Monday, 25 April 2016

ResearchSpeak: will you be able to choose your PIRT?

Choose your PIRT (pulsed immune reconstitution therapy)? #AAN2016 #ResearchSpeak #MSBlog #MSResearch

"The following are the two posters I presented on PIRTs at the AAN in Vancouver."

"There were many posters and presentations on the durability of the treatment response of MSers to alemtuzumab. The data just gets better, and better with each year of follow-up. What people don’t seem to realise is that the majority of MSers are flat-lining (NEDA) with only two cycles of treatment. In fact a significant proportion of treated subjects have actually improved. Our world-view of MS doesn’t really take into account improvement in fixed disability. The 5-year alemtuzumab data brain volume demonstrates brain atrophy rates well within the range of what we see in normal subjects. This data is almost too good to be true and I have hypothesised that the average data may be contaminated by a subgroup of subjects with reversal of pseudoatrophy.

What is reversal of pseudoatrophy? When you have inflammation in your brain it swells from the effects of inflammation. When you switch off this inflammation the brain shrinks; this is typically seen within the first 6 months after starting an anti-inflammatory therapy. It is likely that when inflammation returns the brain will swell again and increase in volume. We know that a proportion of subjects who receive alemtuzumab will have recrudescence of their disease activity and if their brains swell this may bias the brain atrophy data towards being supranormal, i.e. better than normal. 

Another possibility is that alemtuzumab causes disability improvement in pwMS. Could subjects who improve post-alemtuzumab rewire, or expand, their brain sizes due to axonal sprouting, synaptogenesis (new synapses) and plasticity? I have put in a request to the statisticians at Sanofi-Genzyme to analyse the data to look for reversal of pseudoatrophy and/or brain recovery. The latter may not be that far fetched, in a very early MRI follow-up study on alemtuzumab-treated patients from Cambridge using MTR (magnetization ratios) a marker of structural integrity showed improvement in the MTR suggesting recovery of brain function.

The other poster is on the CLARITY extension study and the durability of cladribine as a PIRT. MSers in the phase 3 trial who were randomised to placebo in years 3 and 4 of the extension study did very well with very low levels of recurrent disease activity. Unfortunately, we don't have as rich a data set with cladribine, as we do with alemtuzumab, to see how these MSers do over the long-term. If cladribine tablets get licensed by the EMA, as I hope they do, maybe the NHS will allow us to do a randomised head-2-head study to compare alemtuzumab with cladribine? An even better study would be to include a HSCT arm to test three PIRTs in parallel. 

The billion dollar question is whether or not you the NHS will allow you to choose between PIRT 1 and PIRT 2?"

CoI: multiple


  1. "If cladribine tablets get licensed by the EMA, as I hope they do, maybe the NHS will allow us to do a randomised head-2-head study to compare alemtuzumab with cladribine?"

    This would be such an irony given we - unsuccessfully - submitted a substantial grant about 1.5 years ago to the NIHR for funding of exactly this trial, but with generic Cladribine as the comparator. Not only would this have answered the scientific question but also saved the NHS a vast amount of money in the process - but with hindsight it was obviously never going to happen regardless.

    1. Do you know how approvation process of Cladribine is going?

    2. Not sure if it has even started, ProfG will probably know but will be presumably gagged. Once submitted I think the EMA has a year to decide what to do, so another few million down the toilet. It has been over 6 months since this was officially announced but it has only been five years of lost revenue so far no rush then.

      If cladribine gets licenced why not a head to head with generic:-)

      P.S. I wonder if PIRT is the correct term maybe the PIST is better:-)

      Pulsed immunsennescnce therapy, because what is evident with Alemtuzumab there is not reconstitution for a very, very , very long time. The treatment wipes ot T cells for months and months and months.
      and makes it less able to respond to immune targets

      Is it that you wipe out the cells and they simly dont repopulate properly because the bone marrow is indeed affected, in contrast to that published, and you don't have a fully functional thymus (it atrophies with age) so that new cells are not properly replaced.

      It is argued that if you look at the percentage of cells that the memory cells come back, but if you look at the absolute numbers they are simply wiped out relative to health for a long long long long time. They are kept in check by enhanced regulatory activity.

      It is argued that if they can stimulate the thymus to get more naive cells back you may get rid of the autoimmunity. However there is the potential to do just the opposite as you may be bringing potentially pathogenic cells into a world of lack of immune regulation

      T regs and othe regs are also wiped out of sight but on a percentage basis they are relatively spared

      Therefore the situation may well be worse not better. The trial has stopped recruiting and so we will see what happens, better, no effect or worse.

  2. The lack of richer data on month in Cladribine is obviously this still not be "commercially approved for such." It would be nice to see data on the effects of Cladribine in pseudoatrofia, recovery of brain synaptogenesis and neuroplasticity. Already I suspect that the data would be very good as the injectable Cladribine penetrates 100% brain.

  3. Prof G,

    Could you please discuss the Alemtuzumab 10 year data?

    You said 'the majority of MS'ers are flat-lining (NEDA) with only two cycles of treatment". What is the actual statistic here and where is it from? Last I read (based on the CARE-MS studies), this was 39%, which is certainly not the majority. And this was only at 2 years.

    Great news about the brain volume data. I'd love to see the 10 year data that was presented at the AAN2016, or your summary of it.

    Thank you

  4. Prof G, in your PIRT slide deck above, you mention that Maintenance Therapy is accompanied by cumulative or increased risk with time, as opposed to front loading risk with PIRT. Is that accumulated risk a result of limited/lower efficacy or exposure to daily/weekly immunosuppression? And if the latter, what is the risk and what are we seeing in the long term data?

    1. Risk to constant daily weekly monthly immunosuppression.....what are the risks in the long term data.increased risk of PML, then there will be infections cancers etc

    2. There is data out there showing increased infection/cancer risk with 10+ years of IFN or GA use?


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