End of year round-up may end on a good note for Biogen

Eur J Neurol. 2017 Mar 22. doi: 10.1111/ene.13272. [Epub ahead of print]

Effect of delayed-release dimethyl fumarate on no evidence of disease activity in relapsing-remitting multiple sclerosis: integrated analysis of the phase III DEFINE and CONFIRM studies.

Havrdova E, Giovannoni G, Gold R, Fox RJ, Kappos L, Phillips JT, Okwuokenye M7, Marantz JL.


Significant effects on clinical/neuroradiological disease activity have been reported in patients with relapsing-remitting multiple sclerosis treated with delayed-release dimethyl fumarate (DMF) in phase III DEFINE/CONFIRM trials. We conducted a post hoc analysis of integrated data from DEFINE/CONFIRM to evaluate the effect of DMF on achieving no evidence of disease activity (NEDA) in patients with relapsing-remitting multiple sclerosis.


The analysis included patients randomized to DMF 240 mg twice daily, placebo or glatiramer acetate (CONFIRM only) for ≤2 years. A time-to-event method was used to estimate the percentage of patients achieving NEDA. Clinical NEDA (no relapses/no 12-week confirmed disability progression) was analysed in the intention-to-treat (ITT) population. Neuroradiological (no new/newly enlarging T2 hyperintense lesions/no gadolinium-enhancing lesions) and overall NEDA (clinical and neuroradiological NEDA) were analysed in the magnetic resonance imaging (MRI) cohort.


The ITT and MRI populations comprised 1540 and 692 patients, respectively. The percentage of patients with clinical NEDA (ITT population) and neuroradiological NEDA (MRI cohort) was higher with DMF versus placebo over 2 years [clinical NEDA: 38.9% relative reduction; hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.52-0.72; P < 0.0001; neuroradiological NEDA: 40.0% relative reduction; HR, 0.60; 95% CI, 0.49-0.73; P < 0.0001]. The percentage of patients achieving overall NEDA (MRI cohort) was also higher with DMF (26%) versus placebo (12%) over 2 years, with a relative risk reduction of 42.7% (HR, 0.57; 95% CI, 0.48-0.69; P < 0.0001).


A significantly higher percentage of patients treated with DMF achieved NEDA status over 2 years compared with placebo.

The year 2016 was a colossal mistake for most and ditto for many of our large biotechs. Firstly, the increasing momentum on biosimilars in the US, closely followed by the twitterings of Donald Trump on soaring drug prices, which certainly did not do any favors for consumer confidence. So if you were pharma, how would you set about re-couping some modicum of composure that you did not have the day before?...Why, remind everyone of your infallibility, that is!!!

As far as treatment success is concerned in MS therapeutics, it's all about NEDA, or No Evidence of Disease Activity (a composite readout based on clinical and MRI measures of disease activity). Biogen, with natalizumab (in their posthoc analysis of the AFFIRM study) were the first to report on such back in 2009; registering under 40% absence of disease activity with natalizumab vs. under 10% in the placebo/no treatment arm over 2 years. Here, again Havrdova et al. evaluate the achievement of NEDA, but this time with the first line oral drug dimethyl fumerate (DMF or tecfidera) using combined analysis from the DEFINE and CONFIRM studies. The bottom line is that percentage of overall NEDA was 26% in the DMF vs 12% in the placebo arm over 2 years (see figure below).

Figure: Effect of delayed‐release DMF (blue) on NEDA in relapsing–remitting multiple sclerosis vs placebo (red): integrated analysis of the phase III DEFINE and CONFIRM studies

So what does this data add to what we already know about DMF? It tells us that DMF is not only effective at single end-points, such as relapse rate reduction and MRI activity, but can achieve a certain degree of overall NEDA as well. NEDA individuals of course have a better prognosis for the future than those who don't achieve NEDA, and that is the key here. Therefore, even on first-line therapy it is possible to achieve this. Of course, the caveat to this is that the success rate of achieving NEDA is even greater with the most highly-active treatments, such as natalizumab and alemtuzumab, but the trade-off is the risk-benefit profile with the latter.

The key, therefore, it would seem in the current climate of MS therapeutics is to be able to cater for all comers. Have the option of the highly-active treatment, but at the same time offer a less effective one with a better risk profile; and there within comes the power to swap strategies to one's complete inner satisfaction.

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