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 was able to dose-dependently reverse deficits in a rat model of cognitive impairment (Upton et al., 2008; Arnt et al., 2010).

Lu AE58054 was being developed as a symptomatic adjunct to cholinesterase inhibitor treatment in Alzheimer's disease. The compound was originally discovered by Lilly, which licensed it to the biotechnology company Saegis for clinical development in 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 consisted of four trials that planned to enroll a total of nearly 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 adjunct 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 90 mg/day 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. Elevated liver enzymes in the treatment group, and higher dropout than in the placebo group, were also noted in this trial (see Jun 2012 news).

In October 2013, the first of four Phase 3 studies began, called STARSHINE. All Phase 3 trials in this program enrolled patients with mild to moderate Alzheimer's disease who were already taking a stable dose of 10 mg/day of an acetylcholinesterase inhibitor; two studies required that patients be on donepezil, one allowed any of the three available drugs of that mechanism, the fourth is an extension study. All phase 3 trials dosed well below the 90 mg/day reported to be effective in phase 2. STARSHINE compared a six-month, adjunct course of once-daily 30 or 60 mg capsules of idalopirdine to placebo in 930 participants for added benefit on cognition as measured by the ADAS-cog as a single primary outcome. Secondary outcomes assessed various aspects of global clinical function and behavior. No biomarkers were embedded in this development program.

In spring 2014, Lundbeck started up three additional Phase 3 studies. STARBEAM compared a lower dose of 10 mg to 30 mg once daily for six months in 840 patients,  STARBRIGHT was a worldwide study comparing 30 to 60 mg once daily for six months in 720 patients. The third was an open-label study to enroll 1,770 patients who completed one of the two trials comparing the higher two doses; it assessed safety, cognition, clinical, and psychiatric measures for another seven months. These studies were set to end between November 2015 and August 2016.

In 2013 and 2014, Phase 1 studies evaluating pharmacokinetics of single and multiple ascending doses in healthy volunteers and in people with liver impairment were added. In 2015, Lundbeck conducted four additional Phase 1 trials in France, Germany, and the United Kingdom. One evaluated the bioequivalence of two different formulations, the others investigated idalopirdine's effect on kidney function, excretion, and heart repolarization.

In July 2016, Idalopirdine received Fast Track designation by the FDA; however in September, Lundbeck announced that topline results showed weak efficacy: none of the two doses in the STARSHINE phase 3 trial reached the primary endpoint (see 30 Sept news). Negative findings from the STARBEAM and STARBRIGHT trials were presented at the 2017 AAIC (Aug 2017 conference news), and Lundbeck announced in its 2017 annual report that the results “did not demonstrate efficacy to support a regulatory submission” and removed the drug from its pipeline. Complete results of all three trials were published in JAMA (Jan 2018 news).

For listed trials on Lu AE58054, see clinicaltrials.gov; some of the 2015 Phase 1 studies are registered under idalopirdine at clinicaltrials.gov.

Clinical Trial Timeline