Therapeutics

Intepirdine

Overview

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 (Phase 3), Dementia with Lewy Bodies (Phase 2/3)
Company: Axovant Sciences Ltd.

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., 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).

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).

In December 2014, Axovant Sciences acquired rights to this drug and renamed it RVT-101. At AAIC 2015, Axovant presented a completer analysis of prior Phase 2b GSK data 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 October, 2015, Axovant began screening for MINDSET, a trial of a six-month course of 35 mg RVT-101 once daily added to stable donepezil therapy in 1,150 patients with mild to moderate AD. Set to run until October 2017, this registration trial aims to confirm the prior GSK study, with a standard co-primary outcome of ADAS-cog and ADCS-ADL. A 12-month open-label extension is also being offered.

In December 2015, at the CTAD conference, Axovant presented a poster 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).

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 chance since baseline on the CIBIC+ scale. Secondary endpoints include visual hallucinations and safety parameters. This trial will run until March 2018 at 39 locations in the United States and Europe, and is offering a six-month extension to 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 quantitative gait measurement. This study will run for one year at two U.S. sites.

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

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
Axovant Sciences Ltd. NCT02585934
N=1150
Axovant Sciences Ltd. NCT02586909
N=1150
Axovant Sciences Ltd. NCT02910102
N=40

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References

News Citations

  1. Chicago: More News From Phase 2s

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. . 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics. 2008 Jul;5(3):458-69. PubMed.
  3. . 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.
  4. . 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.
  5. . 5-HT(6) receptor and cognition. Curr Opin Pharmacol. 2011 Feb;11(1):94-100. Epub 2011 Feb 15 PubMed.

External Citations

  1. clinical trials.gov
  2. clinical trials.gov

Further Reading

Papers

  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.