Contributions
Abstract: P637
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Background: Neurofilament light chain (NfL) is released into blood circulation following neuroaxonal injury and is a marker for monitoring disease activity and treatment response in multiple sclerosis (Kuhle et al. S50.005, AAN 2017; Kuhle et al. P6.376, AAN 2017). A recent study suggests that NfL levels in serum may be prognostic of future disease worsening (Disanto et al. Ann Neurol 2017 epub).
Objective: To assess the prognostic value of blood NfL for relapses and disability progression in patients with RRMS in a placebo-controlled phase 3 study of fingolimod (FREEDOMS).
Methods: A retrospective analysis of blood NfL levels in patients with RRMS (n=164) treated with fingolimod or placebo. Patients who consented and had 4 or 5 serial blood samples available, including baseline and month 24 samples, were selected. NfL levels at baseline were measured using Single Molecule Array (SIMOA) technology and grouped in 3 categories (low: < 30, medium: 30-60, high: >60 pg/mL; n=97, 47, 20, respectively). High and low baseline NfL categories were compared using Chi-square and Wilcoxon rank sum tests for binary outcomes, and Cox regression for time to confirmed relapse and time to 3-months confirmed disability progression (CDP).
Results: In the overall analysis population, ´high´ compared with ´low´ NfL levels at baseline were associated with higher MRI and clinical disease activity at Month 24: proportion of patients with new or enlarging T2 lesions (88.9% vs 54.7%, p=0.0069), average number of Gd+ lesions (0.9 vs 0.3, p=0.1165), annualised rate of brain atrophy (−1.11% vs −0.42%, p=0.0003), annual relapse rate (ARR, 0.65 vs 0.22, p=0.0011), and CDP (40.0% vs 18.6%, p=0.0365). Patients with high baseline NfL levels were at a 2.8-fold higher risk of experiencing confirmed relapses (95% CI: 1.45, 5.43; p=0.0022) and had a 3.6-fold higher risk for CDP (1.48, 8.74; p=0.0047) than patients with low baseline NfL. Fingolimod, compared with placebo, reduced the risk of relapses and disability progression (both p< 0.01), in NfL-defined low- and high-risk patients. The proportion of patients with new/enlarging T2 lesions in high/low NfL groups: 80%/46% for fingolimod and 100%/64% for placebo; ARR in high/low NfL groups was 0.5/0.14 in fingolimod and 0.84/0.32 in placebo.
Conclusion: NfL in blood qualifies as a mid-term prognostic marker of future relapses and disability worsening in RRMS. Fingolimod reduced disease activity and worsening in both high and low blood NfL groups.
Disclosure: This study was funded by Novartis Pharma AG, Basel, Switzerland.
Jens Kuhle and Harald Kropshofer contributed equally to this work.
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.
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.
Harald Kropshofer, Dieter A. Häring, David Leppert, and Davorka Tomic are employees of Novartis.
Abstract: P637
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Background: Neurofilament light chain (NfL) is released into blood circulation following neuroaxonal injury and is a marker for monitoring disease activity and treatment response in multiple sclerosis (Kuhle et al. S50.005, AAN 2017; Kuhle et al. P6.376, AAN 2017). A recent study suggests that NfL levels in serum may be prognostic of future disease worsening (Disanto et al. Ann Neurol 2017 epub).
Objective: To assess the prognostic value of blood NfL for relapses and disability progression in patients with RRMS in a placebo-controlled phase 3 study of fingolimod (FREEDOMS).
Methods: A retrospective analysis of blood NfL levels in patients with RRMS (n=164) treated with fingolimod or placebo. Patients who consented and had 4 or 5 serial blood samples available, including baseline and month 24 samples, were selected. NfL levels at baseline were measured using Single Molecule Array (SIMOA) technology and grouped in 3 categories (low: < 30, medium: 30-60, high: >60 pg/mL; n=97, 47, 20, respectively). High and low baseline NfL categories were compared using Chi-square and Wilcoxon rank sum tests for binary outcomes, and Cox regression for time to confirmed relapse and time to 3-months confirmed disability progression (CDP).
Results: In the overall analysis population, ´high´ compared with ´low´ NfL levels at baseline were associated with higher MRI and clinical disease activity at Month 24: proportion of patients with new or enlarging T2 lesions (88.9% vs 54.7%, p=0.0069), average number of Gd+ lesions (0.9 vs 0.3, p=0.1165), annualised rate of brain atrophy (−1.11% vs −0.42%, p=0.0003), annual relapse rate (ARR, 0.65 vs 0.22, p=0.0011), and CDP (40.0% vs 18.6%, p=0.0365). Patients with high baseline NfL levels were at a 2.8-fold higher risk of experiencing confirmed relapses (95% CI: 1.45, 5.43; p=0.0022) and had a 3.6-fold higher risk for CDP (1.48, 8.74; p=0.0047) than patients with low baseline NfL. Fingolimod, compared with placebo, reduced the risk of relapses and disability progression (both p< 0.01), in NfL-defined low- and high-risk patients. The proportion of patients with new/enlarging T2 lesions in high/low NfL groups: 80%/46% for fingolimod and 100%/64% for placebo; ARR in high/low NfL groups was 0.5/0.14 in fingolimod and 0.84/0.32 in placebo.
Conclusion: NfL in blood qualifies as a mid-term prognostic marker of future relapses and disability worsening in RRMS. Fingolimod reduced disease activity and worsening in both high and low blood NfL groups.
Disclosure: This study was funded by Novartis Pharma AG, Basel, Switzerland.
Jens Kuhle and Harald Kropshofer contributed equally to this work.
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.
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.
Harald Kropshofer, Dieter A. Häring, David Leppert, and Davorka Tomic are employees of Novartis.