Therapeutics

Lu AE58054

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Overview

Name: Lu AE58054
Synonyms: SGS 518
Chemical Name: 2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine
Therapy Type: Small Molecule
Target Type: Other Neurotransmitter Systems
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Phase 3), Schizophrenia (Inactive)
Company: Eli Lilly & Co., Lundbeck, Otsuka Pharmaceutical Co., Ltd.

Background

This orally available drug is an antagonist of the serotonin 6 (5-HT6) receptor. This receptor subtype is expressed primarily in the brain, particularly in the cerebral cortex and hippocampus, where it has been proposed to play a role in cognitive impairments associated with schizophrenia and Alzheimer's disease.  The 5-HT6 receptor antagonists are thought to enhance cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission. Apart from some affinity for adrenergic receptors, Lu AE58054 has been reported to be highly selective over other G-protein coupled receptors. The compound enters the brain and dose-dependently reversed deficits in a rat model of cognitive impairment (Upton et al., 2008; Arnt et al., 2010).

Lu AE58054 is being developed as a symptomatic adjunct to cholinesterase inhibitor treatment in Alzheimer's disease. Lu AE58054 was originally discovered by Lilly, which licensed it to the biotechnology company Saegis for the development of cognitive impairment in thinking disorders such as schizophrenia. In 2006, Saegis was acquired by Lundbeck, which in October 2013 launched a global Phase 3 program in AD. This program consists of four trials planned to enroll a total of about 3,000 patients (see company press release).

 

Findings

No Phase 1 trials on this drug are listed in publicly available databases. In 2005, Saegis conducted a Phase 2a trial in 20 schizophrenia patients in the United States, evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of giving this drug as an add-on to Risperidone (see company press release). In 2009 and 2010, Lundbeck conducted a Phase 2 trial in Europe and Asia to evaluate the compound as an adjuct to Risperidone for its effect on cognitive deficits in 124 patients with schizophrenia. Results were not published in the peer-reviewed literature, but development of Lu AE58054 for cognitive deficits in schizophrenia appears to have ended.

In 2010 and 2011, Lundbeck evaluated Lu AE58054 in a Phase 2 study in 278 patients with probable Alzheimer's disease. Conducted in Australia, Canada, and Europe, the trial compared the effects of a six-month course of an undisclosed dose of Lu AE58054 with 10 mg/day of Donepezil to the same dose of placebo. In June 2012, the company announced that the trial had met its primary cognition endpoint as measured by the ADAS-cog. On secondary endpoints, such as measures of global status and activities of daily living, Lu AE58054 treatment showed trends for a benefit but fell short of achieving statistical significance (see Jun 2012 news story).

In July 2013, a Phase 1 study evaluating pharmacokinetics of single and multiple ascending doses in 42 healthy volunteers was added, and in October 2013, the first of four planned Phase 3 studies began. This study is set to enroll 930 patients with mild to moderate Alzheimer's disease who are already taking a stable dose of 10 mg/day of Donepezil. The trial compares a six-month course of once-daily 30 or 60 mg capsules of drug to placebo for added benefit on cognition as measured by the ADAS-cog. Secondary outcomes will assess various aspects of global clinical function and behavior. No biomarkers are embedded in this trial, which is expected to last until September 2015. For all listed trials on Lu AE58054, see clinicaltrials.gov.

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References

Paper Citations

  1. . 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics. 2008 Jul;5(3):458-69. PubMed.
  2. . Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol. 2010 Sep;13(8) Epub 2010 Jun 23 PubMed.

External Citations

  1. company press release
  2. Jun 2012 news story
  3. clinicaltrials.gov
  4. company press release

Further Reading

Papers

  1. . 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.
  2. . The serotonin-6 receptor as a novel therapeutic target. Exp Neurobiol. 2011 Dec;20(4):159-68. PubMed.
  3. . Identification of Multiple 5-HT(4) Partial Agonist Clinical Candidates for the Treatment of Alzheimer's Disease. J Med Chem. 2012 Nov 8;55(21):9240-54. PubMed.
  4. . Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14968-73. PubMed.