intepirdine (SB-742457) / Roivant - LARVOL DELTA

In-silico Design, ADMET Screening, Prime MM-GBSA Binding Free Energy Calculation and MD Simulation of Some Novel Phenothiazines as 5HT6R Antagonists Targeting Alzheimer's Disease. (PubMed, Curr Comput Aided Drug Des) - "The results of this study reveal strong evidence supporting the potential of coumarin- substituted phenothiazine derivatives as effective Serotonin-6 receptor antagonists. Ligands [A2 to A50], which exhibited noteworthy Glide scores, hold promise for significant anti- Alzheimer activity. Further in-vitro and in-vivo investigations are warranted to explore and confirm their therapeutic potential."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Superiority of the Triple-Acting 5-HTR/5-HTR Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HTR Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats. (PubMed, J Med Chem) - "PZ-1922, but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HTR/5-HTR/MAO-B in AD."

Head-to-Head • Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Selective 5-HT Receptor Ligands (Agonist and Antagonist) Show Different Effects on Antipsychotic Drug-Induced Metabolic Dysfunctions in Rats. (PubMed, Pharmaceuticals (Basel)) - "The present study aimed to examine the chronic effects of the selected APDs (haloperidol, risperidone, olanzapine), administered alone and in combination with a selective 5-HT agonist (WAY-181187) or antagonist (SB-742457), on weight gain, food intake, serum lipid profile, glucose level, and a spectrum of hormones derived from adipose (leptin, adiponectin) and gastrointestinal (insulin, ghrelin) tissue in rats. The greatest benefits were obtained when WAY-181187 or SB-742457 were co-administered with haloperidol. It is difficult to assess whether the modification of the serum levels of insulin, leptin, ghrelin, and adiponectin depended on the treatment applied or other drug-independent factors; therefore, further research is needed."

Journal • Preclinical • CNS Disorders • Diabetes • Dyslipidemia • Gastrointestinal Disorder • Genetic Disorders • Metabolic Disorders • Obesity • LEP

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders. (PubMed, Biomolecules) - "Several 5-HT receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing...Masupirdine, a selective 5-HT receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Psychiatry • Schizophrenia

Effect of 5-HT Receptor Ligands Combined with Haloperidol or Risperidone on Antidepressant-/Anxiolytic-Like Behavior and BDNF Regulation in Hippocampus and Prefrontal Cortex of Rats. (PubMed, Neuropsychiatr Dis Treat) - "Acute and chronic (21 days) administration of haloperidol or risperidone in combination with a selective 5-HTR agonist (WAY-181187) or antagonist (SB-742457) to rats was performed for detecting antidepressant- and anxiolytic-like behaviors. It seems that the anxiolytic-like effects induced by haloperidol or risperidone with the addition of 5-HTR ligands are task-specific. The data on BDNF protein and gene expression did not fully correspond with the behavioral outcomes, and thus it appears that other factors/mechanisms are involved in the observed antidepressant- and/or anxiolytic-like effects."

Journal • Preclinical • CNS Disorders • Mood Disorders • Psychiatry • Schizophrenia • BDNF

An international, randomized, placebo-controlled, phase 2b clinical trial of intepirdine for dementia with Lewy bodies (HEADWAY-DLB). (PubMed, Alzheimers Dement (N Y)) - "Intepirdine treatment did not lead to improvements over placebo in patients with DLB. As one of the largest DLB studies to date, HEADWAY-DLB demonstrates that international trials for DLB are feasible within a reasonable timeframe."

Clinical • Journal • P2b data • Alzheimer's Disease • CNS Disorders • Dementia • Gastrointestinal Disorder • Lewy Body Disease • Movement Disorders • Parkinson's Disease

Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer's disease: A randomized, placebo-controlled, phase 3 clinical trial (MINDSET). (PubMed, Alzheimers Dement (N Y)) - "Intepirdine demonstrated a favorable safety profile similar to placebo. Intepirdine as adjunctive therapy to donepezil did not produce statistical improvement over placebo on cognition or activities of daily living in mild-to-moderate AD dementia patients."

Clinical • Journal • P3 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Imidazopyridine-Based 5-HT Receptor Neutral Antagonists: Impact of N-Benzyl and N-Phenylsulfonyl Fragments on Different Receptor Conformational States. (PubMed, J Med Chem) - "In cell-based assays, neutral antagonists of the 5-HTR (7e and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HTR."

Journal

5-HT6 receptor agonist and antagonist improve memory impairments and hippocampal BDNF signaling alterations induced by MK-801. (PubMed, Brain Res) - "The aim of the present study was to investigate and compare the effects of acute and chronic (21-day) administration of agonist (WAY-181187) and antagonist (SB-742457) of the 5-hydroxytryptamine 6 receptor (5-HTR) on MK-801-induced memory impairments in novel object recognition (NORT) and Y-maze continuous spontaneous alternation tests (Y-CAT). Collectively, both the 5-HTR agonist and the antagonist, administered acutely and chronically, prevent memory impairments and alterations in BDNF signaling induced by MK-801 in rats. The present results confirm the pro-cognitive properties of both types of 5-HTR ligands and suggest that BDNF pathways may be involved in their mechanism of action."

