Therapeutics

RVT-101

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Overview

Name: RVT-101
Synonyms: SB-742457 , GSK 742457
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Dementia
U.S. FDA Status: Alzheimer's Disease (Phase 2), Dementia (Phase 2)
Company: Axovant Sciences Ltd.

Background

Originally developed by GSK under the name SB-742457, RVT-101 is an antagonist of the serotonin receptor 6 (5-HT)6, a largely CNS-specific member of the serotonine 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; see clinicaltrials.gov.

In December 2014, Axovant Sciences acquired rights to this drug and renamed it RVT-101. Axovant announced that a Phase 3 program for mild to moderate AD, as well as trials in other forms of dementia, are in planning for a start in late 2015 (see company press release).  

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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. company press release

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.