Exposure–disease response analysis of natalizumab in subjects with multiple sclerosis

Natalizumab, a human immunoglobulin monoclonal antibody that targets α4β1/α4β7 integrin, is an effective therapy approved for the treatment of multiple sclerosis (MS). The objective of this analysis was to develop a population exposure–response model utilizing gadolinium-enhancing (Gd) lesion count data from four clinical studies and annualized relapse rate (ARR) data from three clinical studies. The natalizumab exposures were derived for the individuals using a population pharmacokinetic model. A log-linear exposure effect on Gd lesion count and ARR adequately characterized the relationship between exposure and disease response. In the case of the Gd lesion count model, a bimodal model that distributed subjects into two subpopulations based on low or high baseline Gd lesion count provided a superior goodness of fit. The mean (95% confidence interval) slopes from the exposure–Gd lesion count model and exposure-ARR model are −0.0903 (−0.100, −0.081) and −0.0222 (−0.026, −0.015) (mg/L)−1, respectively. From these slopes, it can be inferred that both Gd lesion count and ARR decrease with increasing exposure to natalizumab in MS subjects. Model-based simulations demonstrated that although reductions in Gd lesion count and ARR were observed with lower doses (75, 150, or 200 mg), only the dose of 300 mg every 4 weeks (q4w) was associated with an ARR ≤0.25 and was considered clinically effective. The results from the exposure-Gd lesion count and exposure-ARR models thus support the appropriateness of the approved natalizumab dose (300 mg q4w) in MS subjects.