Topline data from one of three ongoing Phase 3 trials for idalopirdine indicate that patients with mild to moderate Alzheimer’s disease who took the drug declined just as fast as did those on placebo. According to a press release, drug sponsor H. Lundbeck A/S, Valby, Denmark, plans to finish the other two trials and an open-label extension as scheduled.

Exactly how idalopirdine might prevent cognitive decline is unclear, but some studies suggest it boosts cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission. Also called Lu AE58054, the compound blocks 5-HT6 serotonin receptors and stimulates the release of acetylcholine, suggesting it might enhance the effects of acetylcholinesterase inhibitors (Ramírez 2013; Galimberti and Scarpini, 2015). In combination with donepezil, one of three cholinesterase inhibitors approved for treating AD, idalopiridine raised acetylcholine levels in the hippocampi of rats (Herrik et al. 2016). A Phase 2 trial in patients with moderate AD suggested that idalopirdine and donepezil together slowed decline more effectively than the cholinesterase inhibitor by itself (Oct 2014 newsJun 2012 news). 

In the six-month Phase 3 trial dubbed STARSHINE, 932 patients with mild to moderate AD received either 30 or 60 mg of idalopirdine or placebo daily, in addition to 10 mg of donepezil. While the company says their drug was safe and well-tolerated, neither dose improved performance on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) beyond what was seen with donepezil alone. Idalopiridine also failed to improve secondary outcomes, which included activities of daily living, neuropsychiatric symptoms, and cognition measured by the mini-mental state examination (MMSE).

Two other six-month Phase 3 trials are ongoing. STARBEAM tests lower doses of the compound, while STARBRIGHT combines it with other acetylcholinesterase inhibitors. An open-label extension trial, will examine long-term safety and tolerability over seven additional months in patients enrolled in STARBEAM and STARSHINE.—Gwyneth Dickey Zakaib

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References

Therapeutics Citations

  1. Idalopirdine
  2. Donepezil

News Citations

  1. Phase 2 Trial Hints Idalopirdine May Work as Adjunct Therapy in Alzheimer’s
  2. Therapy Reported to Boost Cognition in Phase 2 Clinical Trial

Paper Citations

  1. . 5-HT6 receptors and Alzheimer's disease. Alzheimers Res Ther. 2013 Apr 22;5(2):15. PubMed.
  2. . Idalopirdine as a treatment for Alzheimer's disease. Expert Opin Investig Drugs. 2015;24(7):981-7. Epub 2015 May 28 PubMed.
  3. . The 5-HT6 receptor antagonist idalopirdine potentiates the effects of acetylcholinesterase inhibition on neuronal network oscillations and extracellular acetylcholine levels in the rat dorsal hippocampus. Neuropharmacology. 2016 Aug;107:351-63. Epub 2016 Mar 31 PubMed.

External Citations

  1. press release
  2. STARSHINE
  3. STARBEAM
  4. STARBRIGHT
  5. open-label extension trial

Further Reading

Papers

  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. . Glutamatergic systems in Alzheimer's disease. Int J Geriatr Psychiatry. 2003 Sep;18(Suppl 1):S15-21. PubMed.
  3. . Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT6 receptor antagonists. Design, synthesis and biological evaluation. Eur J Med Chem. 2016 Nov 29;124:63-81. Epub 2016 Aug 11 PubMed.