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Effect of fingolimod on diffuse brain tissue damage in relapsing-remitting multiple sclerosis patients
Multiple Sclerosis and Related Disorders, May 2016, Pages 98 - 101
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.
To investigate if the effects of fingolimod 0.5 mg on BVL are mediated exclusively through its effects on focal damage or if fingolimod also acts independently in reducing diffuse damage.
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).
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 24 M (−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.
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.
- Fingolimod treatment compared to placebo, resulted in a significant reduction of brain volume loss (BVL) over 12 months and 24 months.
- The effect of fingolimod on BVL is partially independent of its effect on focal damage (MRI lesions and relapses).
- This analysis provides additional evidence that, both inflammatory and neurodegenerative components are involved in multiple sclerosis disease processes.
Keywords: Relapsing-remitting multiple sclerosis, Focal damage, Diffuse damage, Brain volume loss, Fingolimod.
a Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
b Novartis Pharma AG, Basel, Switzerland
c Medical Image Analysis Center (MIAC), University Hospital, Basel, Switzerland
d Department of Neurology, DKD Helios Klinik Wiesbaden, Germany
e University of Genoa, Genoa, Italy
⁎ Correspondence to: Dept. of Medicine, Surgery & Neuroscience, University of Siena, Viale Bracci 2, 53100 Siena, Italy.
© 2016 Elsevier B.V., All rights reserved.