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Blood NfL as a potential endpoint in Phase 2 clinical studies in relapsing-remitting multiple sclerosis
ECTRIMS Online Library. Sormani M. Oct 28, 2017; 202641
Dr. Maria Pia Sormani
Dr. Maria Pia Sormani
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Abstract: 277

Type: Oral

Background: Neurofilament light chain (NfL) in blood has recently been identified as a promising biomarker of neuroaxonal loss in MS.
Objective: To assess if NfL could serve as an endpoint in a Phase 2 study in RRMS and estimate the sample size requirements if NfL is used as a primary outcome.
Methods: Our analysis included all patients enrolled in the FREEDOMS study who provided consent for exploratory biomarker analysis and had an NfL assessment at Month (M) 6 (N=258; placebo: 117; fingolimod 0.5mg: 141). NfL levels were measured using SIMOATM technology. We evaluated the correlation of M6 NfL with 2-year T2 lesion formation, relapse activity, brain volume loss (BVL) and disability progression. Using the Prentice criteria we estimated the proportion of treatment effect (PTE) on 2-year relapses and BVL, explained by log-transformed 6M NfL. We conducted a similar analysis with the number of new T2 (nT2) lesions over 6 months from baseline as an explanatory variable.
Results: Blood NfL levels (pg/mL, median [range]) at baseline were similar in the two arms: placebo=26 [9-589]; fingolimod=28 [8-419], while levels were significantly lower in the fingolimod arm at M6 (placebo=26 [9-159]; fingolimod=18 [8-247], p< 0.001). NfL at M6 was correlated to measures of disease activity and severity at M24: nT2 lesions (r=0.46, p< 0.001), number of relapses (r=0.25, p< 0.001), BVL (r=−0.41, p< 0.001) and 6-M confirmed disability progression (HR=1.7, p=0.02). The PTE on M24 relapses explained by the effect on M6 NfL and that explained by the effect on nT2 lesions was 30%, respectively. The PTE on M24 BVL explained by the effect on M6 NfL was 58% and that explained by M6 nT2 lesions was 39%. The sample size to detect with 90% power a reduction of NfL between treated and placebo arms by 30% or 40% was 64 or 30 per arm and for comparison of two active arms it was 80 or 40 per arm.
Conclusion: There is a significant effect of fingolimod on 6M NfL. 6M NfL is correlated to standard measures of disease activity and severity after 2 years and captures similar or a larger proportion of the net effect of treatment on outcomes as compared to nT2 lesions at 6 months. The number of patients needed for a 6-month Phase 2 study (for a drug with similar efficacy to fingolimod vs placebo at 90% power) is in the range of 60-130 patients. NfL may qualify as an informative and convenient endpoint for future Phase 2 clinical studies that captures both inflammatory and degenerative aspects of MS.
Disclosure:
The authors Davorka Tomic and Jens Kuhle contributed equally.
This study was supported by Novartis Pharma AG, Basel, Switzerland.
Maria Pia Sormani 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, TEVA, Genzyme, Roche, GeNeuro, Medday and Novartis; Speakers´ Bureaus from Teva, Merck Serono, Biogen, Novartis, and Genzyme.
Christian Barro has received travel support from Teva and Novartis.
Ludwig Kappos has received no personal compensation. Ludwig Kappos's institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: Steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; license fees for Neurostatus products; and grants from Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, and the Swiss National Research Foundation.
Jens 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 expenses from Merck Serono, Novartis, Roche; grants from ECTRIMS Research Fellowship Programme, University of Basel, Swiss MS Society, Swiss National Research Foundation (320030_160221), Bayer AG, Biogen, Genzyme, Merck, Novartis, Roche.
Dieter A. Häring, Harald Kropshofer, David Leppert, and Davorka Tomic are employees of Novartis.

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