Saturday, 28 July 2018

Pre-natalizumab vs. after-natalizumab

I view MS as having two eras, the pre-natalizumab era and after-natalizumab era. Natalizumab has been a transformational therapy for so many reasons and this study provides a little more evidence to support this position. 


I have always said that flipping the pyramid is the best way to maximise outcomes for a population of MSers. This study shows that MSers on high-efficacy DMTs are much more likely to work and when they do work their work is more productive. 

The Australians, where this study was done, are fortunate to have all high-efficacy DMTs 1st-line. Their healthcare system leaves the decision-making up to the HCP and patient and they don't prescribe strict rules. If I had MS I would want to be living in Australia. 

This study also supports my demand to Biogen to please get the EMA marketing authorisation for natalizumab changed; we need it first-line for MSers who are JCV seronegative. Please! 

Chen et al. Effects of multiple sclerosis disease-modifying therapies on employment measures using patient-reported data. JNNP 2018; http://dx.doi.org/10.1136/jnnp-2018-318228

Background: The direct comparative evidence on treatment effects of available multiple sclerosis (MS) disease-modifying therapies (DMTs) is limited, and few studies have examined the benefits of DMTs on employment outcomes. We compared the effects of DMTs used in the previous 5 years on improving the work attendance, amount of work and work productivity of people with MS.

Methods: The Australian MS Longitudinal Study collected data from participants on DMTs usage from 2010 to 2015 and whether DMTs contributed to changes in employment outcomes. We classified 11 DMTs into three categories based on their clinical efficacy (β-interferons and glatiramer acetate as category 1; teriflunomide and dimethyl fumarate as category 2; fingolimod, natalizumab, alemtuzumab and mitoxantrone as category 3). Each DMT used by a participant was treated as one observation and analysed by log-multinomial regression.

Results: Of the 874 participants included, 1384 observations were generated. Those who used category 3 (higher efficacy) DMTs were 2–3 times more likely to report improvements in amount of work, work attendance and work productivity compared with those who used category 1 (classical injectable) DMTs. Natalizumab was associated with superior beneficial effects on patient-reported employment outcomes than fingolimod (RR=1.76, 95% CI 1.02 to 3.03 for increased work attendance and RR=1.46, 95% CI 1.02 to 2.10 for increased work productivity).

Conclusions: Those using the higher efficacy (category 3) DMTs, particularly fingolimod and natalizumab, reported significant increases in amount of work, work attendance and work productivity, suggesting they have important beneficial effects on work life in people with MS.

ProfG    

25 comments:

  1. This is very important data. Why don't you send it to NICE and NHS England to see if it will change the cost-effectiveness of natalizumab in the UK. You may be able to use it first-line without a change in the EMA label?

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    1. Easier said than done! NICE is an organisation that responds to industry; Biogen will need to do it. I am not aware of any mechanism of academics submitting to NICE. We could make a case to NHS England, but again they are unlikely to rock the boat.

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  2. Very insightful. Thanks prof G. I too started working after my first round of alemtuzumab. Much much more focused. Work in system design. My IQ feels back to annoying levels to others. Would you say alemtuzumab impact would be another era before an after for ms?

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    1. At least we have alemtuzumab first-line in the UK. But wouldn't it be nice if MSers could choose between the high efficacy DMTs based on their attributes? I know that many JCV-ve MSers would opt for natalizumab over alemtuzumab.

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    2. Yes I would agree. But this is how I looked at it. When someone is stealing your crown jewels (Brain and Spine). Do you really care about petty cash being stolen from the cash till? Would you say nat and alem have the same impact ?Or alem is superior?

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    3. But if EBV is the root cause of MS don't these high efficacy DMTs
      just treat downstream effects i.e. relapses and not EBV.
      Thus giving people a more benign MS experience until immune system ageing eventually sets in the 40'-50's when PPMS/SPMS sets in.

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    4. We hypothesise that all high efficacy DMTs are taking out memory B cells and work via purging EBV from one or other compartment. The most effective agents against EBV are B-cell therapies. Interesting?

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    5. Let's not kid ourselves here. Yes..works fine in RRMS. But doesn't seem like peripheral B cell depletion can treat/prevent SPMS/PPMS at all.
      Even if you gave Tysabri so early it was in utero it would not make a difference.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221476/


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    6. Ah but there are compounds coming on stream (BTK inhibitors) for MS that are CNS penetrant that can deplete plasma cells and B cells in the brain and also downregulate activated microglia and astrocytes too Which might be just what we need for SPMS and potentially PPMS too.

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    7. MD2 you keep repeating about BTK inhibitors, how about you make a post about it??? ;)

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    8. Post now up, BTK inhibitors are discussed in the paper (free to view if you click on link).

