nelotanserin (RVT-102) / Roivant, Pfizer - LARVOL DELTA

Nelotanserin, a selective 5-HT2A receptor inverse agonist, attenuates aspects of nicotine withdrawal but not reward in mice. (PubMed, Behav Brain Res) - "However, nelotanserin had no effect on anxiety-like behavior and failed to reduce nicotine reward as measured in the conditioned place preference test. Our results suggest that inverse agonism of the 5-HT2A receptor may be a feasible novel mechanism for smoking cessation by reducing both physical withdrawal and thermal hyperalgesia associated with nicotine abstinence but may require complementary pharmacotherapies targeting affective and reward-associated decrements to improve cessation outcomes."

Journal • Preclinical • CNS Disorders • Mental Retardation • Mood Disorders • Nicotine Addiction • Psychiatry • Tobacco Cessation

Ligand bias and inverse agonism on 5-HT2A receptor-mediated modulation of G protein activity in post-mortem human brain. (PubMed, Br J Pharmacol) - "The results reveal the existence of constitutively active 5-HT2A receptors in human pre-frontal cortex and demonstrate different pharmacological profiles of various 5-HT2A receptor drugs previously considered antagonists. These findings indicate that altanserin and pimavanserin possess biased inverse agonist profile towards 5-HT2A receptor activation of Gi1 proteins."

Journal • CNS Disorders • Psychiatry • Schizophrenia

Effect of the 5-HT2A/2C inverse agonist nelotanserin on dyskinesia in the MPTP-lesioned marmoset (MDS Congress 2023) - "These results provide incremental pre-clinical evidence that 5-HT antagonism is an efficacious anti-dyskinetic approach."

Alzheimer's Disease • Behavior Disorders • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Parkinson's Disease • Psychiatry

Lewy Body Dementia: An Overview of Promising Therapeutics. (PubMed, Curr Neurol Neurosci Rep) - "We review 11 prospective disease-modifying therapies (DMT) including four with phase 2 data (neflamapimod, nilotinib, bosutinib, and E2027); four with some limited data in symptomatic populations including phase 1, open-label, registry, or cohort data (vodabatinib, ambroxol, clenbuterol, and terazosin); and three with phase 1 data in healthy populations (Anle138b, fosgonimeton, and CT1812). We also appraise four symptomatic therapies for cognitive impairment, but due to safety and efficacy concerns, only NYX-458 remains under active investigation. Of symptomatic therapies for psychosis recently investigated, pimavanserin shows promise in LBD, but studies of nelotanserin have been suspended. Although the discovery of novel symptomatic and disease-modifying therapeutics remains a significant challenge, recently published and upcoming trials signify promising strides toward that aim."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Movement Disorders • Parkinson's Disease • Psychiatry

The 5-HT inverse agonist nelotanserin alleviates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset. (PubMed, Eur J Neurosci) - "Nelotanserin had no impact on the anti-parkinsonian action of L-DOPA. Our results highlight that nelotanserin may represent an efficacious anti-dyskinetic drug and provide incremental evidence of the potential benefit of 5-HT antagonism/inverse agonism for drug-induced dyskinesia in PD."

Journal • Alzheimer's Disease • Behavior Disorders • CNS Disorders • Cognitive Disorders • Dementia • Movement Disorders • Parkinson's Disease • Psychiatry

An overview of the active clinical trials for Parkinson's disease psychosis. (PubMed, Neurodegener Dis Manag) - "Tweetable abstract An overview of the active clinical trials for Parkinson's disease psychosis. In this article, we review the drugs currently undergoing clinical testing for Parkinson's disease psychosis and offer some perspectives on the treatment of the condition."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry

[VIRTUAL] A double-blind randomized study with video analysis evaluating Nelotanserin as symptomatic treatment for RBD in DLB/ PDD (EAN 2021) - "Despite negative results, this is the 1st randomized, placebo-controlled study on symptomatic RBD treatment using objective outcome measures based on systematic video analysis. This study provides a new method for outcome research in RBD and proves that movement analysis is a feasible and meaningful outcome for studies evaluating changes in RBD severity."

