Synonyms: 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 (Inactive), Dementia (Phase 2)
Company: GlaxoSmithKline (GSK)
SB-742457 is an antagonist of the serotonin receptor 6 (5-HT)6, a largely CNS-specific type of serotonine receptor subfamily. The serotonergic neurotransmitter systems is impaired as Alzheimer’s develops and progresses, and is seen as an opportunity to boost neurotransmission (Upton et al., 2008). This drug does not target central AD pathways of Aβ amyloidosis and tauopathy, but represents a symptomatic approach to enhancing cognition in Alzheimer's and other forms of dementia.
Phase 1 studies compared SB-742457 formulated as capsule and tablets, and showed that the compound was well tolerated.
GSK has completed four Phase 2 studies of SB-742457, 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 of 5 mg, 15 mg, or 35 mg of SB 742457 taken once daily 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., 2010). In 2006, a smaller, exploratory six-month multinational trial compared the agonist to donepezil in 198 patients. This trial reported small improvements of both study drug and donepezil on global function, but little improvement on cognition (Maher-Edwards et al., 2001, see Aug 2008 conference story).
At the AAIC conference in July 2011, GSK presented results from a six-month, 576-patient trial of once-daily 15 or 30 mg of SF-742457. That trial missed its co-primary endpoints of significant improvement from baseline on the CIBIC-plus global clinical scale and on the ADAS-Cog cognition battery. This trial took place in in the European Union, Chile, Mexico, South Korea, and Russia. At the same conference, GSK also presented results from a six-month, 684-patient trial of once-daily 15 and 35 mg SG-742457 given as add-on therapy to donepezil. That trial, too, missed the same co-primary endpoints. It was conducted at nearly 100 sites in the United States, Canada, Argentina, Chile, Australia, and the European Union. For all clinical trials with this drug, see clinicaltrials.gov.
Since then, no Phase 3 trial in Alzheimer's disease has been announced, but as of November 2013, GSK listed SF-742457 as being in Phase 2 for the indication of dementia.
- Maher-Edwards G, Zvartau-Hind M, Hunter AJ, Gold M, Hopton G, Jacobs G, Davy M, Williams P. Double-blind, controlled phase II study of a 5-HT6 receptor antagonist, SB-742457, in Alzheimer's disease. Curr Alzheimer Res. 2010 Aug;7(5):374-85. PubMed.
- Maher-Edwards G, Dixon R, Hunter J, Gold M, Hopton G, Jacobs G, Williams P. SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry. 2011 May;26(5):536-44. PubMed.
- Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics. 2008 Jul;5(3):458-69. PubMed.
- Codony X, Vela JM, Ramírez MJ. 5-HT(6) receptor and cognition. Curr Opin Pharmacol. 2011 Feb;11(1):94-100. PubMed.
- Rossé G, Schaffhauser H. 5-HT6 receptor antagonists as potential therapeutics for cognitive impairment. Curr Top Med Chem. 2010;10(2):207-21. PubMed.