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Name: Intepirdine
Synonyms: RVT-101, SB 742457 , GSK 742457
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Dementia with Lewy Bodies
U.S. FDA Status: Alzheimer's Disease (Discontinued), Dementia with Lewy Bodies (Discontinued)
Company: Axovant Sciences Ltd.


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., 2013Callaghan 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).


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

Clinical Trial Timeline

  • Phase 2
  • Phase 3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034
Axovant Sciences Ltd. NCT02585934
Axovant Sciences Ltd. NCT02669433
Axovant Sciences Ltd. NCT02586909
Axovant Sciences Ltd. NCT02910102

Last Updated: 25 Jun 2021


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News Citations

  1. Chicago: More News From Phase 2s
  2. Intepirdine Joins the Ranks of Failed Alzheimer’s Drugs
  3. DLB: Intepirdine a No-Go, Nelotanserin Shrouded in Controversy

Paper Citations

  1. . SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry. 2011 May;26(5):536-44. PubMed.
  2. . Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer's disease. Alzheimers Dement (N Y). 2015 Jun;1(1):23-36. Epub 2015 May 7 PubMed.
  3. . Intepirdine as adjunctive therapy to donepezil for mild-to-moderate Alzheimer's disease: A randomized, placebo-controlled, phase 3 clinical trial (MINDSET). Alzheimers Dement (N Y). 2021;7(1):e12136. Epub 2021 May 31 PubMed.
  4. . 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics. 2008 Jul;5(3):458-69. PubMed.
  5. . Effects of risperidone, clozapine and the 5-HT6 antagonist GSK-742457 on PCP-induced deficits in reversal learning in the two-lever operant task in male Sprague Dawley rats. Behav Brain Res. 2013 May 1;244:15-28. Epub 2013 Feb 4 PubMed.
  6. . Age-related declines in delayed non-match-to-sample performance (DNMS) are reversed by the novel 5HT6 receptor antagonist SB742457. Neuropharmacology. 2012 Oct;63(5):890-7. Epub 2012 Jul 2 PubMed.
  7. . 5-HT(6) receptor and cognition. Curr Opin Pharmacol. 2011 Feb;11(1):94-100. Epub 2011 Feb 15 PubMed.

External Citations

  1. clinical

Further Reading


  1. . 5-HT(6) receptor and cognition. Curr Opin Pharmacol. 2011 Feb;11(1):94-100. Epub 2011 Feb 15 PubMed.
  2. . 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment. Curr Top Med Chem. 2010;10(2):207-21. PubMed.