Blood neurofilament light as a potential endpoint in Phase 2 studies in MS.

Objectives: To assess whether neurofilament light chain (NfL) could serve as an informative endpoint in Phase 2 studies in patients with relapsing-remitting multiple sclerosis (RRMS) and estimate the sample size requirements with NfL as the primary endpoint.

Methods: Using data from the Phase 3 FREEDOMS study, we evaluated correlation of NfL at Month 6 with 2-year outcomes: relapses, confirmed disability worsening (CDW), new or enlarging T2 lesions (active lesions), and brain volume loss (BVL). We compared the proportion of treatment effect (PTE) on 2-year relapses and BVL explained by 6-month log-transformed NfL levels with the PTE explained by the number of active lesions over 6 months. We estimated sample size requirements for different treatment effects.

Results: At Month 6, blood NfL levels (pg/mL, median [range]) were lower in the fingolimod arm (fingolimod ( = 132) 18 [8-247]; placebo ( = 114) 26 [8-159],  < 0.001). NfL at 6 months correlated with number of relapses ( = 0.25,  < 0.001), 6-month CDW (hazard ratio 1.83,  = 0.012), active lesions ( = 0.46,  < 0.001), and BVL ( = -0.41,  < 0.001) at Month-24. The PTE (95% CI) on 24-month relapses and BVL explained by 6-month NfL was 25% (8-60%) and 60% (32-132%), and by 6-month active lesions was 28% (11-66%) and 45% (18-115%), respectively. Assuming a 20-40% treatment-related reduction in NfL levels, 143-28 patients per arm will be required.

Conclusions: Blood NfL may qualify as an informative and easy-to-measure endpoint for future Phase 2 clinical studies that captures both inflammatory- and noninflammatory-driven neuroaxonal injury in RRMS.