Table 3.
Clinical Profile of 5-HT6 Antagonists Recently in Development.
| Agents | Indication | NCT Number | Endpoint | Outcome |
|---|---|---|---|---|
| Avisetron | Schizophrenia (Pilot study) [68,69] |
Not available | Key Endpoints: PANSS, CAT | As augmentation therapy, avisetron treatment-related benefits were observed in PANSS total scores, PANSS positive subscores and CAT |
| Schizophrenia (Phase 2 study) [70] |
Not available |
Primary: Change from baseline in the PANSS total scores Other Key Endpoints: Change from baseline in the CGI-S, CGI-I, NSA-16, PSPS, CogFu, BACS and CPT |
As augmentation therapy, a trend towards avisetron treatment-related benefits were observed in PANSS total score, PANSS positive subscores and PANSS general psychopathology scale after 6 weeks of treatment; No notable effects on CGI-S, CGI-I, NSA, PSPS, CogFu, BACS and CPT | |
| Cerlapirdine | Alzheimer’s disease (Pilot study) [71] |
NCT00481520 | Key Endpoints: MMSE, ADAS-Cog and CANTAB | Trend towards improvement was observed with cerlapirdine treatment on the ADAS-Cog 11 and CANTAB at the end of 4 weeks |
| Alzheimer’s disease (Phase 2 study) [72] |
NCT00895895 |
Primary: Change from baseline in the ADAS-Cog 11 total scores Other Key Endpoints: Change from baseline in the ADCS-CGIC, CANTAB and NPI-12 |
No beneficial effects of cerlapirdine were observed at the end of 24 weeks on any of the studied endpoints | |
| Idalopirdine | Schizophrenia (Pilot study) [73] |
Not available | Safety, tolerability, pharmacokinetics and pharmacodynamics (cognitive changes assessed using BACS) | Safe and well-tolerated as standalone treatment for 14 days; Idalopirdine treatment was associated with dose-dependent pattern of improvement in the BACS endpoint; No effect in the placebo treated group |
| Schizophrenia (Phase 2 study) [74] |
NCT00810667 |
Primary: Change in PANSS total scores Other Key Endpoints: Neurocognitive performance using the BACS |
As augmentation therapy, no change was observed in the PANSS total scores or BACS scores or PANSS cognitive subscale scores as compared to placebo after 12 weeks of treatment | |
| Alzheimer’s disease (Phase 2 study) [75] | NCT01019421 |
Primary: Change from baseline in the ADAS-Cog 11 Other Key Endpoints: Change from baseline in the ADCS-ADL, ADCS-CGIC, MMSE and NPI-12 |
As augmentation therapy, significant improvements in ADAS-Cog 11 scores were observed as compared to placebo after 24 weeks of treatment; Parallel trend towards improvement in ADCS-ADL and ADCS-CGIC; Improvements in anxiety and hallucinations domains of the NPI-12 scale in a post hoc analysis | |
| Alzheimer’s disease (Phase 3 studies) [76] | NCT01955161, NCT02006641, and NCT02006654 |
Primary: Change from baseline in the ADAS-Cog Other Key Endpoints: Change from baseline in the ADCS-ADL, ADCS-CGIC, MMSE and NPI-12 |
As augmentation therapy, no significant improvements in ADAS-Cog 11 scores as compared to placebo after 24 weeks of treatment; Similar observations were noted in other endpoints | |
| Intepirdine | Alzheimer’s disease (Phase 2 study) [77] |
NCT00224497 |
Primary: Change from baseline in the ADAS-Cog 11 scores and CIBIC+ Other Key Endpoints: Change from baseline in the MMSE and NPI-12 |
Significant improvement in the CIBIC+ and trend in the ADAS-Cog 11 scores was observed with 24 weeks of intepirdine treatment |
| Alzheimer’s disease (Phase 2 studies) [78,79] |
NCT00348192 and NCT00708552 |
Primary: Change from baseline in the ADAS-Cog 11 scores and CIBIC+ Other Key Endpoints: Change from baseline in the MMSE and ADCS-ADL |
No significant effect was observed on the CIBIC+ or ADAS-Cog 11 scores at the end of 24 weeks of intepirdine treatment | |
| Alzheimer’s disease (Phase 2 study) [79] |
NCT00710684 |
Primary: Change from baseline in the ADAS-Cog 11 scores and CDR-SB Other Key Endpoints: Change from baseline in the MMSE and ADCS-ADL |
As an add-on therapy to donepezil, beneficial effects of intepirdine were observed in the ADAS-Cog 11 scores at the end of 24 weeks and the effects were noted up to 48 weeks; No notable effects were observed on the CDR-SB | |
| Alzheimer’s disease (Phase 3 study) [80] |
NCT02585934 |
Primary: Change from baseline in the ADAS-Cog 11 scores and ADCS-ADL Other Key Endpoints: Change from baseline in the NPI-12 |
As an add-on therapy to donepezil, no beneficial effects of intepirdine were observed in the ADAS-Cog 11 or ADCS-ADL scores at the end of 24 weeks | |
| Dementia with Lewy bodies (Phase 2 study) [81] |
