No evidence of disease activity: indirect comparisons of oral therapies for the treatment of relapsing-remitting multiple sclerosis

Abstract

Introduction: No head-to-head trials have compared the efficacy of the oral therapies, fingolimod, dimethyl fumarate and teriflunomide, in multiple sclerosis. Statistical modeling approaches, which control for differences in patient characteristics, can improve indirect comparisons of the efficacy of these therapies.

Methods: No evidence of disease activity (NEDA) was evaluated as the proportion of patients free from relapses and 3-month confirmed disability progression (clinical composite), free from gadolinium-enhancing T1 lesions and new or newly enlarged T2 lesions (magnetic resonance imaging composite), or free from all disease measures (overall composite). For each measure, the efficacy of fingolimod was estimated by analyzing individual patient data from fingolimod phase 3 trials using methodologies from studies of other oral therapies. These data were then used to build binomial regression models, which adjusted for differences in baseline characteristics between the studies. Models predicted the indirect relative risk of achieving NEDA status for fingolimod versus dimethyl fumarate or teriflunomide in an average patient from their respective phase 3 trials.

Results: The estimated relative risks of achieving NEDA status for fingolimod versus placebo in a pooled fingolimod trial population were numerically greater (i.e., fingolimod more efficacious) than the estimated relative risks for dimethyl fumarate or teriflunomide versus placebo in each respective trial population. In indirect comparisons, the predicted relative risks for all composite measures were better for fingolimod than comparator when tested against the trial populations of those treated with dimethyl fumarate (relative risk, clinical: 1.21 [95% confidence interval 1.06-1.39]; overall: 1.67 [1.08-2.57]), teriflunomide 7 mg (clinical: 1.22 [1.02-1.46]; overall: 2.01 [1.38-2.93]) and teriflunomide 14 mg (clinical: 1.14 [0.96-1.36]; overall: 1.61 [1.12-2.31]).

Conclusion: Our modeling approach suggests that fingolimod therapy results in a higher probability of NEDA than dimethyl fumarate and teriflunomide therapy when phase 3 trial data are indirectly compared and differences between trials are adjusted for.

Figures

Fig. 1

Schematic of the modeling approach. aFinal models selected baseline characteristics that were most predictive of the outcome using a stepwise algorithm that used the Akaike information criterion as the metric to retain the best model. FREEDOMS FTY720 research evaluating effects of daily oral therapy in multiple sclerosis, RR relative risk

Fig. 2

RRs of achieving NEDA status for fingolimod, DMF and teriflunomide versus placebo. Estimated RRs for the pooled FREEDOMS population, pooled DEFINE and CONFIRM population, and TEMSO populations are shown as solid lines as indicated (estimated). Dashed lines represent the predicted RRs for fingolimod versus placebo in alternative trial populations using the final models (predicted). An RR above 1.0 indicates an improved outcome for treatment relative to placebo. CONFIRM comparator and an oral fumarate in relapsing–remitting multiple sclerosis, DEFINE determination of the efficacy and safety of oral fumarate in relapsing–remitting multiple sclerosis, DMF dimethyl fumarate, FREEDOMS FTY720 research evaluating effects of daily oral therapy in multiple sclerosis, MRI magnetic resonance imaging, NEDA no evidence of disease activity, RR relative risk, TEMSO teriflunomide multiple sclerosis oral

Fig. 3

Impact of baseline characteristics on predicted RRs for fingolimod versus placeboa (final model). An RR above 1.0 indicates an improved outcome for treatment relative to placebo. aFor non-categorical covariates, the model predicts the treatment effect for setting that variable at the 1st and 3rd quartile of the distribution while holding all other covariates constant. bVolume of T2 lesions at baseline was not included in the initial model for the teriflunomide analysis, and EDSS-defined progression was reported differently (0–3.5 instead of 0–1.5 in the DMF analysis). BL baseline, DMF dimethyl fumarate, EDSS expanded disability status scale, Gd gadolinium, MRI magnetic resonance imaging, MS multiple sclerosis, NEDA no evidence of disease activity, RR relative risk

Fig. 4

Indirect comparison of RRs of achieving NEDA status for fingolimod versus DMF or teriflunomide. An RR above 1.0 indicates an improved outcome for fingolimod relative to comparator. Indirect comparisons were performed using estimated RR for fingolimod in a pooled FREEDOMS and FREEDOMS II population (solid lines, estimated) or using predicted RRs for fingolimod in a pooled DEFINE and CONFIRM or TEMSO population (dashed line, predicted). CONFIRM comparator and an oral fumarate in relapsing–remitting multiple sclerosis, DEFINE determination of the efficacy and safety of oral fumarate in relapsing–remitting multiple sclerosis, DMF dimethyl fumarate, FREEDOMS FTY720 research evaluating effects of daily oral therapy in multiple sclerosis, MRI magnetic resonance imaging, NEDA no evidence of disease activity, RR relative risk, TEMSO teriflunomide multiple sclerosis oral