Tuesday, 28 March 2017

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.


  1. But really how does the DMF act? Just by reducing the circulation of T and B cells, or the via of NrF2? From what I read once DMF is a nicotinic acid agonist, that is, niacin, and niacin is used in the treatment of hypercholesterolemia, and this makes me wonder if MS would have some way in common with pathologies that involve the imbalance of cholesterol.

    Another thing that I keep wondering why some respond to a medication and others not?
    If everything is the same disease, I know that MS is a spectrum disorder but this intrigues me...

    1. So this is what we know so far about DMF; in a small proportion of individuals it induces lymphopenia, also induces Nrf2-target genes - its purported antioxidant activity. Fumararte class have also been shown to reduce migration of white cells across blood vessels as natalizumab by blocking cytokine-induced E-selection, VCAM-1, ICAM-1 expression at the blood brain barrier, and some also GPR109A agonist in the same way as nicotinic acid, the latter has been marketed for lipid problems. Not certain how much of the overall class effect is present in DMF, but nicotinic acid at high dose causes flushing!

  2. Ok, I'll bite since I am a DMF patient. My most recent MRI (DMF 1 Year) showed no disease activity. In the study it shows a 14% increase in NEDA which is good but, its 26%, 1 in 4 peep's basically.

    Some talk among the MS clinical community is along the lines of if you are on ___xxx___ DMT and have a relapse then you should seriously consider a switch.

    Obviously, no disease activity is the target but does a relapse warrant changing DMT .vs. two relapses or three? Should or would(?) clinical data per patient be considered? Aka: Person A. DX'd 5 years ago had relapse at 1 year, 2nd and third. Now she/he is on DMF and was NEDA through year 4 and most of 5, then BAM, relapse.

    Should or rather could(?) existing relapse data be of use in selection criteria in switching or not to another DMT? All gets rather complex to be sure. But if a med (DMF) has worked then does not (one clinical event) it might be unwise to jump? So patient "A" is advised, go Gilenya or Aubagio or Tysabri whatall only to now have perhaps more events?

    Is it wise to presume a single clinical event would warrant "Lets roll the dice?" when a patient has been NEDA for a year, two, three?

    With me, while certainly anecdotal every exacerbation that resulted in change in my MRI was directly associated to me going through severe life stress. When I was diagnosed I was under the most stress I'd ever experienced in my entire life. I am not alone on this having met others who have described similar.

    Should such things be recorded by Neurologists. Perhaps in some of us catalysts that stress aspects of our emotional/mental/physical existence which influence our lives and Bod's also influences our disease(s)?

    Sure, the mechanisms of MS are still largely mysterious but many diseases have markers pertaining to things such as stress. Hypertension can catalyze varied disorders for example.

    It'd really suck to have an event on DMF, switch to whatall, Gilenya, go through the side effect maybe's and have two incidents on it. Go through wash out, only to jump off yet another bridge when I may have only had the one on DMF?

    Make me understand :)

    1. I understand your dilemma and I believe most PwMS and their clinicians ask the same questions. Personally, I practice didactically (probably the scientist in me); I believe that that NEDA is an aspiration and if it is as close as I can get my patients to a cure I will take it. We need to push boundaries in management so that we solve the problem in entirety. Of course, this is only my opinion...

    2. I really love this question posed. A lot of neurologists are so quick to advise a change in medication as soon as a relapse occurs. Ive been on 3 meds, GA (multiple relapses within 6 months with consistent deterioration, made sense to switch), Plegridy (1 relapse buts lots of MRI activity), and Gilenya (1 relapse with MRI activity). This last one is where Im at now. With one relapse and minimal disease activity on MRI (not NEDA), does this necessitate a switch? I think a whole post could be done on this if hasnt already

  3. I was on DMF for 2 years, no relapse in the first year and 3 relapses in second year. I am now on the Ocrelizumab phase III trial. EDSS 1.5 and mostly sensory symptoms at present numbness and pins and needles for the past few years that won't go away! But so far so far so good.

  4. These NEDA rates are terrible. Yes good vs placebo but are these what patients deserve?
    It feels like being asked to play a game you will lose eventually.


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