Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile x syndrome.

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics (PK) and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding in period 1 of the study, participants who received BPN14770 in the period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

A Randomized Phase 1 Evaluation of Deupirfenidone, a Novel Deuterium-Containing Drug Candidate for Interstitial Lung Disease and Other Inflammatory and Fibrotic Diseases.

LYT-100 (deupirfenidone) is a selectively deuterated form of pirfenidone under development for the treatment of inflammatory and fibrotic diseases, including interstitial lung disease. Adverse events associated with antifibrotics can be a barrier to adoption and persistence in patients with interstitial lung diseases, most of whom are not on standard-of-care therapy. LYT-100 is designed to have a differentiated pharmacokinetic (PK) profile from pirfenidone and could offer a differentiated safety profile compared to current standard-of-care drugs while retaining the biochemical potency and specificity of pirfenidone. We conducted a phase 1b study to ascertain the safety, tolerability, steady-state PK profile, and food effect of LYT-100. This was a 2-part study. Part 1 assessed multiple ascending doses of LYT-100 from 100, 250, 500, 750, and 1000 mg twice daily given over 5 days without titration. Part 2 assessed the effects of fed vs fasting conditions on the PK profile of a single 500-mg dose of LYT-100. All doses up to 1000 mg were well tolerated, with adverse events being mild and transient. Exposure was slightly lower in the fed condition. LYT-100 was well tolerated and has a dose-proportional PK profile. The ratio of parent to major metabolite concentration was higher than reported with pirfenidone, which is consistent with an effect of deuteration on metabolism. No maximum tolerated dose was identified up to 1000 mg twice-daily dosing. These results support further clinical development of LYT-100, particularly considering the adverse event profile of current standard-of-care drugs.

Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial.

The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.

Study of the population pharmacokinetic characteristics of once-daily trospium chloride 60 mg extended-release capsules in patients with overactive bladder and in healthy subjects.

BACKGROUND: Overactive bladder is a common disorder that affects approximately 34 million adults in the United States. Anticholinergic (antimuscarinic) agents are the most widely used pharmacological option for overactive bladder. OBJECTIVE: This study set out to identify and characterize the influence of a number of intrinsic characteristics on the pharmacokinetics of the anticholinergic agent trospium chloride (Sanctura(®)) 60 mg extended release (XR), and to evaluate the correlation between trospium chloride exposure and key efficacy and safety outcomes in subjects and patients. STUDY DESIGN: Pharmacokinetic data were obtained from three studies in which a total of 349 subjects received trospium chloride XR for up to 12 weeks. Plasma trospium chloride concentration data were pooled and a population pharmacokinetic model was derived using non-linear mixed-effects modelling. Demographic factors were assessed for influence on the model. The correlation between trospium chloride exposure and key efficacy variables was evaluated. Correlations between exposure and safety outcomes were also assessed. INTERVENTION: Trospium chloride XR 60 mg once daily for 10 days in healthy volunteers or trospium chloride 60 mg XR once daily for either 2 weeks or 12 weeks in patients with overactive bladder. RESULTS: The best population pharmacokinetic model was determined to be a two-compartment model with zero-order release into the depot compartment and first-order absorption. Body surface area (BSA) was the only covariate to significantly (P < 0.05) impact trospium chloride 60 mg XR pharmacokinetics. Significant relationships (P < 0.05) were observed between exposure [maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve from time zero to 24 h (AUC(24))] and efficacy outcomes in the <65-year age group for change in average number of voids/day, change in number of incontinence episodes, and change in urgency severity, and in the ≥65-year age group statistical significance (P < 0.05) was achieved for C(max), but not for AUC(24), for these same three efficacy measures. Statistically significant relationships (P < 0.004) were also observed between exposure and both dry mouth and constipation, with increased benefit and increased incidence of adverse events (AEs) associated with higher concentrations; the correlation coefficients were low against the aggregate of AEs of interest (0.19 for AUC(24) and 0.18 for C(max)), indicating only mild strength of association. CONCLUSION: This population pharmacokinetic analysis demonstrated that the only demographic characteristic associated with trospium chloride pharmacokinetics was BSA. Thus, treatment of most patients with overactive bladder with once-daily trospium chloride 60 mg XR should not require consideration of key intrinsic demographic parameters. Furthermore, while efficacy and tolerability outcomes were found to be correlated with trospium chloride exposure, the strength of the association was modest in this study.

Effect of trospium chloride on somnolence and sleepiness in patients with overactive bladder.

An objective of a large US phase-3 study was to determine the effects of trospium chloride 20-mg tablets versus placebo, administered twice daily, on central nervous system (CNS) adverse events (eg, somnolence) and on daytime sleepiness using the validated Stanford Sleepiness Scale. The impact of age groups also was assessed. Trospium chloride did not increase daytime sleepiness or appear to produce CNS adverse effects, as measured by the Stanford Sleepiness Scale and the incidence of CNS adverse events. Furthermore, there was no difference in these findings across age groups.