Effect of Ibudilast on Neurofilament-light Chain in Progressive MS: Analysis from a Phase II Trial (P3.2-033)

Objective: To report the effect of ibudilast on serum and CSF neurofilament-light (NfL) from the phase II trial of ibudilast in progressive MS. Background: Serum NfL is a candidate biomarker of treatment response in multiple sclerosis (MS) clinical trials. Ibudilast 100 mg/d was found to slow the progression of brain atrophy in SPRINT-MS, a 255-patient randomized, placebo-controlled 96-week phase II trial of progressive MS. We evaluated the effect of ibudilast on serum and CSF NfL in SPRINT-MS. Design/Methods: Serum samples were collected at screening, 8, 48, and 96 weeks. In an optional sub-study, 75 patients consented to CSF sampling, which was collected at screening, 48, and 96 weeks. NfL was assayed using the SIMOA immunoassay. Analysis utilized a mixed model for repeated measurements with log(NFL) as the response variable and adjusted for treatment, age and log(baseline NFL). The model further included visit-by-treatment and visit-by-log (baseline NFL) interactions, using an AR(1) covariance matrix. Analysis was according to intent-to-treat (ITT) and included all available values in the statistical analysis. Results: Mean baseline serum NfL was 33.5+22.4 and 40.3+54.1 pg/ml in ibudilast and placebo groups, respectively. Mean baseline CSF NfL was 1616.7+1474.4 and 1301.2+822.2 pg/ml in ibudilast and placebo groups, respectively. Over the course of the study, there was no between-group difference in NfL in either serum (P=0.35) or CSF (P=0.62). In some subjects, changes in NfL were observed concomitantly with new/enlarging T2 lesions, which suggests confounding by active inflammation. Conclusions: Ibudilast treatment was not associated with a decline in either serum or CSF NfL. Inflammatory activity may have confounded the intended use of NfL to measure neurodegeneration. Disclosure: Dr. Fox has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Allozyne, Avanir, Biogen Idec, MedDay, Novartis, Questcor, Teva Pharmaceutical Industries, and Xenoport. Dr. Fox has received research support from Biogen (clinical trial contracts) and Novartis (research study support). Dr. Karafa has nothing to disclose. Dr. Konig has nothing to disclose. Dr. Natarajan has nothing to disclose. Dr. Barro has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva and Novartis. Dr. Bermel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Genzyme, Genentech, Novartis, Roche. Dr. Bermel has received research support from Biogen, Genentech, Roche. Dr. Coffey has nothing to disclose. Dr. Goodman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda Therapeutics, Actelion, Biogen-Idec, Genzyme-Sanofi, GW Pharma, Mylan, Novartis, Teva, and Vaccinex. Dr. Goodman has received research support from Acorda Therapeutics, Avanir, Biogen Idec, EMD Serono, Genzyme-sanofi, Novartis, Ono, Roche, Sun, Takeda, and Teva Neuroscience. Dr. Klawiter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda, Atlas5D, Biogen, Celgene, EMD Serono, Genentech, and Shire. Dr. Klawiter has received research support from Atlas5d, Biogen, EMD Serono, and Roche. Dr. Matsuda has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Medicinova Inc. Dr. Naismith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda, Alkermes, Biogen, Celgene, EMD Serono, Genentech, Genzyme, and Novartis. Dr. Naismith has received personal compensation in an editorial capacity as the Associate Editor NEJM Journal Watch. Dr. Naismith has received research support from Acorda, Alkermes, Biogen, Celgene, EMD Serono, Genentech, Genzyme, and Novartis. Dr. Kuhle’s institution has received compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis Pharmaceuticals, Protagen AG, Roche, Teva, Sanofi Genzyme, Swiss MS Society, and Merck Serono,. Dr. Kuhle has received research support from ECTRIMS Research Fellowship Programme, Bayer AG, Biogen, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Roche, Swiss MS Society, Swiss National Research Foundation, and University of Basel. Dr. NN102 SPRINT MS Investigators has nothing to disclose.