Use of a Biomarker in Exposure–Response Analysis to Support Dose Selection for Fingolimod

Fingolimod 0.5 mg q.d. (once daily) has been approved for the treatment of patients with relapsing and remitting forms of multiple sclerosis (RRMS). Fingolimod at two doses (0.5 and 1.25 mg) showed superior effectiveness in the frequency of relapse with little difference between the two dose groups. At the same time, fingolimod manifests a number of dose-dependent adverse events. Given the safety concerns and similar effect size at both dose groups, it was reasonable to raise the question whether doses even lower than 0.5 mg would produce sufficient effectiveness. Therefore, our analysis focused on estimating the effect size of the primary endpoint at doses lower than 0.5 mg via exposure–response analysis. Specifically, we aim to show how biomarker data can be used as a bridge in exposure–response analysis to estimate the clinical endpoint response at certain doses when the direct relationship between exposure and the clinical endpoint can not be quantified reliably.