In the combined double-blind and open-label extension periods, plasma neurofilament light levels were lower in those on teriflunomide and were prognostic of relapse or MRI activity.
Jens Kuhle, MD, PhD
Post-hoc findings from the phase 3 TERIKIDS study (NCT02201108) of teriflunomide (Aubagio; Sanofi) in children with relapsing multiple sclerosis (MS) showed that treatment with the disease-modifying therapy resulted in significant reductions in plasma neurofilament light (pNfL) levels, a biomarker of axonal damage.
TERIKIDS was a 96-week, multicenter, multinational, randomized, double-blind (DB), placebo-controlled, parallel-group study assessing teriflunomide in pediatric relapsing MS, followed by a 96-week open-label extension (OLE). Despite similar least square mean pNfL levels observed at baseline, over the combined DB and OLE periods, the values were significantly lower in patients on teriflunomide vs placebo (week 192: 10.61 vs 17.32 pg/mL; P <.01).
Lead investigator Jens Kuhle, MD, PhD, senior physician and head of the Multiple Sclerosis Centre at University Hospital Basel, and colleagues concluded that, "Further investigation is warranted on the utility of pNfL as a biomarker for monitoring disease activity and treatment effects in clinical practice."
From the original patient cohort, 111 (67%) individuals volunteered to participate in the substudy and had available measurements. This included 33 patients from the placebo arm and 78 patients from the teriflunomide arm. Plasma NfL was measured using the single-molecular Simoa array immunoassay, with a calibration range of 500-0.167 pg/ml. All samples were briefly centrifuged to pellet aggregates and the clear supernatant was diluted at least 4-fold in sample diluent and plated into 96 well microtiter plates that were processed in a Quanterix HD-X Analyzer.
Baseline demographic and disease characteristics were similar to the overall trial population, with patients in the substudy followed up for a median of 193 (interquartile range [IQR], 191.1-196.1) weeks. In the DB period, pNfL levels for placebo increased to week 24 before decreasing at week 36, by which time 10 of the 33 patients on placebo (30.3%) compared with 12 of the 78 patients on teriflunomide (15.4%), had transferred early to the OLE after experiencing relapse or high MRI activity. Notably, week 24 of the DB showed the greatest between-group differences in pNfL values, with a geometric least square means ratio (GLSMR) of 0.74 (95% CI, 0.53-1.05; P = .09) for teriflunomide vs placebo.
At 5 of the 6 time points during the OLE, pNfL values differed significantly between the 2 treatment groups, with GLSMRs for teriflunomide/teriflunomide vs placebo/teriflunomide ranging from 0.61 to 0.65. In exploratory analyses that included adjustment for MRI lesion counts at DB week 24, the GLSMR at DB week 24 for teriflunomide versus placebo was attenuated from 0.74 in the main analysis, to 0.98 and 1.00, after including Gd-enhancing lesion and new/enlarged T2 lesion counts as covariates, respectively.
After adjusting for DB week 24 gadolinium-enhancing lesion and new/enlarged T2 lesion counts, investigators observed attenuated GLSMRs in the OLE at each time point, ranging from 0.74 to 0.94 and 0.76 to 0.96, respectively. None of these analyses were significant. Sensitivity analyses that adjusted for sex and region also showed results that were similar to the main analysis.
In analyses of prospective outcomes, each doubling of baseline pNfL was associated with an increased hazard of high MRI activity of clinical relapse for all patients during the DB period (hazard ratio, 1.22; 95% CI, 1.01-1.48; P = .04). The associations between baseline pNfL level and all other prospective outcomes did not reach statistical significance, regardless of whether patients were on teriflunomide or placebo.