Sunday, 11 January 2015

ClinicSpeak: How quickly does DMF (Tecfidera) work

How bold is Biogen-Idec? Switching from natalizumab to DMF. #ClinicSpeak #MSResearch #MSBlog

"How quickly a DMT works may be important. This post-hoc (after the event) analysis of the dimethyl fumarate (DMF, Tecfidera) phase 3 studies shows it working within 24 weeks. Is this quick enough? It may not be for MSers with highly active MS or those switching from natalizumab. DMF does not look like it prevents the rebound we see in approximately a third of MSers after stopping natalizumab. In comparison fingolimod when started within 4 weeks of the last natalizumab infusion stops most rebound. Is this because DMF is less effective than fingolimod or is it because DMF needs more time to start working? A simple experiment will be to take natalizumab-treated MSers and start them on DMF 3 months before their last infusion, i.e. overlap the treatments. This would mean that DMF has had 6 months to start working by the time natalizumab is out of the system. If this strategy prevents rebound post-natalizumab then its is not efficacy that is in doubt, but the time for DMF to have it maximum therapeutic effect. I wonder if Biogen-Idec would be interested in doing this study? I have mentioned it to them already but have had no feedback. I think this study should be done as it will provide an important bit of information that we require to help us make decisions regarding the sequencing of DMTs."



Epub: Kappos et al. Time course of clinical and neuroradiological effects of delayed-release dimethyl fumarate in multiple sclerosis. Eur J Neurol. 2015. doi: 10.1111/ene.12624.

BACKGROUND AND PURPOSE: Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF), demonstrated efficacy and safety in relapsing-remitting multiple sclerosis in the 2-year, randomized, placebo-controlled, phase 3 DEFINE and CONFIRM trials. A post hoc analysis of integrated data from DEFINE and CONFIRM was conducted to determine the temporal profile of the clinical and neuroradiological effects of DMF.

METHODS: Eligible patients were randomized to receive placebo, DMF 240 mg twice (BID) or three times (TID) daily or glatiramer acetate (GA; reference comparator; CONFIRM only) for up to 96 weeks. Patients in the GA group were excluded from this analysis.

RESULTS: A total of 2301 patients were randomized and received treatment with placebo (n = 771) or DMF BID (n = 769) or TID (n = 761). DMF significantly reduced the annualized relapse rate beginning in weeks 0-12 (BID, P = 0.0159; TID, P = 0.0314); the proportion of patients relapsed beginning at week 10 (BID, P = 0.0427) and week 12 (TID, P = 0.0451); and the proportion of patients with 12-week confirmed disability progression beginning at week 62 (BID, P = 0.0454) and week 72 (TID, P = 0.0399), compared with placebo. These effects were sustained throughout the 2-year study period. DMF significantly reduced the odds of having a higher number of gadolinium-enhancing lesions by 88% (BID) and 75% (TID) and the mean number of new or enlarging T2 lesions by 72% (BID) and 67% (TID), from the first post-baseline magnetic resonance imaging assessment at 24 weeks (all P < 0.0001 versus placebo).

CONCLUSIONS: In phase 3 clinical trials, DMF demonstrated rapid and sustained clinical and neuroradiological efficacy in relapsing-remittingmultiple sclerosis.

CoI: multiple, I am a co-author on this study

7 comments:

  1. Question - if the reason for cessation of natalizumab/Tysabri was because the patient was JCV positive, and given that there has been a PML death with DMF/Tecfidera - would you be putting such a patient on DMF?
    Would you also be recommending some sort of ongoing regular testing for JCV in any case for patients who are on Tecfidera?
    The suggested study is still an interesting prospect.

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    1. Re: "Question - if the reason for cessation of natalizumab/Tysabri was because the patient was JCV positive, and given that there has been a PML death with DMF/Tecfidera - would you be putting such a patient on DMF?"

      The reason the person developed PML on DMF was due to prolonged lymphopenia and necessarily due to the mode of action of DMF. So I don't have too many concerns about this sequence of DMTs provided you monitor for lymphopenia and stop DMF if the total lymphocyte count drops below 800 or 500 depending on your local guidelines.

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  2. Is such a study really necessary? If a patient has highly active inflammation (=MS activity) then corticosteroids followed by a DMT, if switching from natalizumab for JCV + patients, use fingolimod or tecfidera 4 weeks before the switch to prevent rebound activity. It seems lke a "no brainer".

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    1. It is one thing having an hypothesis and another thing having data. We need to have data to inform decision making, otherwise it is based on opinion and we know how often opinion can be wrong.

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  3. Why do Biogen-Idec have to be bold? Surely, it is in their best interests to do this study?

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    1. Re: "Why do Biogen-Idec have to be bold? Surely, it is in their best interests to do this study?"

      If they did the study and it was negative, i.e. overlapping DMF with natalizumab before stopping natalizumab did not prevent rebound, their competitors would use it say that their drug is not that effective. It would be scoring an own goal. If Biogen-Idec don't do this study the community may do it themselves. It is very important as DMF may turn-out to be the drug of choice for women wanting to have children women switching from natalizumab to DMF will want to be reassured that there is no risk of rebound.

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  4. What happens if you are changing to oral meds (tecfidera) because it is now available and because it may be more effective at reducing relapse than injectables? Does this mean that there is quite a long period when you have no effective active cover? Should there be an overlap with interferon? Probaly can't be recommended either for lack of evidence.

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