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

Abstract

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.

Effect of ceralifimod (ONO‐4641) on lymphocytes and cardiac function: Randomized, double‐blind, placebo‐controlled trial with an open‐label fingolimod arm

“…CD4þ T cells are generally considered central to MS pathogenesis. 14,[16][17][18] NK cells were not affected by any of the active treatments in the current study. It is important to note that the S1P5 receptor is the most prominent receptor on NK cells in rodents and humans.…”

“…The most pronounced effect of both ceralifimod and fingolimod was seen in CD19 (B cells), CD4+ (T‐helper cells), and CD4+/CD25(high) cells. CD4+ T cells are generally considered central to MS pathogenesis . NK cells were not affected by any of the active treatments in the current study.…”

“…The optimal level of lymphocyte reduction with MS therapy is currently unknown, as is whether there are differences in the optimal reduction between different S1Pn receptor modulators. Results of a biomarker/response model suggested that lymphocyte reduction by >70% may be associated with efficacy for fingolimod . The DreaMS study showed that even a 40% reduction in lymphocyte count was associated with positive MRI outcomes with ceralifimod 0.05 mg. Preclinical models that tested both ceralifimod and fingolimod head to head suggested that there may be compound differences, for example, less lymphopenia is required for ceralifimod to obtain comparable efficacy .…”

Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1receptor modulator: Favorable impact of dose up-titration

“…With a dose of 40 mg ponesimod, total lymphocyte counts were reduced by more than 80%. It has been postulated recently that, based on a modeled dose–response relationship, lower doses of fingolimod than the one currently marketed (0.5 mg) may still be efficacious . A relationship between clinical efficacy and lymphocyte count reduction has as yet not been established for fingolimod.…”

Pharmacometric Analysis of the Relationship Between Absolute Lymphocyte Count and Expanded Disability Status Scale and Relapse Rate, Efficacy End Points, in Multiple Sclerosis Trials

“…Blood samples used for ALC measurements were collected at screening, study day 1 (SD1) and at weeks 5,9,13,24,44,48,52,72, and 96 during the CLARITY study and at screening, SD1, and at weeks 2, 5,9,13,16,24,36,44,48,52,55,60,66,72,78,84, and 96 during the CLARITY EXT study. Blood samples were also collected during 24-week follow-up period at day 1 and weeks 13 and 24.…”