Crenezumab exposure-response across Alzheimer’s Disease endpoints supports a higher dose for Phase 3
Dan Polhamus (2), James Rogers (2), Robert Paul (1), Smita Kshirsagar (1), Srikumar Sahasranaman (1), Jin Y Jin (1), Angelica L Quartino (1)
(1) Genentech, San Francisco, CA, USA (2) Metrum Research Group, Tariffville, CT, USA
Objectives: Crenezumab is an antibody to treat Alzheimer’s Disease (AD). Two Phase 2 studies in mild-to-moderate AD patients evaluated a high 15 mg/kg IV Q4W dose and a low 300 Q2W SC dose.In both Phase 2 studies, crenezumab was well-tolerated with only one case of ARIA-E across both studies. The aim of this analysis was to characterize the exposure-response of Crenezumab to support the Phase 3 dose
Methods: A disease progression model for mild to moderate AD was established that described the longitudinal changes of the clinical endpoints ADAS-Cog and CDR sum-of-boxes (CDR-SB) simultaneously for patients in the Phase 2 studies. The model was extended to describe the effect of covariates on disease progression, and the effect of crenezumab on each endpoint. Clinical trial simulations (CTS) of the Phase 3 study across a range of doses were done, to compute the likelihood of achieving a percent relative reduction of disease progression in treated patients compared to placebo for ADAS-Cog and CDR-SB.
Results: Model validation demonstrated that the model replicated the Phase 2 longitudinal data accurately and is fit for purpose for simulation. The analysis showed faster disease progression in patients with moderate AD disease (lower baseline MMSE), ApoE4 positive genotype, female gender, and younger age. A relationship was seen between crenezumab exposure and treatment effect, which appeared to asymptote at the higher end of the range of exposures measured in Phase 2. Crenezumab treatment effect was associated with high baseline MMSE and ApoE4 positive genotype supporting better treatment effect in patients with mild AD. Compared to 15 mg/kg Q4W dose, a 4-fold increase to 60 mg/kg Q4W dose in Phase 3 is predicted to achieve a 41% greater relative reduction on ADAS-Cog, and 44% on the CDR-SB in the mild AD population.
Conclusions: A 60 mg/kg Q4W dose was selected for Phase 3 (NCT02353598), supported by a drug-disease model for mild to moderate AD. The model adequately summarized longitudinal progression in ADAS-Cog and CDR items, preserving correlation between the endpoints. CTS suggest substantially increased efficacy at higher exposures in patients with mild AD. As the model was trained on Phase 2 dosing, uncertainty in the predicted efficacy increases with increasing exposure where exposure falls outside that observed in Phase 2.