Otsuka stops developing AVP-786 therapy for Alzheimer’s agitation

Treatment failed to lower agitation in patients after 12 weeks in Phase 3 trial

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by Andrea Lobo |

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Otsuka Pharmaceutical has stopped the development of AVP-786, an investigational oral therapy to treat agitation in people with Alzheimer’s disease.

The decision comes after the company’s recent announcement that the treatment failed to meet its primary efficacy goal of lowering agitation in ALS patients after 12 weeks (or three months) in a Phase 3 trial (NCT03393520). After a detailed analysis of the trial’s data, the company announced the decision to terminate development of AVP-786.

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Agitation — abnormal displays of emotion — common in Alzheimer’s

Alzheimer’s disease is the most common cause of dementia, which is a decline in cognitive function, including memory, reasoning, learning, and planning skills. Agitation — abnormal or inappropriate displays of emotion, such as shouting, shoving, or beating — is also common in Alzheimer’s patients.

Developed by Avanir Pharmaceuticals, now part of Otsuka, AVP-786 is an oral medication containing a combination of dextromethorphan, quinidine, and deuterium, which is an isotope (alternative form) of hydrogen. Dextromethorphan is thought to block certain neuronal pathways that regulate mood swings and related behaviors, while quinidine and deuterium help increase the amount of dextromethorphan available in the body.

A combination of dextromethorphan and quinidine, sold as Nuedexta, is approved to treat pseudobulbar effect — characterized by uncontrollable episodes of laughing or crying — in people with neurological diseases. AVP-786 was designed to be a second generation of Nuedexta to treat agitation in people with Alzheimer’s and other neurological conditions.

The Phase 3 trial enrolled 601 adults, ages 50 to 90, with a probable Alzheimer’s diagnosis and moderate to severe agitation. Patients were randomly assigned to receive AVP-786 at a low or high dose, or a placebo, as oral capsules twice daily, for 12 weeks.

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No significant difference found in Cohen-Mansfield Agitation Inventory score

The primary outcome was to assess changes in the Cohen-Mansfield Agitation Inventory score, a tool used to measure the frequency of agitation based on the observations of caregivers. After 12 weeks, the mean change in the score was not statistically different between the treatment and the placebo groups.

AVP-786 had been shown to decrease agitation in adults with possible Alzheimer’s and moderate to severe agitation at one of the doses tested in a previous Phase 3 study (NCT02442765), dubbed TRIAD-1. However, the results could not be replicated in the TRIAD-2 Phase 3 trial (NCT02442778) in a similar patient population.

The therapy was given fast track designation in 2015 by the U.S. Food and Drug Administration, as a potential treatment for agitation in patients with Alzheimer’s. Otsuka plans to continue research and development efforts on addressing agitation associated with Alzheimer’s disease, which is a current unmet medical need for patients.