#MSBlog: BG12 works within 12 weeks of starting treatment.
Kappos et al. Timecourse of Treatment Effects of BG-12 (Dimethyl Fumarate) for Relapsing–Remitting Multiple Sclerosis. AAN 2013; S41.005.
OBJECTIVE: To characterize the temporal profile of BG-12 (dimethyl fumarate) treatment efficacy in an integrated analysis of data from the Phase 3 DEFINE and CONFIRM studies.
BACKGROUND: Oral dimethyl fumarate has demonstrated significant reductions in relapses and brain magnetic resonance imaging (MRI) activity over 2 years in patients with relapsing–remitting multiple sclerosis (RRMS) in DEFINE and CONFIRM.
DESIGN/METHODS: MSers with RRMS were randomized equally to oral dimethyl fumarate 240 mg twice (BID) or three times daily (TID) or placebo in both studies. CONFIRM also included glatiramer acetate as reference comparator. Primary endpoints were proportion of MSers relapsed (DEFINE) and annualized relapse rate (ARR; CONFIRM). MRI was performed at baseline and Weeks 24, 48 and 96, in a subset of MSers. The integrated analysis was contingent upon homogeneous baseline characteristics and treatment effects across the studies.
RESULTS: The intent-to-treat population for the integrated analysis comprised 769, 761 and 771 MSers assigned to dimethyl fumarate BID, TID and placebo, respectively. Dimethyl fumarate treatment reduced the proportion of patients relapsed and ARR, with significant separation versus placebo achieved at Week 12 (post-hoc analyses); the hazard ratio (and 95% confidence interval [CI]) for risk of relapse at Week 12 was 0.68 (0.48, 0.96) for the BID group (p=0.0282) and 0.70 (0.50, 0.99) in the TID group (p=0.046), and the rate ratio (95% CI) for ARR was 0.66 (0.47, 0.92) (BID; p=0.0149) and 0.69 (0.49, 0.96) (TID; p=0.0299). Significant separation was maintained thereafter; by 2 years, dimethyl fumarate BID and TID reduced the risk of relapse by 43% and 47% versus placebo, and ARR by 49% for both, (all p<0.0001). MRI outcomes were consistent with the time course of clinical effect.
CONCLUSIONS: Dimethyl fumarate treatment resulted in significant improvements in disease activity over placebo that were apparent by 3 months, and sustained over 2 years.
Supported by: Biogen Idec Inc.
“In response to a question yesterday about the onset of action of BG12; according to this analysis the curves go apart very soon after starting the drug and are signficant by 12 weeks. This suggests to me that BG12 is probably working as an anti-inflammatory drug.”
“Does this answer your question?”
Is it possible that inflammation is the result of the MS activity, the inflammation causes the relapse symptoms and so drugs that act as anti-inflammatories suppress the symptoms but have no impact on the actual disease itself? i.e. BG12 just acts in a similar way to steroids? I'm not saying that's a bad thing as the symptoms can be really bad and permanent but I'd like to think there was a somewhat greater impact on the actual disease course by taking BG12 than just suppressing the inflammation?
Have a look on the blog of 30.5.11 when it shows you how the oral DMD's stack up against each other. It shows you how BG12 has an effect on the rate of progression.
In the graph "Anualized Relapse Rate Over Time", the relapse rate of those on placebo decreases over time. To me, it seems like it would be constant. Any explanations for this?
Mainly regression to the mean. This is a statistical term that refers to observation that if you select active MSers for a trial the relapse rate will decrease; i.e. they are more likely to become less active with time. We also no that relapses become less frequent with time; this is simply the natural history of MS.
This med just reduces relapses but doesn't prevent progression. Such a shame.
It had an impact on progression in DEFINE, but not CONFIRM. Please remember that progression in early RRMS trials is driven by relapses.
Thank you. That was very helpful. Does the strong anti-inflammatory effect rule out neuroprotection or just make it more unlikely?
Difficult to tell. The impact of BG12 on atrophy is inconsistent; it only had an effect in the twice daily dose of the DEFINE study (one arm). There was no significant effect on atrophy in the high-dose arm in DEFINE and both dose arms of CONFIRM. Jury is out on whether or not it is neuroprotective, over an above its effect on inflammation, or not. Based on its proposed mechanism of action it should be.
The mechanism proposed for effect on neuroprotection but does the drug get into the CNS?, if it doesn't then it will be hard to be good neuroprotectant
How did this drug compare to GA in the CONFIRM trial? Comparing to placebo looks nice, but would be interested to see how it compares to a standard treatment.
BG12 out-performed GA. The latter was a reference arm and was not double-blind therefore it is not fair to compare it with the double-blind arms.
How much of the difference between Copaxone and BG-12 ARR is attributable to the slow onset of Copaxone's efficacy? In other words, is BG-12 outperforming Copaxone also in the second year or mainly in the first half year?