Journal • Alzheimer's Disease • CNS Disorders

Recent updates in the Alzheimer's disease etiopathology and possible treatment approaches: a narrative review of current clinical trials. (PubMed, Curr Mol Pharmacol) - "The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are the widely chosen targets. It is predicted that some FDA-approved drugs such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR could also use in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggesting approaches for the clinical trial design for this devastating disease in the near future."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Dementia • Immunology

[VIRTUAL] Anxiolytic activity of risperidone co-treated with a selective 5-HT6 agonist, but not antagonist, in the rat conflict drinking Vogel test (ECNP 2020) - " Using the conflict drinking Vogel test in rats, we examined the effect of risperidone (0.2 mg/kg) given in combination with the selective 5-HT6 agonist (WAY-181187, 3 mg/kg) or antagonist (SB-742457, 3 mg/kg). The obtained results demonstrate that only joint administration of risperidone and WAY-181187 produced the pronounced and significant anxiolytic activity visible as the increase in the number of accepted shocks and the number of lickings. The present findings suggest that co-administration of risperidone with a selective 5-HT6 agonist, but not antagonist, may have a synergistic action and be effective in reducing anxiety disorders. Founding by NCN No UMO-2015/19/B/NZ7/00227"

Preclinical • CNS Disorders • Mood Disorders • Pain • Psychiatry • Schizophrenia

[VIRTUAL] 5-HT6 agonist, but not antagonist, alleviates pro-depressive effect of haloperidol in the modified forced swim test in rats (ECNP 2020) - "In the same conditions SB-742457 (3 mg/kg) had no influence on haloperidol-induced depressive-like behavior. The present findings suggest that co-treatment with a selective 5-HT6 agonist, but not antagonist, may prevent pro-depressive effects of the first generation antipsychotic drug - haloperidol."

Preclinical • CNS Disorders • Depression • Psychiatry • Schizophrenia

[VIRTUAL] Impact of co-administration of 5-HT6 receptor ligands with haloperidol on MK-801-induced social impairments in rats (ECNP 2020) - "The aim of this study was evaluation of the impact of selective 5HT6R ligands (SB-742457 – an antagonist and WAY-181187 – an agonist) as addition to haloperidol treatment on MK-801-induced behavioral impairments in rat social interaction test (SIT). The acute co-treatment of 5-HT6R agonist or antagonist with haloperidol, alleviated the adverse effect of antipsychotic on MK-801-induced social behavior deficits in rats. The decreasing in social interaction time observed after prolonged co-administration of WAY-181187 and haloperidol was correlated with the reduction of hippocampal BDNF expression."

Preclinical • CNS Disorders • Psychiatry • Schizophrenia • BDNF

Dual 5-HT6 and D3 Receptor Antagonists in a Group of 1H-Pyrrolo[3,2-c]quinolines with Neuroprotective and Pro-cognitive Activity. (PubMed, ACS Chem Neurosci) - "In contrast to the well characterized 5-HTR antagonist intepirdine, compound 19 displayed neuroprotective properties against astrocyte damage induced by doxorubicin, as shown using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) staining to assess cell metabolic activity and lactate dehydrogenase (LDH) release as an index of cell membrane disruption. This feature is of particular importance considering the involvement of loss of homeostatic function of glial cells in the progress of neurodegeneration. Biological results obtained for 19 in in vitro tests, translated into pro-cognitive properties in phencyclidine (PCP)-induced memory decline in the novel object recognition (NOR) task in rats."

Journal • CNS Disorders

THE EFFICACY OF INTEPIRDINE (RVT-101), A 5-HT6 RECEPTOR ANTAGONIST, AS AN ADJUNCT TO DONEPEZIL IN ADULTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE: COMPLETER ANALYSIS OF A PHASE 2B STUDY (CTAD 2016) - P2b, N=684; NCT00710684; Sponsor: GlaxoSmithKline; "In this analysis of subjects completing a Phase 2b study in subjects with mild to moderate AD, the 35 mg dose of intepirdine was shown to be effective in improving cognition and function as an adjunct to stable donepezil at all time points measured in this 48-week study."

P2b data • Alzheimer's Disease • Biosimilar

INTEPIRDINE (RVT-101), A 5-HT6 RECEPTOR ANTAGONIST, AS AN ADJUNCT TO DONEPEZIL IN MILDTO-MODERATE ALZHEIMER’S DISEASE: EFFICACY ON ACTIVITIES OF DAILY LIVING DOMAINS. (CTAD 2016) - P3; "In this pre-specified secondary analysis of subjects with mild-to-moderate AD completing a Phase 2b study, the 35 mg dose of intepirdine was shown to be effective in improving instrumental ADLs as well as a measure of independence through the total independence scale. These results suggest that intepirdine treatment has the potential to provide benefits on important aspects of function in Alzheimer’s disease. The 35 mg dose of intepirdine has advanced into a confirmatory Phase 3 study (Study RVT-101-3001 (NCT02585934)) that is now underway."

