Saturday, 26 November 2016

#ClinicSpeak & #NeuroSpeak: NEDA defines a pecking order

At last we begin to see treat-2-target of NEDA entering clinical practice. #NeuroSpeak #ClinicSpeak #MSBlog

The study below shows treating-2-target finaling getting traction in the real-world. Interestingly when you treat to target NEDA rates increase substantially. Why? One of the criticisms is that NEDA is very difficult to attain and several data sets have shown that NEDA rates are low. The reason why NEDA rates were low is because all these data were collected in an era when we weren't treating to a target; in other words people failing on a DMT, or with a suboptimal response, were left on their DMT. However, by treating to a target you are enriching for responders on a DMT and if someone is not responding you switch/escalate them to another DMT. By doing this you keep increasing the proportion of pwMS who are NEDA on a particular drug.

The next development that has to enter the field is rebaselining. Not all people understand the need for rebaselining. This means that you exclude the period of time when the drug is not fully effective; with most DMTs this is first 3-6 months; the exceptions being glatiramer acetate (9 months) and PIRTS (pulsed immune reconstitution therapies) when you rebaseline after the treatment period, for example with alemtuzumab and cladribine this will be at 24 months.

Surprise, surprise in the study below natalizumab and fingolimod or more effective at rendering pwMS NEDA than the injectables (interferon-beta and glatiramer acetate) and natalizumab has the edge over fingolimod. These hierarchy of efficacy is what you would expect from pivotal clinical trial results.


Prosperini et al. Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in non-responders and in treatment-naïve patients with multiple sclerosis.
J Neurol. 2016 Nov 22. [Epub ahead of print]

Background: In this independent, multicentre post-marketing study we directly compared the effectiveness of natalizumab (NTZ), fingolimod (FNG) and self-injectable drugs (INJ), in non-responders to first immunomodulating treatment and in highly active treatment-naïve patients with multiple sclerosis.

Methods: As main outcome measure we considered the proportions of patients with no evidence of disease activity (NEDA-3), defined as absence of relapses, disability worsening and radiological activity. A total of 567 non-responders to interferon beta (IFNB) or glatiramer acetate (GA) [dataset A] and 216 highly active treatment-naïves [dataset B] were followed up to 24 months from the beginning of NTZ, FNG or INJ, i.e. switching from IFNB to GA or viceversa (in the case of non-responders) or starting high-dose IFNB (in the case of highly active treatment-naïves). Propensity score matching in a 1:1:1 ratio was used to select only patients with similar baseline characteristics, retaining 330 and 120 patients in dataset A and B, respectively.

Results: In dataset A, the 24-month proportion with NEDA-3 was greater in both NTZ group (67%) and FNG group (42%) than in INJ group (35%) (p ≤ 0.016); however, NTZ was superior to FNG in promoting the attainment of NEDA-3 status (p = 0.034). In dataset B, the 24-month proportion with NEDA-3 was greater in NTZ group (75%) and FNG group (67%) than in INJ group (40%), but the small cohort sizes most likely prevented the detection of any statistically significant difference.

Conclusion: Our study provides real-world evidence that NTZ was more effective than both FNG and INJ in non-responders, while it could seem that, in highly active treatment-naïves, NTZ was as effective as FNG and both were superior to INJ.

CoI: multiple

6 comments:

  1. Why was rebaselining performed annually for each year in the Lemtrada extension study? It's impossible to really know how many are NEDA at the end of that study when the results only give us the NEDA statistic *per year*. I'd like to know what percentage were NEDA at the end of the study?

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  2. i find re-baselining positive and negative: but it can only be effective if all trials are done with it.
    i'm unsure how i feel about re-baselining after the first 6 months post dmt initiation. with lemtrada, i understand the need for post re-dosing re-baselining in the first 2-3 years (after the initial 'induction doses').

    after or outside that point, re-baselining can hide real data and lead to questionable conclusions, in the context of making decisions on re-treating v. treating with another drug like rituximab/ocrelizumab.

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    1. Yes, it's unclear why the data from the extension study with Lemtrada was presented as NEDA *per year*. Was the final result really that bad, that the manufacturers could only talk about each year in isolation?

      I would be very interested to know and have asked several times on this blog what percentage were NEDA at the end of the study? I suspect Prof G may know but as yet has not answered this question. Sometimes, silence speaks loudly...

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    2. I have been following your question with interest for almost as long as you been asking it... :)

      Maybe the big conspiracy is that Lemtrada is not really an induction treatment and its efficacy is as almost as reliant on redosing as Tysabri's.... would be a bit of marketing oops

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  3. My theory on rebaslining is it is staticial manipulation. I accept the need for just after treatment, but agree with Life Goes On above, rebaslining each year for alemtuzumab is a farce. It makes a drug look significantly more effective than it is. Does anyone else know a stat where that is done? Take a drug, it doesn't work, take more of the drug and effectively ignore the year where the drug didn't work.
    Comparing HSCT and alemtuzumab when one is based purely on 1 off treatment and the other is rebaslined is laughable.
    Is natalizumab rebaslined in these studies?

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    Replies
    1. HSCT may or may not be a one off treatment for individuals with MS over their lifetime.

      If a drug reduces new lesion creation and/or progression, then re-baselining can make sense, in some circumstances.

      My problem with the traditional escalation strategy is the cumulative amount of time people would stay unprotected by having to fail one drug after another. It's conceivable that the trip from copaxone to gilenya to tysabri would be in response to 3 new lesions created on each dmt... cept most dmts take between 3 and 6 months to work (conceivably leaving a person unprotected for 9 to 12 months cumulatively). Add the washouts and the rebound...

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