To develop a pharmacokinetic/pharmacodynamic (PK/PD) strategy for the antisense oligonucleotide (ASO) RG6042, enabling dose selection for clinical efficacy in trials.

Huntington’s disease (HD) is a fatal, hereditary, neurodegenerative disease caused by mutant huntingtin protein (mHTT). Roche is developing an ASO, administered intrathecally, which reduces mHTT levels and leads to sustained reversals of deficits in motor performance from mHTT tissue reduction between 30–60% in disease models. Dose selection to reduce mHTT in tissue to levels associated with clinical efficacy is critical. However, mHTT levels cannot be measured in the brains of HD patients; cerebrospinal fluid (CSF) levels must be used. The time course of CSF mHTT lowering in humans is also unknown.

Translational PK/PD models were developed based on PK/PD studies conducted in transgenic mice models and Cynomolgus monkeys. PK was scaled from monkeys to human while similar PD was assumed across species. The PK/PD model was updated with Phase I data to support dose selection for the pivotal study for RG6042 (GENERATION HD1), which has monthly and bimonthly arms.

The translational PK/PD model was used to define the RG6042-induced reductions of 35–50% in CSF mHTT protein anticipated to produce clinical benefit in patients. The PK/PD model updated with clinical Phase I data identified doses and regimens predicted to achieve the defined mHTT CSF target reductions. To address the remaining uncertainty about the relationship between dose and CSF mHTT lowering needed for clinical benefit, the development program includes a dedicated study aiming to characterize the concentration–time profile of mHTT and its relationship to RG6042 PK in CSF.

RG6042 PK/PD data analysis identified doses predicted to result in clinical benefit in patients. The development program aims to further characterize this PK/PD relationship to inform future dose and regimen decisions.