Abstract
Objective: To assess if blood neurofilament light chain (NfL) could serve as a component of the revised definition of ‘no evidence of disease activity’ (NEDA-4) as a substitute for brain volume loss (BVL).
Background: Blood NfL has recently been identified as a promising biomarker of neuro-axonal loss in MS. NEDA is a treatment target in relapsing–remitting MS. To increase the sensitivity of NEDA, adding BVL, a marker of neurodegeneration, was proposed (NEDA-4).
Design/Methods: We included all patients enrolled in the FREEDOMS study who provided consent for exploratory biomarker analysis and had complete data assessed at Month (M) 24 (relapses, number of active T2 lesions, BVL, and NfL levels): N=214; placebo, n=93; fingolimod 0.5mg, n=121. NfL levels were measured using SIMOA™ technology. NEDA definition at M24 was: absence of new/enlarging T2 lesions, relapses, 6M-confirmed disability progression; NEDA-BVL status (included BVL<0.8%), and NEDA-NfL status (included NfL level at M24 lower than a specific cutoff). The optimum cutoff was defined by a ROC analysis as the cut-point better discriminating patients who progressed over M24. Treatment effect on NEDA endpoints was assessed by logistic regression.
Results: Baseline blood NfL levels (pg/mL, median [range]) were similar in both arms: placebo=25 [9–380], fingolimod=28 [8–216]. ROC analysis indicated NfL of 22.7pg/mL as the optimum level discriminating patients with a disability progression at M24 (AUC=72%, sensitivity=76%, specificity=67%). At M24, 24% (n=52/214), 16% (n=34/214), and 20% (n=42/214) patients achieved NEDA, NEDA-BVL, and NEDA-NfL, respectively; of the 42 NEDA-NfL patients, 67% (n=28) were both NEDA-BVL and NEDA-NfL. Probability of achieving NEDA and NEDA-BVL at M24 was higher in fingolimod-treated patients (OR=2.9, p=0.003 and OR=2.4, p=0.03). Adding NfL to NEDA improved this probability (OR=3.5, p=0.002).
Conclusions: Blood NfL may qualify as an additional component of NEDA definition, providing information on neurodegenerative aspects of MS in a similar way as BVL, and is simpler to assess.
Study Supported by:
Novartis Pharma AG, Basel, Switzerland.
Disclosure: Dr. Sormani has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Received compensation for serving on Scientific Advisory Boards from TEVA, Genzyme, Novartis, Roche, and Vertex; funding for travel or speaker honoraria from Merck Serono, TEVA, Genzyme, Novartis, Biogen, and Roche; consultancy from Merck Serono, Biogen,. Dr. Kappos has received research support from Bayer HealthCare Pharmaceuticals, Biogen, F. Hoffmann-La Roche Ltd and Genentech,Novartis, Research grants from: the European Union, Roche Research Foundation, Swiss Multiple Sclerosis Society and Swiss National Research Foundation. Dr. Haering has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG. Dr. Kropshofer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG. Dr. Barro has nothing to disclose. Dr. Leppert has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG. Dr. Tomic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Novartis Pharma AG. Dr. Kuhle has received research support from Dr Kuhle’s institution (University Hospital Basel) received and used exclusively for research support: consulting fees from Biogen, Novartis, Protagen AG, Roche, Teva; speaker fees from the Swiss MS Society, Biogen, Novartis, Roche, Genzyme; travel expens.
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