NCT02669433 |
Primary: Change from baseline in the UPDRS–III total scores Other Key Endpoints: Change from baseline in the ADAS-Cog 11 and CIBIC+ |
No beneficial effects of intepirdine were observed in the UPDRS–III total score at the end of 24 weeks | |
| Landipirdine | Parkinson’s disease dementia (Phase 2 study) [82] |
NCT02258152 |
Primary: Change from baseline in the CDRCOA total scores Other Key Endpoints: Change from baseline in the ADCS-CGIC, MoCA and NPI-12 |
No beneficial effects of landipirdine were observed as an add-on treatment to cholinesterase inhibitor after 16 weeks of treatment; Post hoc analysis suggested beneficial effects on apathy, anxiety, and irritability/lability |
| Latrepirdine | Schizophrenia (Phase 2 study) [83] |
Not available | Key Endpoints: PANSS, CGI-S and NSA-16 | As an add-on therapy, no beneficial effect of latrepirdine was observed in the PANSS total or sub scale scores; Latrepirdine showed statistically significant improvement in the NSA-16 scale |
| Alzheimer’s disease (Pilot study) [44] |
Not available | Key Endpoint: Bukatina scale | Treatment with latrepirdine was associated with improvements in cognitive function and reduction of NPS | |
| Alzheimer’s disease (Phase 2 study) [84] |
NCT00377715 |
Primary: Change from baseline in the ADAS-Cog 11 scores Other Key Endpoints: Change from baseline in the MMSE, ADCS-ADL and NPI-12 |
Significant improvement was observed on the ADAS-Cog 11, MMSE, ADCS-ADL and NPI-12 after 24 weeks of treatment | |
| Alzheimer’s disease (Phase 3 studies) [85] |
NCT00675623 and NCT00829374 |
Primary: Change from baseline in the ADAS-Cog 11 scores and CIBIC+ (NCT00675623) or change from baseline in the ADAS-Cog 11 scores and ADCS-ADL (NCT00829374) Other Key Endpoints: Change from baseline in the MMSE, ADCS-ADL and NPI-12 |
No significant effect of latrepirdine treatment was observed as standalone or add-on to donepezil after 26 or 52 weeks of treatment | |
| Masupirdine | Alzheimer’s disease (Phase 2 study) [86,87,88] |
NCT02580305 |
Primary: Change from baseline in the ADAS-Cog 11 total scores Other Key Endpoints: Change from baseline in the ADCS-ADL, MMSE, CDR-SB and NPI-12 |
No beneficial effects of masupirdine were observed as an add-on treatment to donepezil and memantine in the ADAS-Cog 11 after 26 weeks of treatment; Post hoc analysis suggested potential impact of memantine on the efficacy, and potential beneficial effects on agitation/aggression and psychosis |
| Alzheimer’s disease Agitation (Potentially pivotal study) [89] |
NCT05397639 |
Primary: Change from baseline in the CMAI items scores aligning to the International Psychogeriatric Association agitation criteria domains Other Key Endpoints: Change from baseline in the modified ADCS-CGI-C, MMSE and ADAS-Cog 11 |
Study in progress | |
| SAM-760 | Alzheimer’s disease (Phase 2 study) [90] |
NCT01712074 |
Primary: Change from baseline in the ADAS-Cog 13 total scores Other Key Endpoints: Change from baseline in the COWAT, CFT and NPI-12 |
Trial was stopped after a futility analysis; No beneficial effect of SAM-760 treatment was observed after 12 weeks of treatment |
ADAS-Cog—Alzheimer’s Disease Assessment Scale-Cognitive subscale; ADAS-Cog 11—Alzheimer’s Disease Assessment Scale-Cognitive subscale 11; ADAS-Cog 13—Alzheimer’s Disease Assessment Scale-Cognitive subscale 13; ADCS-ADL—Alzheimer’s Disease Cooperative Study—Activities of Daily Living; ADCS-CGIC—Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change; BACS—Brief Assessment of Cognition in Schizophrenia; CANTAB—Cambridge Neuropsychological Test Automated Battery; CAT—Continuous Attention Task; CDRCOA—Computerized Drug Research Cognition Battery Continuity of Attention; CDR-SB—Clinical Dementia Rating scale Sum of Boxes; CFT—Category Fluency Test; CGI-I—Clinical Global Impression–Improvement; CGI-S—Clinical Global Impression–Severity; CIBIC+—Clinician’s Interview-Based Impression of Change with caregiver input; CMAI—Cohen-Mansfield Agitation Inventory; CogFu—Scale for Rating Functioning Related to Cognitive Impairment in Schizophrenia; COWAT—Controlled Oral Word Association Test; CPT—Continuous Performance Test; MMSE—Mini-Mental State Examination; MoCA—Montreal Cognitive Assessment. NPI-12—12-item Neuropsychiatric Inventory; NPS—Neuropsychiatric symptoms; NSA-16—16-item Negative Symptom Assessment; PANSS—Positive and Negative Syndrome Scale; PSPS—Personal and Social Performance Scale; UPDRS–III—Unified Parkinson’s Disease Rating Scale–Part III.