ACADIA Advances 60 mg Remlifanserin After Near-Miss in Alzheimer’s Psychosis Trial

Key Points

• ACADIA’s 60 mg remlifanserin dose narrowly missed the primary endpoint in a phase II Alzheimer’s disease psychosis trial, but achieved nominal statistical significance on a key secondary measure and showed meaningful improvement over placebo.
• The company will advance the 60 mg dose into phase III and remove the underperforming 30 mg arm. ACADIA is also evaluating whether enrolling patients with somewhat more severe baseline psychosis could improve future trial outcomes.
• Remlifanserin’s safety profile was comparable with placebo, with no new safety signals or evidence of QT prolongation; adverse events, serious adverse events, and treatment discontinuations occurred at similar rates across groups.

ACADIA Pharmaceuticals NASDAQ: ACAD reported top-line results from the phase II portion of its RADIANT clinical program evaluating remlifanserin for hallucinations and delusions associated with Alzheimer’s disease psychosis, or ADP. The company said the 60 mg once-daily dose narrowly missed statistical significance on the primary endpoint but showed nominal statistical significance on a key secondary endpoint, while demonstrating a safety and tolerability profile comparable with placebo.

The global, randomized, double-blind, placebo-controlled RADIANT program is operationally seamless across phase II and phase III. The phase II portion evaluated 30 mg and 60 mg doses of remlifanserin administered once daily for six weeks, with the results intended to guide dose selection and potential refinements to the phase III population.

Phase II Efficacy Results

The modified full analysis set included 326 patients who received at least one dose of study drug, had a baseline SAPS-H+D total score of at least 10, and completed at least one post-baseline assessment. Of those patients, 109 received 60 mg of remlifanserin, 110 received 30 mg, and 107 received placebo. The mean patient age was about 75, and approximately two-thirds of participants were female, according to ACADIA.

The primary endpoint was the change from baseline in the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions, or SAPS-H+D, total score at week six. The 60 mg dose produced an effect size of 0.26 and a p-value of 0.0603, narrowly exceeding the trial’s pre-specified threshold for statistical significance.

On the key secondary endpoint, change from baseline in the Clinical Global Impression-Severity scale for ADP, or CGI-S-ADP, the 60 mg dose generated an effect size of 0.37 with a nominal p-value of 0.0077. Patients receiving 60 mg showed a 12.4-point reduction from baseline in SAPS-H+D, compared with a 10.4-point reduction for placebo. CGI-S scores declined by 1.3 points for the 60 mg group, compared with 0.9 points for placebo.

The 30 mg dose showed minimal improvement relative to placebo, with effect sizes of 0.05 on the primary endpoint and 0.11 on the key secondary endpoint. Based on the results, ACADIA plans to remove the 30 mg arm from the ongoing phase III program and advance the 60 mg dose.

“These phase II results demonstrated meaningful and consistent efficacy trends across endpoints,” Chief Executive Officer Catherine Owen Adams said. “Taken together, we are excited that the efficacy and safety results support the further development of remlifanserin in the two phase III ADP trials currently underway.”

Potential Population Refinement

ACADIA said it is assessing whether modestly increasing the baseline psychosis severity required for enrollment could improve phase III results while preserving broad eligibility. In one pre-specified subgroup example discussed by the company, 80% of phase II participants would have remained eligible under a refined criterion for higher baseline psychosis.

Within that population, ACADIA reported effect sizes of 0.33 for the SAPS-H+D primary endpoint and 0.43 for CGI-S-ADP. The company has not disclosed the specific threshold used in that analysis, citing concerns that publicly identifying it could affect placebo response in future trials.

Liz Thompson, Ph.D., ACADIA’s executive vice president and head of research and development, said the company is considering several potential refinements but views a focus on somewhat higher baseline psychosis severity as a promising approach. She said ACADIA does not currently plan broad protocol changes beyond removal of the 30 mg arm.

The company is also conducting further analyses of the Neuropsychiatric Inventory-Clinician, or NPI-C, an exploratory endpoint that was added later in the study. ACADIA said preliminary results showed a small numerical improvement with the 60 mg dose, though available data were limited because the endpoint was collected only in later-enrolled patients.

Safety and Next Steps

ACADIA reported no new safety signals and no evidence of QT prolongation relative to placebo, an outcome the company described as important given that QT prolongation had limited evaluation of higher doses of pimavanserin.

Rates of adverse events, serious adverse events, and discontinuations due to adverse events were similar to placebo, according to the company. No individual adverse event occurred in more than 5% of patients receiving 60 mg remlifanserin. Somnolence, reported in 3.2% of patients, and nausea, reported in 2.4%, were the only adverse events occurring in more than 2% of 60 mg recipients at numerically higher rates than placebo.

There were no deaths in either remlifanserin group, compared with two deaths in the placebo arm. ACADIA also said the dataset suggested no negative impact on motor symptoms or cognition.

The company plans to present additional efficacy and safety findings from the phase II study at the Clinical Trials on Alzheimer’s Disease conference in Boston from Nov. 16 through Nov. 19. ACADIA is also continuing a phase II study of remlifanserin in Lewy body dementia psychosis.

ACADIA said there are currently no FDA-approved therapies specifically indicated for hallucinations and delusions associated with Alzheimer’s disease psychosis. The company estimates that about 30% of more than 7 million people in the U.S. living with Alzheimer’s disease experience psychosis.

About ACADIA Pharmaceuticals (NASDAQ:ACAD)

ACADIA Pharmaceuticals Inc is a biopharmaceutical company focused on developing and commercializing medicines for neurological and psychiatric disorders. The company is headquartered in San Diego, California, and conducts research and commercial activities primarily in the United States.

ACADIA's marketed products include NUPLAZID (pimavanserin), an atypical antipsychotic approved for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. The company also markets DAYBUE (trofinetide), a therapy for Rett syndrome, a rare neurodevelopmental disorder.

Founded in 1993, ACADIA continues to advance a pipeline of therapies for central nervous system conditions, including additional neurological and psychiatric disorders.

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