Phase 3 Trial to Uncover Therapeutic Potential of 5-HT6 Antagonist Masupirdine to Treat Alzheimer Agitation

An ongoing phase 3, double-blind, randomized, placebo-controlled, parallel group, multicenter study (NCT05397639) will evaluate the efficacy, safety, tolerability, and pharmacokinetics of masupirdine, a 5-HT₆ receptor antagonist, for agitation in patients with Alzheimer disease (AD) related dementia.¹

Presented as a poster at the 18th Clinical Trials on Alzheimer’s Disease Conference (CTAD), held December 1-4, in San Diego, California, the study’s primary endpoint analyzes change in Cohen-Mansfield Agitation Inventory (CMAI) item scores aligned with the International Psychogeriatric Association (IPA) agitation criteria domains from baseline to week 12. In addition, the study’s secondary endpoint evaluates the proportion of participants considered to be improved on the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGI-C) scale for agitation.

Study author Venkat Jasti, chairman and medical director of Suven Life Sciences, and colleagues are currently recruiting patients across the USA and Europe including Poland, Serbia, and Croatia, for the study. In the poster, the authors noted that approximately 50% of the total participants have already been recruited.

In the study, participants will receive masupirdine orally once daily from day 1 through day 85. Screening will take place up to 4 weeks prior to randomization, and eligible participants will be randomized following assessment of inclusion and exclusion criteria.

Inclusion criteria for the phase 3 study require participants to be male or female, over 50 years old, diagnosed with AD-type dementia according to NIA-AA criteria, and to have a confirmed diagnosis of agitation using the IPA consensus provisional definition of agitation in cognitive disorders. Participants must have a Mini-Mental State Examination (MMSE) score between 5 and 26 at their screening visit and may use anxiolytic medications and anti-depressants, provided they have been on a stable dose for at least 4 weeks prior to their screening visit.²

Exclusion criteria include a diagnosis of dementia due to causes other than AD, poorly controlled psychosis, and agitation symptoms that are not secondary to AD. Additionally, patients cannot have a history or current evidence of QT prolongation syndrome and cannot have used centrally acting anticholinergic medication within 2 weeks of baseline visit.

READ MORE: Masupirdine Improves Agitation and Aggression in Alzheimer Disease

Masupirdine, an investigational agent, is a selective 5-HT6 (Serotonin-6) receptor antagonist. These G-protein-coupled receptors with distinct localization and specific distribution in brain regions associated with mood and behavior regulation.¹ Because several clinically used psychotropic drugs act on 5-HT6 receptors, masupirdine is now being studied for its potential to treat agitation.

The phase 3 trial follows a 2021 phase 2a multicenter, randomized, double-blind, proof-of-concept trial (NCT02580305). The study spanned a total of 26 weeks, with patients randomized to receive a 50-mg dose of masupirdine, a 100-mg dose of masupirdine, or placebo. Previously conducted subgroup analyses on the agitation/aggression domain of the 12-item neuropsychiatric inventory scale (NPI-A/A), based on independent patient subgroups and baseline symptoms, found than masupirdine improves agitation and aggression in patients with AD.³

Overall, masupirdine demonstrated a significant attenuation of psychosis in patients with dementia, representing a potential new treatment option for this patient population. Investigators presented additional findings the phase 2a study, which included 564 patients with moderate AD. While the study did not meet its primary end point, 2 potential beneficial effects on cognitive and behavioral outcomes were observed, providing motivation for additional sub-analyses considering combinations of patients’ age, memantine regimen, memantine plasma concentration, memantine treatment duration, and AD duration.

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REFERENCES
1. Jayarajan P, Jetta S, Kumar V, et al. Masupirdine (A Pure 5-HT6 Receptor Antagoinist): Update on the Phase-3 Clinical Study Targeting Agitation in Patients with Dementia of Alzheimer’s Type. Presented at 18^th Clinical Trials on Alzheimer’s Disease Conference; December 1-4; San Diego, California.
2. Nirogi R, Ravula J, Jetta S, et al. Masupirdine for the Treatment of Agitation in Dementia of the Alzheimer's Type. Neurology. 2025;104(April 8, 2025 issue). doi: doi.org/10.1212/WNL.000000000020906
3. Nirogi R, Shinde A, Mohammed AR, et al. Beneficial effects of masupirdine on agitation in patients with Alzheimer disease: A novel non-sedating mechanism. Presented at CTAD 2021; November 9-12. Poster LRP10.