Multiple Rising Doses of Oral BI 425809, a GlyT1 Inhibitor, in Young and Elderly Healthy Volunteers: A Randomised, Double-Blind, Phase I Study Investigating Safety and Pharmacokinetics

Abstract

Background and ObjectiveSchizophrenia and Alzheimer’s disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-d-aspartate receptor hypofunction. Glycine is an N-methyl-d-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-d-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers.MethodsPart 1 evaluated BI 425809 10, 25, 50 or 75 mg once daily or 75 mg twice daily in young subjects, and 25 mg or 50 mg once daily in elderly subjects. Each dose group comprised 12 subjects who received BI 425809 (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; days 4–14: multiple dosing). Part 2 compared pharmacokinetic profiles in 12 subjects who received a single dose of BI 425809 25 mg in the morning and evening.ResultsPharmacokinetic profiles were similarly shaped for all dose groups. Median time to maximum plasma concentration was 3.0–4.5 h with steady state being reached between days 6 and 10. Pharmacokinetic parameters demonstrated dose linearity at the predicted therapeutic exposure range of BI 425809 ≤ 25 mg once daily, but increased less than dose proportionally for ≥ 50 mg once daily. All reported adverse events were of mild-to-moderate intensity, 51/84 (61%; part 1) subjects had one or more treatment-related adverse event, no serious adverse events occurred and no dose dependency was observed.ConclusionsPharmacokinetic properties support both morning and evening dosing. BI 425809 was generally well tolerated at all tested doses.Clinicaltrials.gov identifierNCT02337283.Electronic supplementary materialThe online version of this article (10.1007/s40261-018-0660-2) contains supplementary material, which is available to authorized users.

Evaluation of Pharmacokinetics and Pharmacodynamics of BI 425809, a Novel GlyT1 Inhibitor: Translational Studies

“…BI 425809 is a novel potent and selective GlyT1 inhibitor being developed for the treatment of cognitive impairment associated with schizophrenia and AD . It has previously been observed that the half‐life value of BI 425809 is ~40 hours, consistent with attainment of steady state within 8 days after administration . The objective of the preclinical study described here was to characterize the potency and selectivity of BI 425809, and its effects on glycine concentration in rat cerebrospinal fluid (CSF).…”

“…6,7 It has previously been observed that the half-life value of BI 425809 is ~40 hours, consistent with attainment of steady state within 8 days after administration. 6,8 The objective of the preclinical study described here was to characterize the potency and selectivity of BI 425809, and its effects on glycine concentration in rat cerebrospinal fluid (CSF). To translate this preclinical study into humans, BI 425809 was further evaluated in a phase I study with healthy volunteers.…”

Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia

“…Furthermore, BI 425809 was recently developed by Boehringer Ingelheim as a novel, investigational GlyT1 inhibitor to improve cognitive function and memory in patients with schizophrenia and Alzheimer's disease (224)(225)(226). A recent randomized doubleblind, placebo-controlled phase II study revealed that BI 425809 improved cognitive functions after 12 weeks in patients with schizophrenia (215), suggesting that BI 425809 can provide an effective treatment for cognitive impairment associated with schizophrenia.…”

Evaluation of the Efficacy of BI 425809 Pharmacotherapy in Patients with Schizophrenia Receiving Computerized Cognitive Training: Methodology for a Double-blind, Randomized, Parallel-group Trial

“…Glycine is an obligatory co-agonist for NMDA receptor activation; inhibitors of synaptic glycine uptake are therefore thought to enhance NMDA receptor signaling [29] and may promote downstream plasticity processes [30]. BI 425809 is generally well tolerated in healthy volunteers, and the most commonly reported adverse events (AEs) in Phase I studies included headache, back pain, nausea, vomiting, and neck pain [31,32]. A Phase II clinical proof-of-concept and dose-finding study investigating the potential benefits of BI 425809 as add-on therapy to standard of care for CIAS in patients with schizophrenia is currently underway (NCT02832037).…”