Brexpiprazole shows positive phase III results. (Courtesy of SOPA Images/Getty Images)

Otsuka Pharmaceutical and Lundbeck announced positive Phase III clinical trial results Monday regarding brexpiprazole (Rexulti) as a treatment for agitation in patients with Alzheimer’s dementia. The companies plan to submit a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration based on the results.

Brexpiprazole is being co-developed by the two companies and is approved for a variety of mental health indications. The therapeutic was originally approved by the FDA for the treatment of schizophrenia and as an adjunctive therapy for major depressive disorder in adults. Earlier this year, an sNDA for brexpiprazole as a treatment for schizophrenia in patients ages 13 to 17 was approved.

In 2018, Otsuka and Lundbeck began a 12-week Phase III trial to investigate the drug’s use in reducing agitation in Alzheimer’s patients, a difficult symptom of the disease. Agitation is reported in about 45% of patients with the disease and is associated with poor caregiver outcomes. Agitation covers a broad spectrum of behaviors including pacing, restlessness, profanity, shouting and shoving or hitting.

The trial population planned to include 330 individuals ages 55 to 90 with probable Alzheimer’s disease. In early 2016, the FDA granted Fast Track Designation for brexpiprazole for the treatment of agitation in patients with Alzheimer’s dementia.

Although full study results are not yet available, the companies have announced that an analysis demonstrated a statistically significant difference in mean changes from baseline to week 12 of the trial in an assessment of agitation, meaning that those taking the drug experienced a reduction in agitation. The companies stated that further prespecified and exploratory analyses of the data set will be conducted to examine other potentials the drug could provide to Alzheimer’s patients.

The drug was well-tolerated, and headaches were the treatment-emergent adverse events that occurred with more than 5% incidence in patients. Otsuka and Lundbeck will submit an sNDA to the FDA based on its results and the results of two earlier trials and plan to publish the findings in a scientific journal.

Brexpiprazole is a small molecule that modulates serotonin-dopamine activity at several receptors. It is a partial agonist at the serotonin 5-HT1A and dopamine D2 receptors and an antagonist of serotonin 5-HT2A and noradrenaline receptors. All three neurotransmitter systems may be involved in the behavioral symptoms seen in patients with Alzheimer’s.

Some researchers have posed that agitation in patients is caused by the erosion and destruction of serotonergic pathways, which leads to an imbalance of the serotonergic-dopaminergic axis. Others have investigated the use of antidepressants in reducing agitation in Alzheimer’s patients.

Brexpiprazole is also being investigated for the treatment of post-traumatic stress disorder (PTSD) by Lundbeck and Otsuka for a reduction in re-experiencing symptoms as well irritability. It is also being studied in pediatric autism for the reduction of irritability symptoms. Additionally, Avanir Pharmaceuticals, a subsidiary of Otsuka, is investigating AVP-786 for the reduction of agitation in Alzheimer’s dementia, a different type of therapy for the symptom.