Background

This compound is a glycine transporter inhibitor that was being develped for the treatment of Alzheimer's disease, then discontinued; it remains in development for schizophrenia. The rationale behind this approach is that abnormalities in glutamatergic signaling downstream of neuronal NMDA receptors contribute to cognitive impairment in both these diseases, hence boosting NMDA receptor function might benefit synaptic plasticity and cognition (Lakhan et al., 2013; Rosenbrock et al., 2022). The amino acid neurotransmitter glycine is an obligatory NMDA receptor co-agonist. Glycine transporters GlyT-1 and GlyT-2 located in presynaptic and astrocyte membranes take up glycine into the nerve terminal and adjacent glial cells, thus modulating glycine levels in the synaptic cleft (Hashimoto, 2010). By blocking these receptors, BI 425809 is proposed to increase glycine levels and its ability to modulate NMDA receptor function. No preclinical data related to Alzheimer’s are published on this compound.

Findings

In March 2014, Boehringer Ingelheim started up a series of Phase 1 trials—seven as of May 2018—to evaluate the safety, bioavailability, and pharmacokinetics of BI 425809, as well as its potential interactions with commonly used drugs. These trials were conducted in 298 young and elderly men and women in Germany, Belgium, and Korea. Single- and multiple-ascending-dose results were reported as showing BI 425809 to be generally well-tolerated and suitable for once-daily dosing (Moschetti et al., 2016; Moschetti et al., 2018). In one multiple-dosing study, healthy volunteers showed a dose-dependent increase in CSF glycine by an average of 50 percent two weeks after the last administration (Rosenbrock et al., 2018). Detailed pharmacokinetic and safety data from a study in 83 healthy men were reported as showing safety and tolerability within the target dose range of up to 25 mg. Higher doses generate adverse events previously reported for glycine reuptake inhibition, such as drowsiness, fatigue, vertigo, blurred vision (Moschetti et al., 2018; Hirayasu et al., 2016). Pharmacokinetics and safety were similar in Caucasian, Chinese, and Japanese adults (Tsuda et al., 2019).

In August 2016, a Phase 2 study started comparing 2, 5, 10, or 25 mg daily doses of BI 425809 to placebo, taken for three months, in 610 people with early signs of Alzheimer's dementia. The primary outcome was change on the ADAS-Cog11; secondary outcomes were change on the ADCS-ADL and CIBIC+ scales. The trial made no use of biomarkers. It took place at 27 sites in North America, Austria, Finland, France, Germany, Greece, Hungary, and Spain. The study was completed in October 2019. In February 2020, Boehringer Ingelheim announced that top-line data indicated the trial was negative and that further development for Alzheimer's had stopped (press release). Data presented at the July 2020 AAIC showed that the drug had not improved cognition on any of the primary or secondary measures compared with placebo at any dose. The results were published after peer review (Wunderlich et al., 2023).

For all trials of this compound, see clinicaltrials.gov.

Clinical Trial Timeline