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

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