title: Epoch Analysis of On-Treatment Disability Progression Events over Time in the Tysabri Observational Program (TOP).
abstract: OBJECTIVE
  To evaluate the effect of natalizumab on disability progression beyond 2 years of treatment in clinical practice.
  
  
  METHODS
  Analyses included the 496 relapsing-remitting multiple sclerosis (RRMS) patients among 5122 patients in the Tysabri Observational Program (TOP) who had completed 4 continuous years of natalizumab treatment and had baseline (study enrollment) and postbaseline Expanded Disability Status Scale (EDSS) assessments. Proportions of patients with 6-month or 12-month confirmed ≥1.0-point EDSS progression relative to baseline were compared in treatment months 1-24 and 25-48. Sensitivity analyses compared progression rates in months 13-24 and 25-36.
  
  
  RESULTS
  Baseline characteristics appeared similar between the overall TOP population (N = 5122), patients who had completed 4 years of natalizumab treatment (n = 469), and patients eligible to complete 4 years in TOP who had discontinued natalizumab after 2 years of treatment (n = 514). Among 4-year completers, the proportion of patients with 6-month and 12-month confirmed EDSS progression decreased between months 1-24 and 25-48 of natalizumab treatment by 42% (from 10.9% to 6.3%; p < 0.01) and 52% (from 9.5% to 4.6%; p < 0.01), respectively. Few patients had 6-month or 12-month confirmed EDSS progression in both epochs (0.6% and 0.2%, respectively). Between months 13-24 and 25-36 of treatment, the proportion of patients with 6-month and 12-month confirmed EDSS progression decreased by 60% (from 7.5% to 3.0%; p < 0.01) and 58% (from 6.7% to 2.8%; p < 0.01), respectively. Significant reductions in disability progression events between months 13-24 and 25-36 were also observed in relapse-free patients.
  
  
  CONCLUSIONS
  In this observational study, the disability progression rate decreased further beyond 2 years of natalizumab treatment. Patients who responded well and remained on continuous natalizumab therapy for over 4 years had sustained and potentially enhanced reductions in EDSS progression over time.
authors.affiliation: Department of Neurology-Inflammatory Disorders of the Nervous System and Neurooncology, University of Münster, Münster, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia.|Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia.|Department of Neurology, Box Hill Hospital, Monash University, Victoria, Australia.
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
authors.affiliation: Neurology, Department of Medicine, University Hospital Basel, Basel, Switzerland.|Neurology, Department of Clinical Research, University Hospital Basel, Basel, Switzerland.|Neurology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Department of Neuroscience and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Trojano
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pellegrini
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Dominic
authors.initials: D
authors.lastname: Paes
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Annie
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Biogen, Cambridge, Massachusetts, United States of America.
authors.forename: Shibeshih
authors.initials: S
authors.lastname: Belachew
mesh_terms: D000328:Adult; D004185:Disability Evaluation; D006233:Persons with Disabilities; D018450:Disease Progression; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy*; D000069442:Natalizumab / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D000069442:Natalizumab