Saturday, 4 June 2016

Tissue Damage protection with fingolimod

Wolinsky et al. Brain Volume as a Predictor of Disability in Primary Progressive Multiple Sclerosis: Evidence from the INFORMS Trial. Neurology , 2016 vol. 86 no. 16 Supplement S51.007


OBJECTIVE: To determine the role of brain volume (BV) as a predictor of disability worsening in primary progressive multiple sclerosis (PPMS). BACKGROUND:Normalized BV (NBV) and on-study BV loss (BVL) are predictive of disability worsening in relapsing MS (RMS). The role of BV in PPMS is unclear. METHODS:We repeated RMS analyses in PPMS data using INFORMS (≥3 years study of fingolimod 0.5mg [N=336] vs placebo [N=487]). INFORMS placebo-treated patients (natural history) were grouped into “low NBV” (n=70), “medium NBV” (n=351) and “high NBV” (n=61) categories using multiple regression to adjust (and test) for baseline characteristics: T2 volume, EDSS, MS duration, age and gender. NBV category was tested as a predictor of disability worsening according to the INFORMS primary efficacy composite endpoint, using Kaplan-Meier (KM) estimates at Year 3, Cox regression and log-rank test. On-study BVL was described by treatment for baseline T2 volume and Gd-T1 counts categories, as previously used in RMS. RESULTS:PPMS patients with baseline high NBV were at lowest risk (KM: 67[percnt]) of disability worsening, followed by medium (74[percnt]) and low NBV (91[percnt]), corresponding to a 35[percnt] risk reduction for high vs. low NBV (Cox’s model hazard ratio: 0.65, p=0.0507; Log-rank test: p=0.0297). Low NBV at baseline was best correlated with high baseline T2 volume and older age (both p<0.0001). BVL over 3 years was best predicted by baseline T2 lesion volume (p<0.0001). A minority of INFORMS patients with BVL measures had baseline Gd+ lesions (n=107/820, 13.0[percnt]); in those patients, BVL was more pronounced and a significant fingolimod effect on BVL was visible. CONCLUSIONS:Low NBV predicted disability worsening in PPMS, similar to RMS. A history of MRI activity (high baseline T2 volume) was the best predictor of on-study BVL. Patients with acute inflammation (baseline Gd+ lesions) experienced greater BVL, which was reduced by fingolimod. 

If your brain doesn't shrink when you are fingo you have a lowerchance of disability worsening. Alot of shrinking and the chances of worsening is higher which is not surprising as it means nerves are being lost. This shrinkage is associated with MRI lesions. So relapses (lesions) are bad for you, so try to stop them.

De Stefano N, Tomic D, Radue EW, Sprenger T, Meier DP, Häring D, Sormani MP. Effect of fingolimod on diffuse brain tissue damage in relapsing-remitting multiple sclerosis patients.Mult Scler Relat Disord. 2016 May;7:98-101.

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.

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 evident. 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.

So we all already know that fingo can slow the rate of loss of brain tissue as you would expect with any agent that can truely stop inflammation but in the paper it suggests there is more. 

Does it really affect neurodegeneration? If it did why did it fail to affect PPMS...case rests me lord.

7 comments:

  1. This comment has been removed by a blog administrator.

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    1. Yes. let's hope but it seems we have been doing bad trial design for a London time. Maybe the solution is to do a proper study of hsct abative and monitor people for more than two years if it works then you learn and design trials if it doesn't maybe it is time for pharma to rethink before you have endless failed trials in progressive ms but if it takes five years for an effect to be seen will they wait that long.

      Siponimod on the way .

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    2. why would studying ahsct help with trial design? to my mind, the efficacy or non efficacy of hsct on progressive ms could be explained in a similar way to the ocrelizumab data for progressive ms...

      ps. i'm tired of 2 year data, i want 10, 20 and 30 year data ;)

      pps. while i'm barking up the wishing tree, a crystal ball wouldn't go astray either.

      thanks!

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    3. lol nevermind about the post, it wasn't earth shattering.

      i didn't understand the reference to ahsct trials - did you mean because the trials are mostly 5 years long? I liked Lemtrada trials in that regard too - particularly the post marketing analyses. AHSCT for MS has been around for over 20 years in limited settings - but the data past 5 years is sorely lacking.

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    4. HSCT is going to be the most effective immunosuppressive/immunomodulatory treatment compared to all other current treatments, if you looked at other agents their influence on disease may not be sufficiently good enough

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    5. lol my partner is trying to register for the aus ahsct register. she seemed to respond to tysabri but had too many ongoing side effects and wanted a break with a lesser chance of secondary autoimmunity. her neuro was supportive, after some to and fro. she's doing exceptionally well and is effectively at a point she was 2 years ago. pre treatment, she had a relatively high lesion load at diagnosis (in my opinion anyway - 12+) an enhancing component 8 months before HSCT, very mild disability in most areas, had no restrictions to walking or mobility, and moderate disability in relation to bladder function. she did have ongoing symptoms like pins and needles in legs. was a year from diagnosis, 39 years old, ms labelled aggressive by 4 of 5 neuros (5th one questioned what aggressive ms is lol). We have no idea how long any of it will last - but in some ways, if it holds out until Ozrelizumab comes out we'll be on a high horse (anything after that would be icing on the cake). After going through all possible phenotypes, her ultimate diagnosis was RRMS, though by which definition (current or pre DMDs or the theory associated with there being a component of relapsing and progressive ms present at the same time) is anyone's guess lol. whatever my partner's long term outlook ultimately is, I'm looking forward to seeing what's happening in 20 and 30 years (according to my maths, we should still be around to appreciate it ;)

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