Quantitative relationship between tominersen concentrations in cerebrospinal fluid and biomarker changes in Huntington's disease patients

Abstract

Aim: Intrathecally administered antisense oligonucleotide tominersen aims to slow Huntington's disease progression by lowering mutant huntingtin (mHTT) protein levels. This study used non-linear mixed effects population pharmacokinetic and pharmacodynamic (PKPD) modelling to characterize the relationship between tominersen concentration in cerebrospinal fluid (CSF) and CSF mHTT reduction. Additionally, the relationship between tominersen CSF exposure and changes in other CSF biomarkers was investigated to understand tominersen's pharmacodynamic profile. Finally, PKPD model simulations were conducted to inform the dose selection in the GENERATION HD2 study. Methods: Data from four clinical studies, including 915 participants receiving placebo or tominersen doses (30–120 mg) every 4, 8 or 16 weeks for up to 25 months, were used to develop the PKPD model. The model was utilized to predict tominersen CSF exposure metrics for individual patients in the GENERATION HD1 study for the exposure–response (ER) analysis and to simulate the PK and PD profiles for lower doses. Results: An indirect-response model described the relationship between tominersen CSF concentration and mHTT reduction, estimating a half-maximal inhibitory concentration (IC50) of 4.18 ng/mL. The ER analysis revealed that the highest exposure quartile showed a 54% mHTT reduction at steady state and transient elevations in biomarkers of neuroinjury and inflammation. In contrast, the lowest exposure quartile had a 24% mHTT reduction and a favourable biomarker profile. Conclusions: The PKPD model quantitatively confirms the relationship between tominersen exposure and CSF mHTT lowering. The ER analysis suggests that lower tominersen exposure levels may offer a better benefit–risk profile.