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  3. I would assume that these are all RRMS cases Dr. G.? It does not include any SPMS or PPMS cases as they would not likely be approved to be on neuro-inflammatory DMDs.

    I would interested to see study like this with progressive cases only and highly doubt it would have the same shine. The treatment pyramid is currently a rectangle and not pyramid. It focuses sadly on neuroinflammmation only and has ignored 100% of neurodegeneration, remyelination and neurorestoration and provides very little hope for progressive patients, which currently makes up a massive amount of MS patients.

    When will help be on the way for progressive patients Dr. G?

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    1. MS is one disease not 3 diseases, particularly in Australia. I suspect some of the patients on natalizumab in Australia would have so called active SPMS and PPMS.

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    2. It is a bit worrying that many readers still don't get the concept that MS is one and not 2 or 3 diseases and that MS is modifiable regardless of how one classifies it clinically. We believe it is still modifiable when people are in wheelchairs, which is why we are doing the ORATORIO-HAND and CHARIOT-MS trials.

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    3. Pharma, not the patients, made up the faulty 3 divisions solely for monetary purposes. Now, this has come full circle and will hurt every progressive patient without relapses or being Gd+ on MRI (ie. majority of SPMS and PPMS patients).

      As for "it is still modifiable when people are in wheelchairs". I think your expectation of modifiable is different than that of the patients.

      You want patients to not worsen or delay the inevitable, which is great, but I think patients actually want improved QOL and to actually improve clinically, which will only happen through stopping neurodegeneration, remyelination and neurorestoration.

      Say your neuroinflammatory cladribine trial works, like the siponimod or ocrezulimab trials, this is great and will delay progression by maybe 25% (maybe slightly higher taking into account your therapeutic lag and length dependent axonopathy hypothesis). How does this improve the clinical condition, not just delay the decline, of an MS patient?

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    4. " MS is modifiable regardless of how one classifies it clinically. We believe it is still modifiable when people are in wheelchairs, which is why we are doing the ORATORIO-HAND and CHARIOT-MS trials."

      Really????

      You said otherwise 3 months ago

      "I am going to spell out more clearly how we define active PPMS so that when patients come for follow-up assessments they are forewarned and prepared for a possible decision of no treatment."

      http://multiple-sclerosis-research.blogspot.com/2018/05/not-managing-expectations-in-someone.html

      Maybe its better to "manage expectations of ORATORIO-HAND and

      CHARIOT-MS patients" ;)

      Obrigado

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    5. The Chariot trials will provide an evidence base in a controlled trial environment. This is not the same as compassionate treatment as there is no comparitor group.

      We have been prescribing off-label cladribine, but many places /people do not so you will get nothing.

      Had Cambridge done a placebo arm when they did their progressive MS studies withh alemtuzumab maybe there would have been a formal trial years ago. Maybe now it is too late to do it as ocrelizumab has stolen the lead. We know that people got worse but does not mean it didnt do anything. Similarly do we know how useful HSCT is in progressive MS.

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  4. shouldnt it be the pre and post cladribine era?? dr k should speak up!!! we know cladribine is better than natlizumab!!

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  5. MD couldn't answer my questions, so here they are again:

    1. What is the mean duration of natalizumab treatment before discontinuation and what are the main causes of discontinuation.

    2. What are the total PML incidents up to present day? The counter seems to have stopped 8 months ago.

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    1. Not sure I could answer the questions, but they are rhetorical ass you know the answer.

      (1) 24 months if you are JC positive and have had previous immunosuppression I suspect.
      (2) ProfG does those figures but you tap into the info provided by

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    2. Rephrasing,
      1. In real life, how long do patients stay on natalizumab before stopping or changing treatment? How many stop because of PML risk? How many change treatment? How many stop because they feel cured?
      2. Last update on December 7th 2017, with 756 PML cases total. No update since then. Why? How many PML cases up to present day?

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    3. In real life it depends on JCV status, if JC negative there is probably no reason to change, if JCV positive we would suggest changing. No one should stop because there is no evidence that it is curative and quite the opposite there is evidence it isn't stop and disease comes back.

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  6. Tysabri is the beloved drug of pwMS (imagine that its fb group is called Tysabri: As long as my body tolerates it, I'm not scared of PML!)! Second favorite would be Rituxan while Mavenclad is gaining ground fast.
    Ocrevus patients on the other hand have many complains for its side effects.
    The three out of four drugs are "locked" for most patients. Isn't it time to reconsider their status?

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  7. The point about this post is pre and post high efficacy DMTs. It is those DMTs that prevent end organ damage and slow the rate of brain volume loss into the 'normal' range. Natalizumab was the first

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