Masupirdine (development code: SUVN-502) is a selective serotonin 6 (5-HT6) receptor antagonist developed by Suven Life Sciences Ltd. (Hyderabad, India) for the treatment of Alzheimer's disease. This compound was investigated as an adjunct therapy to background acetylcholinesterase inhibitor (donepezil) and memantine treatment for patients with moderate AD[1][2].
While the primary Phase 2 trial (NCT02580305) did not meet its primary cognitive endpoint, post-hoc analyses explored effects on neuropsychiatric symptoms including agitation, aggression, and psychosis — which are common and debilitating complications of Alzheimer's disease[3].
| Parameter | Value |
|---|---|
| NCT Number | NCT02580305 (primary); NCT05397639 (agitation analysis) |
| Status | Completed |
| Phase | Phase 2 |
| Sponsor | Suven Life Sciences Ltd. |
| Intervention | Masupirdine 50 mg or 100 mg daily (oral) |
| Indication | Moderate Alzheimer's Disease (adjunct therapy) |
| Population | 564 patients (randomized 1:1:1) |
| Duration | 26 weeks |
Masupirdine is a highly selective 5-HT6 receptor antagonist. The 5-HT6 receptor is a G-protein coupled receptor (GPCR) expressed predominantly in the central nervous system, particularly in brain regions associated with cognition and emotion:
The 5-HT6 receptor offers several theoretical advantages for AD treatment:
Cognitive enhancement: 5-HT6 antagonism increases acetylcholine and glutamate release in cortical and hippocampal regions, potentially improving memory and learning[4]
Neuroprotective effects: 5-HT6 signaling influences amyloid precursor protein (APP) processing and may affect amyloid-beta production
Neuropsychiatric symptoms: The receptor is implicated in mood and behavioral regulation, making it a target for agitation and psychosis in AD
Adjunct potential: 5-HT6 antagonists may enhance the effects of acetylcholinesterase inhibitors like donepezil
Agitation affects up to 70% of AD patients during the disease course and represents:
A published post-hoc analysis examined masupirdine's effects on agitation, aggression, and psychosis in moderate AD patients[3:1]:
The exploration of agitation outcomes led to interest in a dedicated agitation trial (NCT05397639).
| Phase | Duration | Arms |
|---|---|---|
| Screening | 4 weeks | N/A |
| Treatment | 26 weeks | Masupirdine 50mg vs. 100mg vs. Placebo |
| Follow-up | 4 weeks | Safety monitoring |
ADAS-Cog 11: The study did not meet its primary efficacy endpoint. Both masupirdine doses (50mg and 100mg) showed statistically non-significant differences compared to placebo in change from baseline at week 26[1:1].
No significant treatment effects were observed in:
Masupirdine was generally safe and well tolerated:
Exploratory post-hoc analyses on NPI agitation subdomain suggested potential beneficial effects that warrant further investigation in a prospective trial focused on agitation[3:2].
| Drug | Company | Status | Indication |
|---|---|---|---|
| Masupirdine (SUVN-502) | Suven Life Sciences | Phase 2 complete | AD, agitation |
| Idalopirdine (Lu AE58054) | Lundbeck/Otsuka | Phase 3 failed | AD |
| SB-742457 | GlaxoSmithKline | Phase 2 | AD |
| PRX-070980 | Epix Therapeutics | Phase 1/2 | AD |
The 5-HT6 antagonist class has faced challenges in AD clinical trials, with multiple compounds failing to meet primary endpoints.
AD Drug Repositioning
Clinical Trials in AD
5-HT6 Receptor Agonists and Antagonists
Neuropsychiatric Symptoms in AD
Suven Life Sciences
Semba J, et al. A phase 2 randomized, double-blind, placebo-controlled study of masupirdine (SUVN-502) as adjunctive therapy in patients with moderate Alzheimer's disease. J Prev Alzheimers Dis. 2022. ↩︎ ↩︎
ClinicalTrials.gov. Study of SUVN-502 in Patients With Moderate Alzheimer's Disease. NCT02580305. ↩︎
Menon V, et al. Potential beneficial effects of masupirdine (SUVN-502) on agitation/aggression and psychosis in patients with moderate Alzheimer's disease: Exploratory post hoc analyses. Int J Geriatr Psychiatry. 2022. ↩︎ ↩︎ ↩︎
Geldenhuys WJ, Van der Schyf CJ. Role of serotonin 5-HT6 receptors in neurodegeneration: Therapeutic strategies. CNS Drugs. 2023. ↩︎