ResearchSpeak & #ThinkHand: ECTRIMS highlight sustained improvement in SPMS

Wow who would have thought you would get improved function in advanced SPMS? #ThinkHand #ECTRIMS2016 #ResearchSpeak #MSBlog

"The poster below is one of my ECTRIMS highlights. It has made me think differently about MS, in particular about the mechanisms behind the improvement in neurological function. In short if the natalizumab in SPMS trial (ASCEND study) had been designed with the primary outcome being sustained improvement in function then we would have had a drug available for SPMS. It is quite amazing given what 'we think we know about SPMS' that this study was positive. I thought that advanced SPMS was progressive with little room for recovery of neurological function. How wrong I was!"

"As you know the ASCEND trial was 'negative' in that it did not hit its primary outcome at 2-years, which was a composite loaded with lower limb function (EDSS and timed-25ft-walk or T25W). However, the trial was positive on the 9-HPT. In other words SPMSers on natalizumab have something to gain from natalizumab in relation to protecting arm and hand function. In fact natalizumab was so good in the ASCEND trial that it almost flat-lined upper limb function. Why the difference in outcomes between lower and upper limbs? I have made the argument many time before that if you have lost your reserve capacity in a particular system, which was the case in the lower limbs in this study (most subjects had an EDSS of >= 6.0) then it would take years to see a positive outcome. I have referred to the latter as therapeutic lag. However, if you have neuronal reserve in a pathway, the arms and hands in this case, then you get a read-out in relation to anti-inflammatory effects much sooner. It is a great tragedy that the ASCEND study was not 3, or 4, years in duration. I am sure based on other insights this would have been sufficient to see an effect on lower limb function. Unfortunately, long trials in SPMS are a problem because of drop-outs so it not really feasible to do studies much beyond 2 years. To overcome this issue we need to focus on arm & hand function as the primary outcome, or after the analysis below sustained improvement."

"What is important about this study is that the time course of disease improvement (early) and disease progression (late) must be due to different mechanisms. I suspect disease improvement is directly linked to switching off inflammation and reversing conduction block and allowing remyelination and axonal and synaptic plasticity to occur. These process occur over weeks to months and are well described in acute lesions, for example optic neuritis. The latter indicates that SPMS, even advanced SPMS, is characterised by focal inflammation. I therefore suspect SPMSers are still having relapses, or focal lesions, which are probably occurring below the detection threshold of  the MRI. Dare I call these micro-relapses? In comparison, reducing delayed disability progression is the impact of anti-inflammatories, on preventing chronic axonal damage and with the resultant delayed fall-out of damaged axons over months to years."

"The results of this ASCEND study are simply stunning and mean that progressive MS is a tractable problem. I don't think the sustained improvement is due to neuro-restoration, but simply due to recovery of function of existing axons. We talk about developing new techniques and method for doing progressive trials, but I  think we already have the toolbox at our disposal. All we need to do now is get on with doing as many SPMS and PPMS trials as possible with a focus on disease improvement (early) and delayed progression (late) with the primary outcome being upper limb function (#ThinkHand), over lower limb function, in MSers with more advanced MS (EDSS >= 6.0)."

"I sincerely hope all of you are as excited by this as I am. If Biogen don't go to  the regulators with this data then we the MS community need to start the discussion. Yes, I am aware that natalizumab is expensive and the cost-effectiveness of natalizumab in SPMS may not hold up to NICE, but natalizumab will eventually come off patent and hopefully cheap biosimilars will make it cost-effective. If I had SPMS I would want to be on natalizumab; I value my hand and arm function far too much."


‘Now that I can’t walk, my hands and arms have become my legs….’
a person with MS


Deb Steiner and Prof G at the poster at ECTRIMS!



CoI: multiple

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