Results of a Phase 2 trial for idalopirdine, also known as Lu AE58054, were formally published October 6 in Lancet Neurology. Developed by the pharmaceutical company Lundbeck, based in Copenhagen, Denmark, this antagonist of the serotonin 6(5-HT6) receptor improved cognitive performance in patients with moderate Alzheimer’s disease (AD) who were already taking donepezil. Alzforum reported on these findings in 2012 (see Jun 2012 news story). David Wilkinson, Moorgreen Hospital, Southampton, U.K., led the study, which was funded and designed by Lundbeck.

Idalopirdine blocks serotonin from activating 5-HT6 receptors expressed in learning and memory centers of the brain. Antagonizing these receptors stops them from suppressing cholinergic function; this may enhance acetylcholine and glutamate levels, although the exact mechanism of idalopirdine remain unknown (see Dawson and Nguyen, 2000; Ramírez, 2013).

The researchers enrolled 278 patients 50 and older and gave them either 90 mg/day of idalopirdine or placebo for six months. The 145 people who received the drug improved their mean score on the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog) by 0.77 points, while those taking placebo worsened by 1.38 points. The 2.16-point treatment difference reached statistical significance. Change on the Mini-Mental State Examination (MMSE) was not pre-specified as an outcome; still, the researchers noted that the mean score rose in the idalopirdine group and dropped in the placebo group. “Our findings suggest that idalopirdine is effective in improving cognitive function in patients with moderate Alzheimer’s disease who are receiving donepezil,” wrote the authors.

Serious adverse events occurred in 10 percent of both treatment and placebo groups; they included fainting and epilepsy. Eight serious adverse events were judged to be probably or possibly related to treatment. One patient from each group died during the course of the trial; however, the authors claim the reasons were unrelated to treatment. Seven people from the placebo group and 18 from the drug group dropped out. This difference reflects a transient rise in liver enzymes in the blood, including aspartate aminotransferase, alanine aminotransferase, and γ-glutamyltransferase, indicating mild liver toxicity. This is a fairly common finding that occurs with many drugs while the liver gets used to metabolizing them, and is akin to what someone might experience after a night of heavy drinking, Wilkinson told Alzforum. Patients did not experience symptoms of liver toxicity, and liver enzymes returned to normal regardless of whether patients stayed on the drug.

Lundbeck is now recruiting for four six-month Phase 3 trials of 10 to 60 mg/day of idalopirdine in patients with mild to moderate Alzheimer’s. These doses reflect receptor occupancy data obtained in the Phase 2 trial, which suggests that less drug is needed. This might reduce the potential for adverse events, Wilkinson suggested. Three of those trials use different doses of acetylcholinesterase inhibitor and adjunct idalopirdine; one is an extension trial to evaluate idalopirdine safety for an additional seven months. Researchers expect to finish data collection in 2016.—Gwyneth Dickey Zakaib

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References

Therapeutics Citations

  1. Idalopirdine

News Citations

  1. Therapy Reported to Boost Cognition in Phase 2 Clinical Trial

Paper Citations

  1. . 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.
  2. . 5-HT6 receptors and Alzheimer's disease. Alzheimers Res Ther. 2013 Apr 22;5(2):15. PubMed.

External Citations

  1. Phase 2
  2. Phase 3

Further Reading

Papers

  1. . 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):1021-33. Epub 2010 Jun 23 PubMed.
  2. . 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer's disease. Neurotherapeutics. 2008 Jul;5(3):458-69. PubMed.

Primary Papers

  1. . Safety and efficacy of idalopirdine, a 5-HT6 receptor antagonist, in patients with moderate Alzheimer's disease (LADDER): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2014 Nov;13(11):1092-9. Epub 2014 Oct 5 PubMed.