Dimethyl fumarate is good for inhibiting relapses

Giovannoni G, Gold R, Fox RJ, Kappos L, Kita M, Yang M, Sarda SP, Zhang R, Viglietta V, Havrdova E. Relapses Requiring Intravenous Steroid Use and Multiple-Sclerosis-Related Hospitalizations: Integrated Analysis of the Delayed-Release Dimethyl Fumarate Phase III Studies.
Clin Ther. 2015 Oct 30. pii: S0149-2918(15)01136-4. doi: 10.1016/j.clinthera.2015.09.011. [Epub ahead of print]

PURPOSE:The purpose was to report the effects of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on the number of relapses requiring intravenous (IV) steroids and multiple sclerosis (MS)-related hospitalizations using integrated data from the Phase III DEFINE and CONFIRM studies.
METHODS: DEFINE and CONFIRM were randomized, double-blind, placebo-controlled, multicenter studies that evaluated the efficacy and safety of DMF over a 2-year period in patients with relapsing-remitting MS (RRMS). Patients were randomized (1:1:1) to receive oral DMF 240 mg BID or TID, placebo, or glatiramer acetate (CONFIRM only). Eligible subjects (aged 18-55 years) had an EDSS score of 0-5.0 and experienced either ≥1 relapse in the 12 months or had ≥1 gadolinium-enhanced lesion on brain MRI in the 6 weeks, before randomization. Data DEFINE and CONFIRM were pooled and analyzed using a negative binomial regression model (adjusted for study and region). Data obtained after subjects switched to an alternative MS therapy were not included in the analysis. Only relapses confirmed by the Independent Neurology Evaluation Committee were included in the analysis of relapses requiring IV steroids.
FINDINGS: The study population (intention-to-treat) comprised 2301 patients who received either placebo (n = 771), DMF BID (n = 769), or DMF TID (n = 761). Baseline demographic and disease characteristics were generally well balanced among treatment groups. Throughout the 2-year studies, the total number of relapses treated with methylprednisolone was 402, 221, and 209 in the placebo, DMF BID, and DMF TID groups, respectively. A smaller proportion of patients in the DMF BID (168 of 769 [21.8%]) and DMF TID (151 of 761 [19.8%]) groups experienced ≥1 relapse requiring IV steroids compared with the placebo group (284 of 771 [36.8%]). The total number of MS-related hospitalizations over 2 years was 136, 94, and 74 in the placebo, DMF BID, and DMF TID groups. A smaller proportion of patients in the DMF BID (73 of 769 [9.5%]) and DMF TID (57 of 761 [7.5%]) groups had ≥1 MS-related hospitalization compared with the placebo group (104 of 771 [13.5%]).
IMPLICATIONS: DMF is an effective and well tolerated therapy for RRMS. In addition to clinical benefits, the use of DMF may be associated with reduced patient burden and health economic savings, resulting from a decrease in resource utilization associated with relapses. ClinicalTrials.gov identifiers: NCT00420212 and NCT00451451.

This is one of ProfGs new papers you can all read it and it says that tecfidera reduces relapses and the consequences of relapses. Can we do better? Should they call it gastro-resistant DMF when this is the main side-effect?

CoI ProfG is an authour and multiple

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  • It's a good news, and Tec is effective 'flareblocker', but very important the other parts of MS measurement so I have some question:
    What is it's effect the EDSS, or quality of life, and progression or brain atrophy? Some articles mention as a very effective neuroprotective drug and others as a typical first line drug with moderate efficacy.
    When doesn't work well?
    How quickly does it work?
    Is it a highly effecitve drug or not?

    • This is an interesting study. Will Professor G be following this trial up with the effect of DMF on EDSS, NEDA, disease progression, brain atrophy on MRI, etc? DMF is supposed to stop disability progression by about 38% compared to placebo. Short term it may increase health economic savings, which is great, but in the long term nobody will know if DMF decrease healthcare costs as the MS patient may just end up using these healthcare resources anyways if DMF is not working.

