Laura Boles 1, Alessandro Di Deo 1, Alison McMorn 2, Stuart Evans 2, Joseph Horrigan 2, Oscar Della Pasqua 1
1 Clinical Pharmacology & Therapeutics Group, University College London (UCL) (London, United Kingdom), 2 AMO Pharma, Ltd. (Leeds, United Kingdom)
Objectives. Tideglusib is an orally administered, brain-penetrant, irreversible inhibitor of glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase involved in multiple signalling pathways and highly expressed in muscle and central nervous system tissue [1]. It is formulated as an oral suspension and has been investigated as a treatment for myotonic dystrophy type 1 (DM1) [2]. Congenital DM1 (CDM1) is associated with significant morbidity and premature mortality, highlighting the need for effective therapies in paediatric patients [3]. The pharmacokinetics (PK) of tideglusib has been evaluated in multiple studies, including a Phase I trial in healthy elderly adults (NP03112-07A03) and a Phase II study in adolescents and adults with congenital and juvenile-onset DM1 (NCT02858908) [1]. A population PK model was initially developed in healthy elderly participants and subsequently updated with DM1 data [1]. Here, we present results from the Phase II/III trial (NCT03692312) in children and adolescents with CDM1. This analysis aimed to characterise the population PK of tideglusib following weight-adjusted 1000 mg once-daily dosing in children and adolescents with CDM1 and derive metrics of systemic exposure (e.g., Cmax, AUC0-24h) as basis for subsequent evaluation of the exposure-response relationships, as assessed by core measures of efficacy.
Methods. Tideglusib concentrations (N = 152) obtained from sparse blood sampling in 25 patients were available for the purpose of this analysis. The pharmacokinetics of tideglusib in children and adolescents with CDM1 was characterised using a previous PK model and priors from adolescents and adults with congenital and juvenile-onset DM1 supporting parameter estimation. Model diagnostics included goodness-of-fit plots, visual predictive checks, normalised prediction discrepancy error, and mirror plots. Individual predicted concentration-time profiles were then generated to derive secondary PK parameters. Given the irreversible binding of tideglusib to GSK-3β, Cmax was selected as the metric of exposure for the assessment of a putative correlation between concentration and efficacy measures. Subjects were categorised into three groups: those with Cmax above the 50th percentile, those with Cmax below the 50th percentile, and placebo. Key efficacy endpoints included the 10 m Walk/Run (preferred speed), Peabody Picture Vocabulary Test (PPVT), plasma creatine phosphokinase (CPK), and the Multi-Domain Responder Index (MDRI). Differences in median response between exposure groups and placebo were evaluated using both parametric (t-test) and non-parametric (Wilcoxon) tests. All modelling and simulation steps were implemented in NONMEM 7.5 and PsN 5.2.6. Data handling, graphical and statistical summaries were performed in R 4.1.2.
Results. The PK of tideglusib following oral administration was adequately described by a two-compartment model with first-order absorption and elimination. In addition to the effect dose on KA (≤400 mg and >400 mg), interindividual variability was assessed for CL, Q, V2, V3, and KA. Residual variability was best described using a proportional error model. Body weight was the primary demographic covariate influencing drug disposition and was incorporated using standard allometric scaling. Parameter estimates for CL, Q, V2, and V3 were 341 L/h, 986 L/h, 154 L, and 986 L, respectively. Diagnostic evaluations, including visual predictive checks, supported adequate model performance. Median (5th-95th percentiles) AUC0-24 and Cmax observed previously in adolescents and adults (3398.7 [1651.9-5287.1] ng·h/mL and 1170.9 [573.3–1450.1] ng/mL) were higher than in children and adolescents with CDM1 (1854.2 [540.3–3472.6] ng·h/mL and 617.1[230.9–1164.1] ng/mL). The assessment of the correlation between Cmax and response revealed clinically meaningful trends for subjects within the upper Cmax group for 10 m Walk/Run (-1.5 seconds) and PPVT (+12 points), while changes in CPK (-9%) and MDRI response rates were less pronounced.
Conclusions. The PK of tideglusib was adequately characterised after a weight-adjusted once-daily dosing regimen in children and adolescents with CDM1. Despite relatively lower exposure compared to adolescents and adults with congenital and juvenile DM1, this initial exploratory analysis of core measures of efficacy and markers of treatment effect showed clinically meaningful trends in 10 m Walk/Run and PPVT for subjects with higher Cmax, supporting continued clinical development of tideglusib for the treatment of CDM1.
References:
[1] Di Deo A, Oosterholt S, Horrigan J, Evans S, McMorn A, Della Pasqua O. Population Pharmacokinetics of Tideglusib in Congenital and Childhood Myotonic Dystrophy Type 1: Influence of Demographic and Clinical Factors on Systemic Exposure. Pharmaceutics. 2025 Aug 16;17(8):1065.
[2] Horrigan J, Gomes TB, Snape M, Nikolenko N, McMorn A, Evans S, et al. A Phase 2 Study of AMO-02 (Tideglusib) in Congenital and Childhood-Onset Myotonic Dystrophy Type 1 (DM1). Pediatric Neurology [Internet]. 2020 Nov 1 [cited 2023 Mar 15];112:84–93. Available from: https://pubmed.ncbi.nlm.nih.gov/32942085/
[3] Jain A, Al Khalili Y. Congenital Myotonic Dystrophy [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560518/
Reference: PAGE 34 (2026) Abstr 12116 [www.page-meeting.org/?abstract=12116]
Poster: Drug/Disease Modelling - Paediatrics