AVP-786 fails to ease Alzheimer’s-related agitation in Phase 3 trial
Otsuka to study AVP-786's 'future potential' after 'disappointing' trial
A Phase 3 clinical trial of AVP-786 failed to meet its main goal of easing agitation in adults with dementia due to Alzheimer’s disease, said sponsor Otsuka Pharmaceutical.
The clinical trial (NCT03393520), also dubbed 17-AVP-786-305, tested AVP-786’s safety in addition to evaluating its effectiveness compared with a placebo.
Top-line data also showed a greater frequency of falls as a side effect of AVP-786 than with placebo. Full results are not yet available.
“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 press release.
“We are deeply grateful to all of the study participants, their caregivers, and the investigators who took part in this trial and contributed to this research,” Kraus said.
Alzheimer’s causes dementia, or a decline in memory, reasoning, learning, and planning skills over time severe enough to interfere with everyday activities. Many people with Alzheimer’s also experience personality changes, including agitation or acting out.
Only one US-approved medication for Alzheimer’s dementia-related agitation
The antipsychotic Rexulti (brexpiprazole), co-developed by Otsuka and Lundbeck, last year became the first and only medication approved in the U.S. to treat agitation associated with Alzheimer’s-related dementia. It works by tuning the mood-regulating brain chemicals dopamine and serotonin.
Otsuka is “committed to expanding and innovating in this area,” said Kraus.
Developed by Avanir Pharmaceuticals, now part of Otsuka, AVP-786 is an oral medication containing a combination of dextromethorphan, quinidine, and deuterium, an isotope (alternative form) of hydrogen.
A combination of dextromethorphan and quinidine is approved as Nuedexta to treat pseudobulbar affect, or uncontrollable episodes of laughing or crying. Deuterium is designed to reduce the breakdown of dextromethorphan in the liver, increasing the amount available in the body.
The Phase 3 clinical trial enrolled 601 adults with probable Alzheimer’s, ages 50 to 90, who had clinically significant moderate to severe agitation. They were randomly assigned a low or a high dose of AVP-786, or a placebo, as a capsule, twice a day for 12 weeks.
The primary outcome — the variable researchers were using to gauge the trial’s results — was a change in the Cohen Mansfield Agitation Inventory (CMAI) score, a tool used to measure the frequency of agitation. After 12 weeks, the mean change in CMAI total scores between AVP-786 and placebo were not statistically significant.
Falling was a side effect
Falls occurred more frequently as a side effect of the high dose (8.6%) and low dose (9.1%) of AVP-786 compared with the placebo (2.8%). Four people died during the trial, one of whom was taking the low dose of AVP-786 and three who were on the placebo.
Earlier Phase 3 clinical testing of a 12-week course of twice-daily AVP-786 showed mixed results. In the TRIAD-1 (NCT02442765) study, one of the two doses of AVP-786 tested eased agitation in 410 adults with probable Alzheimer’s, ages 50 to 90, who had moderate to severe agitation.
TRIAD-2 (NCT02442778), however, failed to replicate these results in a similar population of 522 adults with probable Alzheimer’s. In that trial, AVP-786 was no better than a placebo at easing moderate or severe agitation over 12 weeks.
A global long-term clinical trial (NCT02446132) testing the safety and efficacy of AVP-786 for as long as a year is currently recruiting participants who have completed TRIAD-1, TRIAD-2, 17-AVP-786-305, or an earlier Phase 2 clinical trial (NCT01584440).
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