Baseline neurofilament light levels were associated with future disability progression and degree of brain atrophy regardless of the presence or absence of acute disease activity.
In a post hoc blinded analysis of 2 phase 3 trials of patients with progressive multiple sclerosis (MS), investigators found that plasma neurofilament light (pNfL) levels were associated with future disability progression, cognitive decline, and brain volume loss in a setting with little or no signs of acute disease activity at baseline.1
Using the pivotal EXPAND study (NCT01665144) of secondary progressive MS (SPMS) and the INFORMS study (NCT00731692) of primary progressive MS (PPMS), higher baseline pNfL levels were associated with older age, higher Expanded Disability Status Scale (EDSS) score, more gadolinium-enhancing (Gd+) lesions, and higher T2 lesion load (all P <.05). Based on these findings, lead investigator David Leppert, MD, professor of neurology, University of Basel, and colleagues concluded that pNfL may be a potential efficacy end point in early treatment trials in progressive MS.
"The early clinical development of PMS [progressive MS] could benefit from sensitive and dynamic phase 2 end point measures which are better associated with the clinical outcomes of interest than currently established clinical and MRI tools,” Leppert et al wrote. “Based on the observation of a prognostic effect of pNfL for brain volume change and disability outcomes in our study, and given that treatment effects on pNfL can be shown by relatively smaller samples sizes, if anticipated treatment effects are larger, pNfL could be a plausible and feasible biomarker in progressive MS. Moreover, pNfL measurements are minimally invasive and relatively inexpensive."1
In the analysis, a total of 4185 samples from 1452 patients with SPMS and 1171 samples from 378 patients with PPMS were quantified using the single molecule array homebrew Simoa immunoassay. They represented 88% and 39% of patients enrolled overall in retrospective studies. pNfL levels, categorized as either high (≥30 pg/mL) or low (<30 pg/mL) at baseline, were higher in those with SPMS (geomean, 32.1 pg/mL) than those with PPMS (22.0 pg/mL; P <.0001) at baseline.
On linear regression models, high baseline pNfL levels were strongly and independently associated with high baseline T2 lesion volume, indicated by 0.7% and 1.4% higher levels per cm3 T2 lesion in patients with SPMS and PPMS, respectively. These levels were also associated with relapses in the previous 2 years in the SPMS group, but were not associated with factors such as gender, disease duration, normalized brain volume, and prior treatment.
Risk of time to 3-month confirmed disability progression (3mCDP) was increased by 32% and 49% in the SPMS and PPMS groups, respectively, with higher pNfL levels. When stratified by treatment group in EXPAND, high baseline pNfL levels in the siponimod group, the study drug being used, were associated with greater risk of 3mCDP events (hazard risk [HR], 1.32; 95% CI, 1.03-1.69; P = .0312). Additionally, high pNfL levels were associated with a 26% and 48% increased risk for 6-month CDP (6mCDP) in SPMS (P = .0417) and in PPMS (P = .0431), respectively.
In patients with PPMS, the risk of wheelchair dependence, demonstrated by scores of at least 7 on the EDSS, was increased by 197% in patients with high baseline pNfL (P = .0031). In the SPMS group, high baseline pNfL levels were associated with a risk of wheelchair dependence that was numerically 50% higher than those with low pNfL (P = .0737). Overall, investigators found no significant association between treatment and pNfL, suggesting that “pNfL was prognostic of disability progression independent of therapy," they wrote.
Baseline pNfL levels also showed an effect on rates of brain volume in both the SPMS and PPMS patients populations. At months 12 and 24, this association was sustained in those without Gd+ lesions at baseline. Investigators also observed more pronounced brain atrophy at the same time points in patients with SPMS who had high baseline pNfL levels regardless of pre-baseline relapses.
At months 12, 24, and 36, treatment with siponimod and fingolimod reduced pNfL levels significantly relative to placebo in both populations. A combination of high pNfL and age remained the strongest prognostic factors of high pNfL at the end of the study; this was also the case for high T2 lesion volume at baseline, as well as occurrence of new or enlarging T2 lesions during the studies. “Noteworthy, patients with a 6mCDP event during the EXPAND study had a 9% higher pNfL level at end of study, independent of clinical or MRI activity during the trial,”1 the investigators pointed out.