  • Today, you would never have used a placebo group. And once anybody relapsed, you would put them on one of the more effective treatments–right?

    • Should be …but Teva have 600MSers on placebo in their laquinimod trial….I think this is scandelous and says something about regulators

    • My fiance' is on Tecfidera. The main reason we decided on Tecfidera (yes, we, as she doesnt have MS, "We do") was because she does not wish to stop taking LDN and Tecfidera is the only oral her Neurologist (very credentialed) said should be fine to continue to use. Biogen actually took the effort to look into this and communicated back same.

      Interestingly as well we were at an event 48 hours ago re: alemtuzumab and the speaker is an MS Nurse who's hubby is a very very well known Neuro in the US. Their offices were involved in the alemtuzumab trials .vs. Rebif as well as the long term monitoring of patients in the alemtuzumab clinical trials (which btw she said is remarkable in respect to long term efficacy).

      But she actually said in front of the crowd something that's always "bugged me". That is the having patients get a placebo. Morally. A patient in a clinical trial with MS should not be prospectively forfeit to an exacerbation risk of placebo in a trial.

      She explained how randomized blind / double blind trials take place and that too was rather amazing.

  • Dear MD,

    Am not medically trained but I don't understand this. In 2015 how can we have an MS trial for RRMS running vs placebo? Who signed off on that?

    • https://clinicaltrials.gov/ct2/show/study/NCT01707992
      I personally find it very very distasteful that they (Teva) have so many people on no treatment for 2 years, compared to laquinimod which is known to to be pretty bad at treating relapses indeed possibly worse than beta interferons. The saving grace could be an effect on brain atrophy. I think we will find it to be a neuroprotectant and not a very good DMT.

      I am also sorry to say that London is one of the them. Shame on us. ProfG & DrK.

  • Surely its not uncommon and from a business aspect as well as scientific aspect it makes some sense. A medication in trials being compared against a baseline. If the baseline is modified via another medication then really do not have a "Matter of fact" result. Marketing wise of course same type deal. If "xxx" is 42% more effective then "yyy" the number does not look "Taco Bellgrande' ". Alot of people see 42%. They do not see the cumulative or the presentations end up misrepresenting "yyy". If shows 35% in a trial and another in compare to Rebif is 50% one tends to things 85% better than placebo (nothing) which is of course erroneous. Nor do they necessarily marketing wise want show say Rebif has a significant database of efficacy. Thats marketing. I get it.

    There really should be a better algorithm to go by at least towards chronic disease mitigation. Logic might say something along the lines of must be compared to a similar medication and delivery should it exist with a fallback towards one in which delivery is different. So oral delivery gets compared to an oral delivery med. Infused is compared to infused etc, Marketing wise that makes a far less versatile capability but, if one has a "winner" one has a "big winner" in that market segment. Side effects can be more closely compared since delivery (even if metabolizing is different) is same.

    There should be some form of balance but marketing is marketing. I get that.

    In respect to Placebo with a chronic disorder though thats just so unwise. The goals are to manage the disease not leave a segment of people who are also wanting manage their disease with no defense at all.

  • I don't get the logic of someone with RRMS agreeing to be on a placebo in this day and age. Is it someone who has tried and failed all of the approved therapies and this is there last chance? Not likely.

    I could understand someone with progrssive disease agreeing to this but there are too many options for a RRMSer

    • I met someone at MS life and they had slipped through the NICE imposed system such that they weren't eligible for anything at the time we spoke so it was definately getting nothng or a one in three chance of getting nothing.

      Pharma also go eastwards where there is insufficient access to compounds however the FDA are approving placebo control trials so shame on them. If the regulators and also ethical commitees got a spine then this would change however it has cost implications and this means that you are unlikely to get many new DMT for RRMS if they push the no placebo and there will be no academic trials unless the comparator is paid for.

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