#NeuroSpeak: DMF as a second-line agent or not

Did you know that dimethyl fumarate is not as effective when used 2nd- or 3rd-line? #NeuroSpeak #MSBlog

The Mouse Doctor did a good deed this weekend; he kindly agreed to speak about MS treatments at a meeting the allied HCPs hosted at Queen Square our former Institution. At the meeting he was asked about why dimethyl fumarate (DMF) had not being recommended by NICE as a second-line therapy for patients with highly-active or rapidly-evolving severe MS? He wasn't sure so he dropped me an email.  The reason is that DMF is a much more effective treatment in pwMS who are naive to treatment. When DMF is used 2nd-line it has an impact on relapses, but in the post-hoc analysis it had no impact on disability progression. All the NICE cost-effective models are driven by disability progression and hence in this subgroup of patients it was not considered cost-effective.

This data was presented at ECTRIMS in 2013, but has not subsequently been published. I have uploaded the poster for you so that you can see the data for yourself. The answer to your question is in Figure 4 in relation to disability progression. Please note that the data on DMF in newly diagnosed patients, which is very good has been published. I have suggested to Biogen that they should also publish the 2nd-line data, but my request seems to have fallen on deaf ears. I wonder why?

Based on the post-hoc analysis below I don't recommend DMF second-line unless the reason for switching treatments is due to a tolerance issue or there are specific reasons for someone requesting DMF. The latter is usually linked to fingolimod or teriflunomide being contraindicated. Whilst we are the topic of 1st-line vs. 2nd-line efficacy some of you may be remember a post I did on Terifluomide being more effective as a 2nd- or 3rd-line DMT compared to when it is used 1st-line. It the only DMT to be more effective when used later than earlier. The finding was consistent across both phase 3 trials and therefore must be linked to real biology. If you can work out why Teriflunomide is an outlier in this regard you may be able to explain something important about the biology of MS. We have some ideas, but I will keep you in suspense. We are trying to get a grant from Genzyme-Sanofi to explore our hypothesis in more detail and will keep you posted. 



Gold et al. Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing-remitting multiple sclerosis (RRMS). Mult Scler. 2015 Jan;21(1):57-66.

BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials.

OBJECTIVE: To evaluate delayed-release DMF in newly diagnosed relapsing-remitting multiple sclerosis (RRMS) patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM.

METHODS: Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy.

RESULTS: The newly diagnosed population comprised 678 patients treated with placebo (n = 223) or delayed-release DMF 240 mg BID (n = 221) or TID (n = 234). At 2 years, delayed-release DMF BID and TID reduced the annualized relapse rate by 56% and 60% (both p < 0.0001), risk of relapse by 54% and 57% (both p < 0.0001), and risk of 12-week confirmed disability progression by 71% (p < 0.0001) and 47% (p = 0.0085) versus placebo. In a subset of patients (MRI cohort), delayed-release DMF BID and TID reduced the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, gadolinium-enhancing lesion activity by 92% and 92%, and mean number of new non-enhancing T1-hypointense lesions by 68% and 70% (all p < 0.0001 versus placebo). Flushing and gastrointestinal events were associated with delayed-release DMF.

CONCLUSION: Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.

CoI: multiple

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