This week, H. Lundbeck A/S, an international pharmaceutical company based in Denmark, announced positive results of a Phase 2 trial. Given along with donepezil, an acetylcholinesterase inhibitor commonly prescribed in Alzheimer's disease (AD), the serotonin/5-hydroxytryptamine receptor antagonist Lu AE58054 provided some added cognitive benefit in patients with moderate AD, according to a company press release. Detailed trial data will be presented this year.

The 5-hydroxytryptamine-6 (5-HT6) receptor is expressed primarily in the central nervous system, especially in learning and memory centers such as the cerebral cortex and hippocampus. Activation of this receptor usually represses cholinergic function (see Bentley et al., 1999), which is important for a range of cognitive functions, including memory and attention. Antagonists of 5-HT6 elevate glutamatergic neurotransmission (see Dawson et al., 2000), which is important for long-term potentiation, learning, and memory. Since Lu AE58054 selectively blocks serotonin from activating 5-HT6 receptors, it may cause an overall enhancement of acetylcholine and glutamate levels.

In the randomized Phase 2 trial, 278 patients in Europe, Canada, and Australia took either Lu AE58054 or placebo in addition to their daily donepezil dose for six months. Compared with patients on donepezil alone, those treated with both drugs improved scores on the Alzheimer's Disease Assessment Scale-cognitive sub-scale (ADAS-cog) and trended positive on measures of Global Status and Activities of Daily Living. The 5-HT6 antagonist was well tolerated, according to the press release. Phase 3 trials are in planning, a company spokesperson said.

Lu AE58054 is not the first 5-HT6 antagonist to be tested for AD. GlaxoSmithKline’s drug SB-742457 (see ARF related news story) completed four Phase 2 trials (see NCT00348192, NCT00224497, NCT00708552, and NCT00710684). It modestly improved function, as judged by the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC+) in patients with mild to moderate AD (see Maher-Edwards et al., 2010), and had similar benefits when compared to donepezil (see Maher-Edwards et al., 2011). Other 5-HT6 antagonists are currently in or have completed Phase 1 trials, including Suven Life Sciences Ltd.'s SUVN-502; Avineuro Pharmaceuticals Inc.'s AVN-322; Biotie Therapies Corp./Roche's SYN-120; Abbott Laboratories' ABT-354; and Pfizer's PF-5212377. Dimebon, a drug that, among other things, antagonizes 5-HT6 receptors, showed cognitive benefits in Phase 2 trials (see ARF related news story on Doody et al., 2008), but failed in Phase 3 (see ARF related news story and ARF news story).—Gwyneth Dickey Zakaib.


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News Citations

  1. Chicago: More News From Phase 2s
  2. AD Clinical Pipeline: Immunotherapy Woes, Dimebon Boons
  3. Dimebon Disappoints in Phase 3 Trial
  4. CONCERT Trial of Dimebon Falls Flat

Paper Citations

  1. . Investigation of stretching behaviour induced by the selective 5-HT6 receptor antagonist, Ro 04-6790, in rats. Br J Pharmacol. 1999 Apr;126(7):1537-42. PubMed.
  2. . In vivo effects of the 5-HT(6) antagonist SB-271046 on striatal and frontal cortex extracellular concentrations of noradrenaline, dopamine, 5-HT, glutamate and aspartate. Br J Pharmacol. 2000 May;130(1):23-6. PubMed.
  3. . 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.
  4. . SB-742457 and donepezil in Alzheimer disease: a randomized, placebo-controlled study. Int J Geriatr Psychiatry. 2011 May;26(5):536-44. PubMed.
  5. . Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008 Jul 19;372(9634):207-15. PubMed.

External Citations

  1. Phase 2 trial
  2. company press release
  3. NCT00348192
  4. NCT00224497
  5. NCT00708552
  6. NCT00710684

Further Reading


  1. . Dimebolin is a 5-HT6 antagonist with acute cognition enhancing activities. Biochem Pharmacol. 2009 Oct 15;78(8):1035-42. PubMed.
  2. . Two novel 5-HT6 receptor antagonists ameliorate scopolamine-induced memory deficits in the object recognition and object location tasks in Wistar rats. Neurobiol Learn Mem. 2011 Sep;96(2):392-402. PubMed.
  3. . Central nervous system effects of the interaction between risperidone (single dose) and the 5-HT6 antagonist SB742457 (repeated doses) in healthy men. Br J Clin Pharmacol. 2011 Jun;71(6):907-16. PubMed.
  4. . Signalling pathways associated with 5-HT6 receptors: relevance for cognitive effects. Int J Neuropsychopharmacol. 2010 Jul;13(6):775-84. PubMed.