Friday, 7 June 2013

Should natalizumab be first-line in JC virus negative MSers? The data says yes.

After Prof G's recent post about about whether Natalizumab (Tysabri) will get a first line licence , this new work is interesting

Campbell et al. Comparative effectiveness of early Natalizumab treatment in JC virus-negative relapsing-remitting multiple sclerosis. Am J Manag Care. 2013;19(4):278-285

Objectives: To estimate the long-term comparative effectiveness of first-line treatment in patients negative for anti-JC virus (JCV) antibodies with glatiramer acetate (GA), fingolimod, or natalizumab for relapsing-remitting multiple sclerosis (RRMS). 

Study Design: We developed a simulation model to estimate the average 20-year clinical risks and benefits of GA, fingolimod, and natalizumab for RRMS patients initially negative for anti-JCV antibodies. 

Methods: Model inputs included published natural history progressions of the Expanded Disability Status Scale (EDSS), treatment effects from randomized controlled trials on slowing disease progression and reducing relapse rates, risk of progressive multifocal leukoencephalopathy (PML), and utility preference scores. Outputs were long-term risks (PML risk and other non-PML risks), benefits (average relapse rate and time to disability [EDSS >7]), and quality-adjusted lifeyears (QALYs). 

Results: Compared with GA, natalizumab resulted in 4.6 fewer relapses, 0.6 more years of disabilityfree time, 0.0165 more cases of PML per treated patient, and an incremental 1.2 QALYs gained. Compared with fingolimod, natalizumab resulted in 1.7 fewer relapses, 0.1 more years of disabilityfree time, 0.0165 more cases of PML per treated patient, and an incremental 0.4 QALYs gained. The probability that incremental QALYs favored natalizumab over GA was 0.963 and natalizumab over fingolimod was 0.720. 

Conclusions: Average QALYs, a measure that aggregates across risks and benefits, favored natalizumab, suggesting more aggressive early intervention with natalizumab in the negative anti-JCV population. For certain decision makers, more evidence may be needed to further reduce the uncertainty in these comparative projections prior to making population-based adoption decisions.

It looks like the EMA do need more evidence.


  1. Epidemiology of JCV negative switching to positive should be taken into account in young patients. What happens then when you stop natalizumab? (is there a publication bias on this subject ?) Are study data from trials on severe patients transferable to patients seen at an earlier stage of the disease? What is the PML risk of Alemtuzumab in MS patient? There is a need for these answers. Then if everything is clear, there will a huge fight between alemtuzumab and natalizumab for first line treatment.
    I always wondered why we had to wait for 6 years between the first PML under Natalizumab and the test for JCV (JCV known wince 1952 and PML welknown in AIDS cases early 1980 -1990. Is Alemtuzumab the problem ?

    1. I suspect as JCV mediated PML was a pretty rare phenomenon usually only seen in rare AIDS patients, the impetus to develop a test was lacking until the natalizumab-mediated PML cases started showing up. Don't think there's anything sinister.
      As far as I'm aware PML has not been reported in alemtuzumab-treated Msers.

  2. Data says yes, EMA says no. Go figure............................

    1. Markov chains that project 20 years into the future are not exactly data.

    2. Many cannot afford to wait 20 years before your criteria are met.

    3. In other words you agree that the study provides prediction, not data.

  3. I actually would love to see a post on this:

  4. Study authors:
    Jonathan D. Campbell, PhD;
    R. Brett McQueen, PhD;
    Augusto Miravalle, MD;
    John R. Corboy, MD;
    Timothy L. Vollmer, MD; and
    Kavita Nair, PhD

    "Augusto A. Miravalle, MD is a consultant for Bayer Healthcare Pharmaceuticals Inc, Biogen Idec, and Questcor Pharmacueticals, Inc; is on the speakers bureau for EMD Serono and Teva Neuroscience; and has received consulting fees from Bayer Healthcare Pharmaceuticals Inc, Biogen Idec, Questcor Pharmaceuticals, Inc, and Teva Neuroscience."


    "Disclosure: Timothy L. Vollmer, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Acorda Therapeutics; Biogen Idec Inc.; Novartis Pharmaceuticals Corporation; Questcor Pharmaceuticals, Inc.; Teva Neuroscience, Inc.; Sanofi; XenoPort, Inc.
    Received grants for clinical research from: Acorda Therapeutics; Biogen Idec Inc.; BioMS Medical Corp; Daiichi Sankyo, Inc.; EMD Serono, Inc.; Genzyme Corporation; Jensen Research Corporation; Lilly USA, LLC; Ono Pharmaceuticals Co., Ltd.; Novartis Pharmaceuticals Corporation; Orasi Software, Inc.; Roche; Sanofi; Teva Neuroscience, Inc."


    Seem like the study suffers from Biogen bias.

    1. Picking up on the first comment 'What happens when you stop Tysabri? I'd like to hear a reply.
      My understanding is that JCV status changes so is it responsible to talk about Tysabri as a first line treatment when there are no clear alternatives to de-escalate to?
      Should we not be talking about the body of evidence around re-bound that happens when Tysabri is stopped and how we can manage this?
      Patients need to know the long term issues especially as this information was not around till fairly recently.

    2. suffers biogen bias (study)

      Well a study on a biogen product would have biogen bias wouldn't it?

      Hear a reply...that is Gs department.


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