ACADIA Pharmaceuticals (NASDAQ:ACAD) executives discussed upcoming clinical readouts and pipeline priorities during the company’s virtual CNS conference, with a focus on remlifanserin (formerly ACP-204) in Alzheimer’s disease psychosis (ADP), an ongoing Phase 2 program in Lewy body dementia psychosis, and ACP-211 in major depressive disorder (MDD).
Remlifanserin positioned as “next-generation” follow-on to pimavanserin
Liz Thompson, who leads research and development at ACADIA, described remlifanserin as the company’s next-generation 5-HT2A inverse agonist built from “learnings from pimavanserin.” Pimavanserin (NUPLAZID) is one of ACADIA’s two marketed medicines and is approved for Parkinson’s disease psychosis.
According to Thompson, remlifanserin is currently in two development programs: ADP and a Phase 2 study in Lewy body dementia psychosis.
Rationale for ADP: exposure-response signals and a redesigned trial
In discussing prior experience with pimavanserin in Alzheimer’s-related settings, Thompson acknowledged that clinical results across indications have been mixed and said differences can stem from “mechanism, molecule, and study design.” Still, she pointed to prior data supporting potential utility in ADP, including a Phase 2 study where pimavanserin met its primary endpoint in an Alzheimer’s-specific population.
She also referenced the Alzheimer’s subpopulation in the HARMONY study, noting it was not adequately powered. Thompson said there were indications of an exposure-response relationship with efficacy, which she views as supportive of the mechanism and a potential opportunity to improve both the molecule and the program.
On dosing and target engagement, Thompson said receptor occupancy information is limited to young healthy volunteers, which she cautioned may not extrapolate well to elderly and diseased populations. While she described pimavanserin as “a pretty high potency molecule” with a marketed dose of 34 mg, she said the exposure-response relationship suggests “potential for higher levels of efficacy at an exposure” beyond what is typically achieved with median exposure at 34 mg, and that remlifanserin provides an opportunity to reach higher exposures.
Study design details: community-based enrollment, biomarkers, and endpoint selection
Thompson outlined key elements of the ADP study design and how it differs from ACADIA’s earlier nursing-home-focused Phase 2 trial. Similarities include a short, placebo-controlled efficacy assessment over six weeks, with a focus on hallucinations and delusions as core manifestations.
Differences highlighted by Thompson included:
- Setting and population: The prior Phase 2 enrolled patients in a focused nursing home population. The new study is more community-based.
- Diagnostic confidence: Participants are being biomarker tested to increase confidence they have Alzheimer’s disease.
- Primary endpoint: Instead of the NPI-NH (Nursing Home Scale), which Thompson described as nonlinear and potentially less sensitive to change, the trial uses SAPS-H+D (hallucinations and delusions), which ACADIA has used in other trials and believes may be more sensitive to detecting an effect.
- Rater training: Thompson said raters are selected for experience with the patient population and undergo rigorous training and qualification to help distinguish delusional thinking from cognitive issues.
Thompson said the Phase 2 portion of the program—part of a Phase 2/Phase 3 “single master protocol”—is powered for a moderate effect size of 0.4 with 80% power. She also noted the inclusion of additional endpoints typical of Phase 2 work, including the NPI-C measure of neuropsychiatric symptoms, including hallucinations and delusions.
Regulatory considerations: black box warning, pivotal utility, and safety database expectations
Asked about the class boxed warning associated with antipsychotics in dementia, Thompson said ACADIA believes it has a mechanistic case to argue against the need for a boxed warning, but emphasized that the determination would depend on the clinical data and a totality-of-evidence benefit-risk assessment. She also said ACADIA is collecting rigorous information on deaths.
On whether the Phase 2 could serve as an adequate and well-controlled trial for regulatory purposes, Thompson said the company’s intent has been to conduct the study rigorously to preserve that possibility. However, she said its regulatory standing could be affected if Phase 3 trials are meaningfully changed based on Phase 2 learnings. She added that ACADIA is closely watching FDA’s evolving views on “single study” approaches, though she said her default expectation remains that the company will need an ICH-level safety database.
Thompson said ACADIA’s program was designed as three similar trials under the master protocol: a Phase 2 and two Phase 3 trials, all currently planned as parallel-group studies. She noted that randomized withdrawal designs can offer different evidence—maintenance of response rather than induction—and agreed such designs can often have higher success rates in these disease areas.
Readout timing and what ACADIA will look for in ADP results
Thompson said the ADP data readout is expected in an “August through October” timeframe, while declining to provide a more specific date.
In terms of what would constitute success, Thompson said she is looking for data consistent with remlifanserin’s target product profile, starting with evidence of an effect in the ADP population. She also highlighted practical and tolerability attributes ACADIA believes support compliance, including once-daily dosing, dosing with or without food, and a lack of drug-drug interaction concerns with other medicines used by these patients.
She said she would like to see a safety profile similar to pimavanserin’s aside from QT prolongation. Thompson added that the six-week study is not designed to definitively answer longer-term questions such as potential effects on cognition or motor function, though she said an open-label extension could provide directional insights and might help identify early signals if outcomes are trending negatively.
Separately, Thompson provided a brief update on ACP-211, which she described as a selectively deuterated R-ketamine program in MDD. She said preclinical and Phase 1 data suggest the potential for ketamine-like efficacy with lower—or “hopefully really negligible”—sedation and dissociation, and said Phase 2 is intended to both inform efficacy and assess whether sedation and dissociation levels are acceptable. Thompson said Phase 2 data for ACP-211 are expected in the “mid-part of next year.”
About ACADIA Pharmaceuticals (NASDAQ:ACAD)
ACADIA Pharmaceuticals Inc is a biopharmaceutical company focused on the development and commercialization of innovative therapies for central nervous system (CNS) disorders. Established in 1993 and headquartered in San Diego, California, ACADIA’s research centers concentrate on conditions with significant unmet medical needs, including Parkinson’s disease psychosis, Alzheimer’s disease psychosis, and schizophrenia. The company utilizes a range of scientific platforms, including selective receptor modulation and precision-targeted compounds, to advance its portfolio of small-molecule therapeutics.
The company’s flagship product, NUPLAZID® (pimavanserin), received U.S.
