D009 Exposure dependent changes in CSF fluid biomarkers following tominersen treatment in generation HD1

<h3>Background</h3> Tominersen is an antisense oligonucleotide that lowers huntingtin (HTT) protein. GENERATION HD1 (HD1) is a Phase III study where post-hoc analyses identified potential benefit in younger individuals with less disease burden at lower tominersen exposure. The lower exposure level from HD1 is targeted in GENERATION HD2 (HD2) which is an ongoing Phase II study. <h3>Aim</h3> The aim was to quantitatively characterize the relationship between tominersen CSF concentration (PK) and mutant HTT protein (mHTT) reduction and to investigate the relationship between PK exposure and CSF fluid biomarkers (BM) from HD1 data. <h3>Methods/Techniques</h3> Non-linear mixed effects analysis was performed to develop a population pharmacokinetic and pharmacodynamic (popPKPD) model. In total, 915 participants from four clinical studies with placebo or tominersen doses of 30-120 mg Q4W, Q8W and Q16W up to 25 months treatment were used for the model development. The exposure-response (ER) analysis graphically investigated the relationship between the model predicted individual PK exposure and BM. <h3>Results/Outcome</h3> The relationship between PK and mHTT reduction was adequately described by an indirect response model, where PK inhibits the production rate of mHTT through an Imax model (IC50 was 4.18 ng/mL). The ER analysis showed that elevations in total protein, NfL, YKL-40, total Tau and GFAP seen at the highest exposures were avoided at the lowest exposures; where trends were seen below placebo. <h3>Conclusions</h3> The popPKPD model quantitatively confirmed the target engagement of tominersen by lowering mHTT. The ER analysis further supported exploring the lower tominersen exposure which is targeted in HD2.