There is more to SPMS than active inflammation

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ASCEND is a clinical trial of natalizumab in secondary progressive MS and based on looking at EDSS (a walking scale at the point tested) the trial failed and natalizumab was, in the eyes of many neuros, chucked on the maggot pile as far as treating progressive MS has been concerned.

However, this view has been challenged based on response to changes in hand function and in relation to effects on neurofilament both indicating that natalizumab has some positive effect and shows the weakness of basing your trial endpoints on outcomes that may have exhausted their reserve and can only respond poorly

It has been said that “All investigated outcome measures in SPMS showed some evidence of random variation and measurement error, the Timed 25 Foot Walk and 9-Hole Peg Test less so than the more established outcome EDSS”. 

However, sadly I am not sure the average neuro is going to change their view and see it as a fail. This is a shame because it hampers progress and accesss to useful treatments.

Thankfully there has been some movement with the regulators and now hand function is a main outcome, because with this natalizumb and others would have been considered to be positive. However that is not to say that natalizumab is the answer for people with secondary progressive MS, but it is an important part of the answer.

We have said until I am blue in the face that active inflammation is damaging and this is a part that we know responds to treatment. However, there are elements of progression that does not respond to these treatments and the paper below indicates that there are elements of progression that cannot be linked to active lesions. However, again I would argue that we should consider that we need to target BOTH or ALL elements. Doing single agent trials is in my opinion a reason for slow progress. There have been many single agent trials, this was the norm in the past, and no doubt this will occur in the future too…..Why?

It complicates studies and can increase costs.

However as licenced agents become available for all elements of MS, it will be increasingly difficult to deny people access to treatment for trials. Due to events in the World I am sure trials in certain parts of the World will become more difficult.

Trials will need to be add-on, but they should be add-on to a highly-effective agent rather than on low-efficacy agents, which seems to be the case, especially with pharma studies where new drugs are compared to agents that are weakly active.

Beynon V, George IC, Elliott C, Arnold DL, Ke J, Chen H, Zhu L, Ke C, Giovannoni G, Scaramozza M, Campbell N, Bradley DP, Franchimont N, Gafson A, Belachew S. Chronic lesion activity and disability progression in secondary progressive multiple sclerosis. BMJ Neurol Open. 2022; 4: e000240. 

Objective: Slowly expanding lesions (SELs), a subgroup of chronic white matter lesions that gradually expand over time, have been shown to predict disability accumulation in primary progressive multiple sclerosis (MS) disease……In this study, we examined the ASCEND phase III clinical trial, which compared natalizumab with placebo in secondary progressive MS (SPMS).

Methods: Patients with complete imaging datasets between baseline and week 108 (N=600) were analysed for SEL prevalence (the number and volume of SELs), disability progression, ALA (assessed by gadolinium-enhancing lesions and new T2-hyperintense lesions) and CLA (assessed by T1-hypointense lesion volume increase within baseline T2-non-enhancing lesions identified as SELs and non-SELs).

Results: Chronic lesion activity in both SELs and non-SELs was greater in patients with SPMS with confirmed disability progression than in those with no progression. In the complete absence of acute lesion activity (assessed by gadolinium-enhancing lesions and new T2-hyperintense lesions) at baseline, SEL prevalence was significantly lower, while CLA within non-SELs remained associated with disability progression. Natalizumab decreased SEL prevalence and CLA in SELs and non-SELs compared with placebo.

Conclusions: This study shows that CLA in patients with SPMS is decreased but persists in the absence of ALA and is associated with disability progression, highlighting the need for therapeutics targeting all mechanisms of CLA, including smouldering inflammation and neurodegeneration.

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MouseDoctor

3 comments

  • So Biogen can do Natalizumab and BTKi trial and Roche can do Ocrelizumab and BTKi trial.
    Please hurry up a bit cause time is QOL for us.

  • We have said until I am blue in the face that active inflammation is damaging

    Yep think about RA

    Nice post

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