Therapeutics

S 38093

Overview

Name: S 38093
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline), Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Servier

Background

This histamine H3 receptor antagonist was being developed for the treatment of Alzheimer's disease in many European, South American, and other countries, though not the United States. Blocking the histamine H3 receptor has been a target of several small-molecule therapeutic programs for cognition disorders at other companies, as well, e.g. GSK239512ABT-288. The approach has been proposed to increase cholinergic signaling, which wanes with neurodegeneration in AD (Passani and Blandina, 1998Bembenek et al., 2008Bertoni et al, 2008). 

No peer-reviewed studies are published on this compound; however, an AAIC meeting presentation on S 38093 reported benefits on attention and executive function in five monkeys treated with the dopaminergic toxin MPTP (Schneider et al, 2009).

Findings

Between 2009 and 2015, four Phase 2 trials, testing doses ranging from 2 to 25 mg of S 38093 per day have been conducted in a total of about 1,600 patients with mild to moderate Alzheimer's disease. Two studies compared S 38093 monotherapy tablets to placebo, and two compared the same doses of S 38093 as an add-on to standard cholinesterase inhibitor therapy.

The most recent trial started in 2012. It was an international Phase 2b study evaluating 2, 5, or 20 mg per day of S 38093 co-administered with 10 mg of donepezil, given for six months, to donepezil alone in 700 patients with moderate AD. Outcomes included a cognitive benefit as measured by the ADAS-cog 11 and a functional benefit as measured by DAD. No biomarkers were used in this study. This trial was completed in January 2015. 

At the November 2015 CTAC conference, S 38093 development was reported to have been discontinued due lack of efficacy in Phase 2. Neither of the three doses, taken for a year, outperformed placebo on any measure of cognition, function, clinical global impression, or caregiver burden (see Nov 2015 conference news).

For all Phase 2 trials of this compound, see EU Clinical Trials Register.

Last Updated: 15 Jan 2016

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References

News Citations

  1. Truly New to Déjà Vu: For Five Hopefuls, Lights Go Out After Phase 2

Therapeutics Citations

  1. GSK239512
  2. ABT-288

Paper Citations

  1. . Cognitive implications for H3 and 5-HT3 receptor modulation of cortical cholinergic function: a parallel story. Methods Find Exp Clin Pharmacol. 1998 Oct;20(8):725-33. PubMed.
  2. . Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling. Bioorg Med Chem. 2008 Mar 15;16(6):2968-73. Epub 2007 Dec 25 PubMed.
  3. . In vitro and in vivo pharmacological analysis of imidazole-free histamine H3 receptor antagonists: promising results for a brain-penetrating H3 blocker with weak anticholinesterase activity. Naunyn Schmiedebergs Arch Pharmacol. 2008 Sep;378(3):335-43. Epub 2008 May 22 PubMed.

External Citations

  1. EU Clinical Trials Register
  2. Schneider et al, 2009

Further Reading

No Available Further Reading