Sustained reduction of serum neurofilament light chain over 7 years by alemtuzumab in early relapsing-remitting MS

Abstract

Background: Alemtuzumab efficacy and safety was demonstrated in CARE-MS I and extension studies (CAMMS03409; TOPAZ).

Objective: Evaluate serum neurofilament light chain (sNfL) in CARE-MS I patients and highly active disease (HAD) subgroup, over 7 and 2 years for alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), respectively.

Methods: Patients received SC IFNB-1a 44 µg 3×/week or alemtuzumab 12 mg/day at baseline and month 12, with further as-needed 3-day courses. sNfL was measured using single-molecule array (Simoa™). HAD definition was ⩾2 relapses in year before randomization and ⩾1 baseline gadolinium-enhancing lesion.

Results: Baseline median sNfL levels were similar in alemtuzumab (n = 354) and SC IFNB-1a-treated (n = 159) patients (31.7 vs 31.4 pg/mL), but decreased with alemtuzumab versus SC IFNB-1a until year 2 (Y2; 13.2 vs 18.7 pg/mL; p < 0.0001); 12.7 pg/mL for alemtuzumab at Y7. Alemtuzumab-treated patients had sNfL at/below healthy control median at Y2 (72% vs 47%; p < 0.0001); 73% for alemtuzumab at Y7. HAD patients (n = 102) had higher baseline sNfL (49.4 pg/mL) versus overall population; alemtuzumab HAD patients attained similar levels (Y2, 12.8 pg/mL; Y7, 12.7 pg/mL; 75% were at/below control median at Y7).

Conclusion: Alemtuzumab was superior to SC IFNB-1a in reducing sNfL, with levels in alemtuzumab patients remaining stable through Y7.

Clinicaltrials.gov identifier: NCT00530348, NCT00930553, NCT02255656.

Keywords: Alemtuzumab; NfL/neurofilament light chain; biomarkers; clinical trials randomized controlled; highly active disease; multiple sclerosis.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.K. reports his institution (University Hospital Basel) received and used exclusively for research support: consulting fees from Biogen, Novartis, Protagen AG, Roche, and Teva, speaker fees from Biogen, Genzyme, Novartis, Roche, and Swiss MS Society, travel expenses from Merck Serono, Novartis, and Roche, and grants from Bayer AG, Biogen, Celgene, Genzyme, ECTRIMS Research Fellowship Program, Merck, Novartis, Roche, Swiss MS Society, Swiss National Research Foundation (320030_160221), and University of Basel. P.B., A.M., and Z.M. have nothing to disclose. C.B. reports travel support from Novartis and Teva. M.P.S. reports consulting fees from Biogen, Celgene, GeNeuro, MedDay, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. N.D., J.G., E.H., C.K., C.P.M., N.R., and S.S. are employees of Sanofi. L.C., A.J., and T.A.S. were employees of Sanofi during study conduct and analysis. D.L. reports personal fees from Novartis, Orion, Roche, and Sanofi; he is chief medical officer at GeNeuro. L.K. reports his institution (University Hospital Basel) received in the last 3 years the following, which was used exclusively for research support: steering committee, advisory board, consultancy fees, and support of educational activities from: Actelion, Allergan, Almirall, Baxalta, Bayer, Biogen, Celgene, CSL Behring, Desitin, EXCEMED, Eisai, F. Hoffmann-La Roche, Genzyme, Japan Tobacco, Merck, Minoryx, Novartis, Pfizer, Sanofi-Aventis, Santhera, and Teva; license fees for Neurostatus-UHB products; the Research of the MS Center in Basel has been supported by grants from Bayer, Biogen, European Union, Innosuisse, Novartis, Roche Research Foundations, Swiss MS Society, and Swiss National Research Foundation.

Figures

Figure 1.

Unadjusted analyses showing the relationship between sNfL levels and (a) Gd-enhancing lesion count, (b) T2 hyperintense lesion volume, and (c) T1 hypointense lesion volume at baseline. Gd: gadolinium; IQR: interquartile range; sNfL: serum neurofilament light chain. aT2 hyperintense lesion volume Tertile 1: ⩽1.997 cm3; Tertile 2: >1.997 and ⩽6.520 cm3; Tertile 3: >6.520 cm3. bT1 hypointense lesion volume Tertile 1: ⩽0.117 cm3; Tertile 2: >0.117 and ⩽0.804 cm3; Tertile 3: >0.804 cm3.

Figure 2.

sNfL levels over time in patients treated with alemtuzumab or SC IFNB-1a in (a) the overall CARE-MS I population and (b) the CARE-MS I HAD subgroup. ANCOVA: analysis of covariance; HAD: highly active disease; IQR: interquartile range; SC IFNB-1a: subcutaneous interferon beta-1a; sNfL: serum neurofilament light chain. Plot shows unadjusted sNfL values. p-Values indicate comparison between treatment groups (baseline: Wilcoxon rank sum test; post-baseline: rank ANCOVA adjusted for age and baseline sNfL). *p < 0.0001 for comparison of baseline with each post-baseline time point (Wilcoxon signed rank test). sNfL values below the lower limit of quantification were imputed; this represented 86/7100 (1.2%) alemtuzumab samples and 5/721 (0.7%) SC IFNB-1a samples. Solid line and shaded area represent median and IQR (20.6 pg/mL (15.6−27.1) sNfL level for healthy controls aged 18–53 years (the age range of CARE-MS I patients).

Figure 3.

Proportions of patients with sNfL level at or below the median level for age-matched healthy controls (left panels) and at or below the 80th percentile of age-matched healthy controls (right panels) for (a) the overall CARE-MS I population and (b) the CARE-MS I HAD subgroup. CI: confidence interval; HAD: highly active disease; HC: healthy controls; SC IFNB-1a: subcutaneous interferon beta-1a; sNfL: serum neurofilament light chain. p-Values indicate comparison between treatment groups and are based on chi-square test.