title: Effect of fingolimod on diffuse brain tissue damage in relapsing-remitting multiple sclerosis patients.
abstract: BACKGROUND
  Multiple sclerosis (MS) affects all areas of the brain resulting in both focal and diffuse damage. In Phase 3 clinical trials, fingolimod showed significant reductions in both focal lesions and rate of brain volume loss (BVL) in patients with relapsing-remitting MS.
  
  
  OBJECTIVE
  To investigate if the effects of fingolimod 0.5mg on BVL are mediated exclusively through its effects on focal damage or if fingolimod also acts independently in reducing diffuse damage.
  
  
  METHODS
  This was a pooled post-hoc analysis of patients from two Phase 3 studies (FREEDOMS [N=1272] and FREEDOMS II [N=1083]), with no evidence of focal disease activity as defined by absence of gadolinium-enhancing lesions at baseline and new active lesions and clinical relapses at follow-up. The percent brain volume change (PBVC), as a measure of diffuse tissue damage, was assessed at Month (M) 12 and M24 by using the Structural Image Evaluation using Normalization of Atrophy (SIENA) method. A regression analysis was performed in the pooled intent-to-treat (ITT) population to quantify the treatment effect of fingolimod on BVL vs. placebo (PBO) in the overall population (unadjusted model), and whether this effect is sustained after adjusting for new active lesions and on-study relapses (adjusted model).
  
  
  RESULTS
  Of 1088 patients, 638 (PBO, n=127; fingolimod, n=511) at M12 and 450 patients (PBO, n=68; fingolimod, n=382) at M24 showed no focal activity. Fingolimod significantly reduced PBVC by 65.5% over 12M (fingolimod vs. PBO: -0.16 vs. -0.45; p=0.001) and by 48.2% over 24M (-0.42 vs. -0.81; p=0.004). An absolute difference in PBVC of -0.27% (p<0.001) in favor of fingolimod vs. PBO over 24M was still evident in the pooled ITT population, after adjusting for active lesions and on-study relapses. The regression model suggests that 54% (-0.27%/-0.51%) of effects of fingolimod on PBVC are independent of its effects on visible focal damage.
  
  
  CONCLUSIONS
  The effect of fingolimod on diffuse damage is partly independent of its treatment effect on focal damage, suggesting that both inflammatory and neurodegenerative components of MS are affected.
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy. Electronic address: destefano@unisi.it.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Stefano
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Davorka
authors.initials: D
authors.lastname: Tomic
authors.affiliation: Medical Image Analysis Center (MIAC), University Hospital, Basel, Switzerland.
authors.forename: Ernst-Wilhelm
authors.initials: EW
authors.lastname: Radue
authors.affiliation: Department of Neurology, DKD Helios Klinik Wiesbaden, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Sprenger
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Daniela Piani
authors.initials: DP
authors.lastname: Meier
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häring
authors.affiliation: University of Genoa, Genoa, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Sormani
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D009929:Organ Size; D012044:Regression Analysis; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride
keywords: Brain volume loss; Diffuse damage; Fingolimod; Focal damage; Relapsing-remitting multiple sclerosis