso Viejo, Calif.: Avanir Pharmaceuticals; March 25, 2019. 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. Accessed March 25, 2019.