Clinical • Video • Alzheimer's Disease • Behavior Disorders • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Mental Retardation • Movement Disorders • Parkinson's Disease • Psychiatry • REM Sleep Behavior Disorder

Nelotanserin as symptomatic treatment for rapid eye movement sleep behavior disorder: a double-blind randomized study using video analysis in patients with dementia with Lewy bodies or Parkinson's disease dementia. (PubMed, Sleep Med) - P2 | "Despite negative results, this is the first randomized, placebo-controlled study on symptomatic RBD treatment using objective outcome measures based on systematic video analysis. This study provides a new method for outcome research in RBD and proves that movement analysis is a feasible and meaningful outcome for studies evaluating changes in RBD severity."

Clinical • Journal • Video • Alzheimer's Disease • Behavior Disorders • CNS Disorders • Cognitive Disorders • Dementia • Lewy Body Disease • Mental Retardation • Movement Disorders • Parkinson's Disease • Psychiatry • REM Sleep Behavior Disorder

Big Data Challenges Targeting Proteins in GPCR Signaling Pathways; Combining PTML-ChEMBL Models and [35S]GTPγS Binding Assays. (PubMed, ACS Chem Neurosci) - "To illustrate its practical use, we used the model to predict the outcomes of six different 5-HT2A receptor drugs, namely, TCB-2, DOI, DOB, altanserin, pimavanserin, and nelotanserin, in a very large number of different pharmacological assays. Our results demonstrate that some of these drugs, previously described as serotonin 5-HT2A receptor agonists, antagonists or inverse agonists, are not so specific and show different intrinsic activity to that previously reported. Overall, this work opens a new gate for the prediction of GPCRs targeting compounds."

Journal • CNS Disorders • Psychiatry • Schizophrenia

[VIRTUAL] Functional selectivity of different serotonin 5-HT2A receptor antagonists in human post-mortem brain cortex (ECNP 2020) - "Objective: Characterization of the functional profile of selective 5­HT2AR inverse agonist/antagonist drugs (altanserin, eplivanserin, ketanserin, MDL-11,939, nelotanserin, pimavanserin and volinanserin) in the coupling of 5-HT2ARs to Gαq/11- and Gαi1-proteins in post-mortem human brain. The present study supports the presence of constitutively active 5-HT2ARs in human brain and demonstrates the differential targeting of G-protein signalling modulation by different 5-HT2AR drugs in post-mortem human prefrontal cortex. These findings also demonstrate that altanserin and pimavanserin display preferential inverse agonist effect on 5-HT2AR coupling to Gai1-proteins, with no effect on Gaq/11-proteins. If the hypothesis of an increase in 5-HT2AR pre-coupling to Gai1-proteins in schizophrenia was finally demonstrated, these two drugs would be a good starting point to develop a new generation of antipsychotic drugs, with potential improved efficacy and, perhaps, a lower..."

CNS Disorders • Psychiatry • Schizophrenia

[VIRTUAL] Functional selectivity of different serotonin 5-HT2A receptor antagonists in human post-mortem brain cortex (ECNP 2020) - "The aim of the present work is the characterization of the functional profile of selective 5-HT2A R inverse agonist/antagonist drugs (altanserin, eplivanserin, ketanserin, MDL11,939, nelotanserin, pimavanserin and volinanserin) in the coupling of 5-HT2A Rs to Gα q/11 - and Gα i1 -proteins in postmortem human brain cortex membrane homogenates. These findings also demonstrate that altanserin and pimavanserin display preferential inhibition of 5-HT2A R coupling to Ga i1 -proteins vs canonical Ga q/11 -proteins. The information about functional selectivity in native tissue will help to develop new generation of antipsycothics, considering that the Ga i1 -protein pathway has been implicated in schizophrenia."

CNS Disorders • Psychiatry • Schizophrenia

Open-label Study of Nelotanserin in Lewy Body Dementia With Visual Hallucinations or REM Sleep Behavior Disorder (clinicaltrials.gov) - P2; N=80; Terminated; Sponsor: Axovant Sciences Ltd.; Trial completion date: Jul 2019 ➔ Jan 2019; Active, not recruiting ➔ Terminated; Trial primary completion date: Jul 2019 ➔ Jan 2019; Changes to the overall development program for the study medication

Clinical • Trial completion date • Trial primary completion date • Trial termination