Acadia's remlifanserin misses Phase 2 primary endpoint in Alzheimer's psychosis but Phase 3 continues
核心洞察
Acadia Pharmaceuticals reported that once-daily 60 mg remlifanserin (搜索) produced a 12.6-point reduction on the SAPS-H+D scale versus 10.4 points for placebo at week 6, an effect size of 0.26 (p=0.0603).
The key secondary endpoint of Clinical Global Impression-Severity showed a 1.3-point improvement with 60 mg remlifanserin (搜索) versus 0.9 points for placebo, an effect size of 0.37 (nominal p=0.0077).
Remlifanserin (搜索) showed adverse event, serious adverse event and discontinuation rates similar to placebo, with no QT prolongation signal, no deaths and no apparent negative impact on motor symptoms or cognition.
Acadia Pharmaceuticals reported that the Phase 2 portion of its RADIANT trial of remlifanserin (搜索) in Alzheimer's disease psychosis (搜索) (ADP) missed its primary endpoint, but the company concluded the data support continuing the ongoing Phase 3 program. The Phase 2 results were described as Phase 3 enabling topline data.
RADIANT is a global, multi-center, randomized, double-blind, placebo-controlled, operationally seamless Phase 2 and 3 program evaluating remlifanserin (搜索) for hallucinations and delusions associated with ADP. The Phase 2 portion tested once-daily remlifanserin at 60 mg and 30 mg against placebo. Patients who complete the study can enroll in a long-term open-label extension.
Efficacy results
On the primary endpoint, change from baseline in the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions subscales (SAPS-H+D), once-daily 60 mg remlifanserin (搜索) produced a change of -12.6 versus -10.4 for placebo at week 6, a standardized effect size of 0.26 (p=0.0603). The p-value fell just above the 0.05 significance threshold, a result BMO Capital analysts characterized as a "near miss" in a note to investors, adding that "some encouraging signals support future development." TD Cowen analysts had named an effect size of 0.35 to 0.4 as the most likely outcome in a Sept. 15 note.
On the key secondary endpoint, Clinical Global Impression-Severity (CGI-S-ADP), the 60 mg dose achieved a change from baseline of -1.3 versus -0.9 for placebo at week 6, a standardized effect size of 0.37 (nominal p=0.0077). On both efficacy measures, the difference between the 60 mg dose and placebo increased through the 6-week treatment period. The 30 mg dose showed minimal improvement across endpoints compared with placebo. All analyses were performed in the pre-specified modified full analysis set (mFAS1), which includes randomized subjects who received at least one dose of study drug, had a baseline SAPS-H+D total score of at least 10, and had at least one post-baseline SAPS-H+D value.
Safety profile
Across both doses, remlifanserin (搜索) showed rates of adverse events, serious adverse events and discontinuations due to adverse events similar to placebo. There was no signal of QT prolongation versus placebo, and the dataset suggests no negative impact on motor symptoms or cognition. There were no deaths in the remlifanserin treatment arms.
Remlifanserin (搜索), also known as ACP-204, is a novel, highly selective 5HT2A receptor (搜索) inverse agonist that hits the same target as Acadia's Nuplazid (pimavanserin) but is designed to be less prone to causing QT prolongation. BMO analysts said the absence of a QT signal shows an improvement over Nuplazid and potentially derisks the Phase 2 study Acadia is running in Lewy body dementia psychosis (搜索). They added that the absence of motor impairment remains critical for future development in Alzheimer's psychosis, "where off-label dopamine agent use can lead to long-term motor impairment in some patients."
Phase 3 amendments
Acadia plans to continue enrolling its two ongoing Phase 3 studies of remlifanserin (搜索) in ADP while implementing amendments to the program, including removing the 30 mg dosage arm. The company is examining how to enrich the Phase 3 population. Possible changes include refining enrollment criteria for modestly higher baseline psychosis, said Elizabeth Thompson, Ph.D., head of research and development at Acadia. Applying the tweaked criteria to the Phase 2 data boosted the primary endpoint effect size to 0.33.
"We really are trying to get that balance between something that doesn't have a meaningful impact on enrollment but does have an opportunity to increase our overall potential phase 3 efficacy," Thompson said on a conference call.
"We are pleased that the Phase 2 RADIANT data support continuation of the Phase 3 ADP program, with new insights helping us to refine the program for future regulatory success," said Catherine Owen Adams, chief executive officer of Acadia. "We are excited about the potential of remlifanserin (搜索) in this area of high unmet need, for which there are no currently approved therapies."
On the same call, Adams said: "We believe with the high unmet medical need in this population, the efficacy that we've seen so far ... as well as the safety and tolerability profile, that this molecule offers the potential for patients with Alzheimer's disease psychosis (搜索), and it is absolutely worth our investment to move this forward into the phase 3 trial."
Unmet need in Alzheimer's psychosis
According to the Alzheimer's Association, more than 7 million people in the United States are living with Alzheimer's disease, and approximately 30% of patients with AD experience psychosis, commonly consisting of hallucinations and delusions. These symptoms may be frequent and severe and may recur over time. Serious consequences have been associated with psychosis in patients with dementia, including increased likelihood of nursing home placement, more severe dementia, and increased risk of morbidity and mortality. There is no FDA-approved drug for the treatment of Alzheimer's disease psychosis (搜索).
"The Phase 2 RADIANT findings provide encouraging evidence that 60 mg once daily remlifanserin (搜索) may have the potential to reduce hallucinations and delusions in patients with Alzheimer's disease," said Jeffrey Cummings, M.D., Sc.D., director of the Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada, Las Vegas. "This patient population has a significant need for an efficacious medication that is well tolerated, convenient to administer, and is compatible with the many concomitant medications commonly used by patients with Alzheimer's disease. In particular, avoiding negative impacts on motor symptoms and cognition is encouraging, and such a medicine could be an important treatment option for patients."
Additional development
Remlifanserin (搜索) is also being investigated in a separate Phase 2 study evaluating its efficacy, safety and tolerability for the treatment of Lewy body dementia psychosis (搜索). Acadia plans to present detailed safety and efficacy results from the RADIANT Phase 2 study in an oral presentation at the Clinical Trials on Alzheimer's Disease conference, taking place November 16-19, 2026 in Boston.