Clinical • Alzheimer's Disease • Biosimilar

AN ASSESSMENT OF DEPENDENCE LEVEL PROGRESSION USING A CONVERSION ALGORITHM OF ACDS-ADL TO DEPENDENCE SCALE AND DATA FROM A DOUBLE BLIND PLACEBO CONTROLLED TRIAL OF INTEPIRDINE (RVT-101). (CTAD 2016) - "In this study, 684 subjects with mild to moderate AD (MMSE score 10-26 points), and receiving stable donepezil treatment, were randomized to receive 35 mg intepirdine, 15 mg intepirdine, or placebo. Here we demonstrate that an add-on therapy of intepirdine was associated with reduced progression in DL over 48 weeks, thus indicating that patients are spending more time in the earlier stages of the disease. It must be recognized that DL was not measured directly here, but estimated from ADCS ADL using a published paradigm. Still, this study helps establish the Dependence Scale as a meaningful and potentially sensitive outcome measure for describing the real-world impact of a therapeutic agent."

Clinical • Alzheimer's Disease • Biosimilar

Alzheimer’s Drugs and Medicare: A case for pre-approval discussions (Pink Sheet - Informa) - "Idalopirdine and RVT-101...are expected to launch in March and October 2018...According to Informa’s Biomedtracker database, a top-line data read out for idalopirdine is due between now and March 31, 2017 and top-line data for RVT-101 are expected between July 31, 2017 and Dec. 31, 2017."

Anticipated launch • Anticipated P3 data: top line • Alzheimer's Disease

Axovant confidence 'not swayed' after rival Alzheimer's drug fails (Investor's Business Daily) - "Lundbeck, however, had changed the dosing scheme for its idalopirdine to once daily to cut down on liver toxicity concerns, a departure from phase two in which patients received 90 milligrams each day. In phase three, Lundbeck tested 10 milligrams, 30 mg and 60 mg....Axovan's confidence was 'not swayed' by Lundbeck's failure, Evercore analyst Mark Schoenebaum wrote in a report. He says the company plans to file a new drug application with the U.S. Food and Drug Administration by the end of 2017."

Anticipated NDA • Clinical protocol • Alzheimer's Disease

RVT-101, a 5-HT6 receptor antagonist, as adjunctive therapy with donepezil in adults with mild-to-moderate Alzheimer’s disease: Responder analysis (AAIC 2015) - Abstract #6010; P2b, N=684; NCT00710684; Sponsor: GlaxoSmithKline; "In a combined responder analysis of the ADAS-cog, ADCS-ADL, and CDR-SB scales at week 24, subjects who received 35 mg RVT-101 and 15 mg RVT-101 demonstrated a 2.03 (p = 0.032) and 1.89 (p = 0.062) adjusted odds ratio respectively compared to subjects who received donepezil alone at 24 weeks. RVT-101 was well-tolerated by subjects in the study."

P2b data • Alzheimer's Disease

Axovant: Jefferies London Healthcare Conference 2016 (Jefferies 2016 London Healthcare Conference, Axovant) - Anticipated patent protection related to composition of matter until 2029; Anticipated patent life extension until 2036

Anticipated patent expiry • Alzheimer's Disease

Axovant: Jefferies London Healthcare Conference 2016 (Jefferies 2016 London Healthcare Conference, Axovant) - Anticipated patent protection related to composition of matter until 2029; Anticipated patent life extension until 2036

Anticipated patent expiry • Alzheimer's Disease

Axovant announces negative results for intepirdine in Phase 2b HEADWAY and pilot Phase 2 gait and balance studies; positive trends in efficacy seen in pilot Phase 2 nelotanserin study (GlobeNewswire) - P2b, N=269; NCT02669433 (HEADWAY-DLB Study); "Axovant Sciences...today announced that its investigational drug intepirdine did not meet its primary efficacy endpoints in the Phase 2b HEADWAY and pilot Phase 2 Gait and Balance studies....In the HEADWAY study of intepirdine in patients with dementia with Lewy bodies (DLB), neither 35 mg nor 70 mg of intepirdine resulted in statistically significant improvements after 24 weeks of treatment compared with placebo-treated patients....Axovant will work with investigators to appropriately conclude the HEADWAY and MINDSET extension studies."

P2b data • Alzheimer's Disease • CNS Disorders

Axovant Sciences (AXON): New CEO expects intepirdine to succeed - Jefferies (Streetinsider.com) - P3, N=1,150; NCT02585934; "The ongoing PIII MINDSET trial evaluating intepirdine in mild to moderate Alzheimer's disease is expected to readout in late Sept."

P3 data • Alzheimer's Disease

Study Evaluating RVT-101 in Subjects With Dementia With Lewy Bodies: The HEADWAY-DLB Study (clinicaltrials.gov) - P2; N=240; Not yet recruiting; Sponsor: Axovant Sciences Ltd.

New P2 trial • Alzheimer's Disease • Biosimilar