Background

Nelotanserin is a serotonin, aka 5HT, 2A receptor inverse agonist. Originally called ADP-125, the compound was developed by Arena Pharmaceuticals as a treatment for insomnia, but failed efficacy measures for this indication in Phase 2. In 2015, Axovant Sciences licensed this compound for development, renamed it nelotanserin, and began evaluating it in dementia with Lewy bodies (DLB).

Findings

In December 2015, Axovant started a Phase 2 study in 30 people who had DLB or Parkinson’s disease dementia (PDD) with visual hallucinations. Participants took first 40 mg, then 80 mg, of nelotanserin or placebo once daily for 28 days, and then underwent evaluation for safety, extrapyramidal signs, and whether the frequency and intensity of their hallucinations had changed since baseline. This study was conducted at eight sites in the U.S. In March 2016, a second Phase 2 trial at 23 centers across the U.S. started enrolling what was to be 60 people with a diagnosis of DLB or PDD and frequent episodes of REM sleep behavior disorder; 29 were actually enrolled. Participants took 80 mg of nelotanserin or placebo once daily for 28 days. They were clinically evaluated on change in frequency of RBD since baseline, as well as on severity of their RBD episodes, and safety parameters. This trial ran until May 2018. An open-label extension study for participants in either trial evaluated safety, and efficacy on the hallucination and RBD endpoints of once-daily nelotanserin doses ranging from 20 to 80 mg. It was to run through summer 2019.

In January 2018, Axovant reported results of the first trial. Nelotanserin was well tolerated but produced no changes in any endpoints except for a trend toward improvement in motor function in the UPDRS-III. In a subgroup analysis of 19 DLB patients, a benefit on UPDRS-III was claimed to be statistically significant (Jan 2018 news).

In December 2018, the company announced it was ending development, after nelotanserin failed to reduce RBD events in the second trial (see company press release).

In 2008, nelotanserin was found to be safe but missed primary and secondary endpoints in a Phase 2b trial in 744 people with primary insomnia. In an earlier trial, completed in 2007, in 173 participants with primary insomnia, both 10 and 40 mg oral doses were reported to have improved maintenance and consolidation of sleep, without detrimental cognitive effects the next morning (Rosenberg et al., 2008). 

For all clinical trials on this compound, see clinicaltrials.gov/nelotanserin and clinicaltrials.gov/APD125.