An exposure-response analysis of ponesimod clinical efficacy in a randomized phase III study in patients with relapsing multiple sclerosis

Abstract

The efficacy of ponesimod and teriflunomide for the treatment of relapsing multiple sclerosis (MS) was compared in a randomized phase III trial. This study explores the exposure-response (E-R) relationships of efficacy end points (annualized relapse rate [ARR] and combined unique active lesions [CUALs]) of ponesimod observed in this trial. The E-R relationships were described using nonlinear mixed effects models for count data. The effect of baseline covariates (demography and prognostic factors) was also explored. Ponesimod 20 mg reduced ARR (primary end point) by 30.5% (95% confidence interval [CI]: 9.8% to 46.4%) and the number of CUALs by 56% (95% CI: 46% to 64%) between baseline and week 108 compared to teriflunomide 14 mg. The E-R analyses indicated a significant relationship between ARR and CUAL. In turn, CUAL was significantly related to ponesimod systemic exposure. Based on these relationships, the predicted reduction of ARR was relatively flat in the range of ponesimod systemic exposure achieved with the 20 mg clinical dose: the expected ARR decrease ranged from 28% (95% CI: 11% to 42%) at the 5th percentile of ponesimod exposure to 34% (95% CI: 19% to 47%) at the 95th percentile. No significant baseline covariates affected the ponesimod effects and, consequently, dosage adjustments are not warranted by these analyses. Although significant relationships were found between ARR and CUAL and between ponesimod exposure and CUAL, these analyses were supportive of the use of a flat 20 mg maintenance dose for ponesimod in adult patients with MS.

Trial registration: ClinicalTrials.gov NCT02425644.

FIGURE 1

ARR distribution by treatment, AUC_ss category, and CUAL category. Observed means are shown as solid blue lines with mean and 95% CI in the legend. Orange histograms show predicted ARR means from the final ARR model. Solid orange lines represent the predicted overall mean and dashed lines represent the 95% prediction interval for the mean. ARR, annualized relapse rate; AUC_ss, area under the curve at steady‐state; CI, confidence interval; CUAL, cumulative number of combined unique lesions from baseline to week 108; mg, milligram; y, years

FIGURE 2

Graphical representation of the models linking ARR to CUAL and CUAL to ponesimod systemic exposure. (a) Observed and model‐predicted ARR versus CUAL, final model; points show observed mean ARR (±95% CI) categorized by CUAL quintiles, solid lines and shaded areas indicate typical behavior and 95% CI based on model uncertainty; teriflunomide arm is represented in orange while ponesimod is represented in blue. (b) Indirect relationship between ponesimod systemic exposure and ARR, based on the AUC_ss‐CUAL and CUAL‐ARR models, points show observed mean ARR (±95% CI) categorized by AUC_ss quintiles, solid lines and shaded areas indicate typical behavior and 95% CI based on model uncertainty. (c) Observed and predicted annualized CUAL by ponesimod AUC_ss; at the bottom, box plot of ponesimod AUC_ss. Points show observed mean (±95% CI) CUAL categorized by AUC_ss quintiles, solid lines and shaded areas indicate typical behavior and 95% CI based on model uncertainty. Teriflunomide arm is represented in orange (no teriflunomide exposure data were considered in this analysis; observed teriflunomide data are referred to AUC_ss = 0), whereas ponesimod is represented in blue. ARR, annualized relapse rate; AUC_ss, area under the curve at steady‐state; CI, confidence interval; CUAL, cumulative number of combined unique lesions from baseline to week 108

FIGURE 3

CUAL, stratified by treatment (left) and exposure (AUC_ss) (right). Observed distributions and means (solid line) in blue. Observed means and 95% CI in legend. Orange dashed lines show the predicted means and orange areas show the 95% prediction intervals of different counts based on the final model. AUC_ss, area under the curve at steady‐state; CI, confidence interval; CUAL, cumulative number of combined unique lesions from baseline to week 108