Early stage development of the glycine‐1 re‐uptake inhibitor SCH 900435: central nervous system effects compared with placebo in healthy men

Abstract

AIMSTo report the first three studies with SCH 900435, a selective glycine-1 re-uptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects. METHODSThree double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the single and multiple dose study SCH 900435 (0.5-30 mg) was given to healthy males and frequent pharmacokinetic and pharmacodynamic measurements were performed. The visual effects study incorporated visual electrophysiological measures of macular, retinal and intracranial visual pathway function. RESULTSIn the single dose study (highest difference, 95% CI, P) increases in smooth pursuit eye movements (8, 12 mg (-6.09, 10.14, -2.04, 0.013), 30 mg), pupil : iris ratio (20 and 30 mg (-0.065, 0.09, -0.04, <0.0001)), VAS colour perception (30 mg (-9.48, 13.05, -5.91, <0.0001)) and changes in spontaneous reports of visual disturbance were found, while FSH (8 mg (0.42, 0.18, 0.66, 0.0015), 12, 20 mg), LH (8-30 mg (1.35, 0.65, 2.05, 0.0003)) and EEG alpha2 activity decreased (12, 20, 30 mg (0.27, 0.14, 0.41, 0.0002)). A subsequent dedicated visual effects study demonstrated that visual effects were transient without underlying electrophysiological changes. This provided enough safety information for starting a multiple ascending dose study, showing less visual symptoms after twice daily dosing and titration, possibly due to tolerance. CONCLUSIONSSeveral central nervous system (CNS) effects and gonadotropic changes resulted from administration of 8 mg and higher, providing evidence for CNS penetration and pharmacological activity of SCH 900435. Antipsychotic activity in patients, specificity of the reported effects for this drug class and possible tolerance to visual symptoms remain to be established.

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

“…Selective GlyT1 inhibition results in increased synaptic glycine levels, which may be favourable for the treatment of cognitive impairment associated with schizophrenia and AD [ 5 – 7 ]. Increases in glycine levels, however, have been associated with visual disturbances and electroretinogram alterations [ 19 , 20 ]. Inhibition of the GlyT1 transporter in the rat retina leads to electroretinogram alterations, which may explain the visual disturbances reported in clinical trials with GlyT1 inhibitors [ 20 ].…”

Efficacy and safety of the novel GlyT1 inhibitor BI 425809 in Alzheimer’s dementia: a randomized controlled trial

“…No meaningful differences between the treatment groups or dose dependencies were observed. Transient visual disturbances and central nervous system side effects have previously been noted for GlyT1 inhibitors [ 23 , 24 ]. However, again, within the SOC ‘eye disorders’, no meaningful differences between the treatment groups were observed, and the frequency of ‘visual impairment’ and ‘dyschromatopsia’ was consistent with previous work on BI 425809 [ 24 ].…”

Further characterization of the GlyT-1 inhibitor Org25935: anti-alcohol, neurobehavioral, and gene expression effects

“…Org25935 has demonstrated long-lasting alcohol intake reducing properties in rodent models with effects superior to most drug candidates for AUD (Spanagel and Kiefer 2008 ). The compound has a good safety profile and neither animal investigations nor human studies indicate a positive hedonic profile (Liem-Moolenaar et al 2013 ). However, the attempt to translate these promising results to AUD patients failed; the proof of concept trial was aborted before completion due to futility in the interim analysis (see last section).…”