Background

Originally developed by GSK under the name SB-742457, RVT-101/intepirdine is an antagonist of the serotonin receptor 6 (5-HT)6, a largely CNS-specific member of the serotonin receptor subfamily. The serotonergic neurotransmitter system is impaired as Alzheimer’s develops and progresses, and modulating it is seen as a potential therapeutic avenue (Upton et al., 2008). SB-742457 has been reported to reverse both experimentally induced and age-related learning deficits in rats (de Bruin et al., 2013; Callaghan et al., 2012). This drug does not target central AD pathways of Aβ amyloidosis and tauopathy; rather, it represents an approach to enhancing cognition in Alzheimer's and other forms of dementia (Codony et al., 2011).

Findings

Several Phase 1 studies compared SB-742457 in capsule and tablet formulations, and showed that the compound was well-tolerated.

GSK completed four Phase 2 studies of this compound, all in patients with mild to moderate AD. Between 2005 and 2007, a six-month dose-ranging trial of SB-742457 monotherapy measured the effect that 5 mg, 15 mg, or 35 mg of the drug taken once daily had on cognition (ADAS-cog) and global clinical function (Change plus Caregiver Input, CIBIC-plus) in 371 patients in the European Union, Croatia, Russia, South Africa, Chile, South Korea, and New Zealand. That trial reported a small but dose-dependent benefit of the study drug on both measures, as well as acceptable tolerability (Maher-Edwards et al., 2011; August 2008 conference news). Other Phase 2 trials failed to meet their primary endpoints, but suggested some benefit of intepirdine as an adjunct to donepezil (Mayer-Edwards et al., 2011; Mayer-Edwards et al., 2015).

In December 2014, Axovant Sciences acquired rights to this drug and renamed it RVT-101, and then intepirdine. At AAIC 2015, Axovant presented a more complete analysis of prior Phase 2b GSK data on RVT-101 added to donepezil that had been analyzed previously based on the intent-to-treat population, and came up with a slightly larger effect size on essentially similar efficacy results. A Phase 3 program for mild to moderate AD, as well as trials in other forms of dementia, was in planning.

In 2015, Axovant began MINDSET, a registration trial of a six-month course of 35 mg RVT-101 once daily added to stable donepezil therapy in 1,315 patients with mild to moderate AD. In December 2015, Axovant presented a poster at the CTAD conference claiming nearly full receptor occupancy at the dose used in Phase 3, and announced plans to evaluate this drug in dementia with Lewy bodies (DLB). Set to run until October 2017, MINDSET aimed to confirm the prior GSK study, with a standard co-primary outcome of ADAS-Cog and ADCS-ADL. In September 2017, Axovant released topline results stating the drug had failed to improve cognition or activities of daily living relative to placebo (Sept 2017 news). The 12-month open-label extension study of MINDSET continued until negative results for the DLB trial of intepirdine were reported several months later. Trial results were published after peer review (Lang et al., 2021).

In January 2016, HEADWAY-DLB, a Phase 2 study, started enrolling an anticipated 240 patients with DLB to compare a six-month course of 35 or 70 mg intepirdine to placebo for change since baseline on the CIBIC+ scale. Secondary endpoints included visual hallucinations and safety parameters. This trial was set to run until March 2018 at 39 locations in the United States and Europe, and offered a six-month extension for completers. In October 2016, Axovant started a trial in 40 people with either AD, DLB, or Parkinson's disease dementia (PDD) to evaluate a three-month course of 35 mg of intepirdine or placebo for effects on quantitative gait measurement. This study was to run for one year at two U.S. sites. However, in January 2018, Axovant reported negative results from both the Headway-DLB and PDD gait trials, announcing an end to extension dosing in MINDSET and HEADWAY-DLB, and discontinuation of intepirdine development (Jan 2018 news).

For trials of this compound, see clinical trials.gov.

Clinical Trial Timeline