I am not sure if you are tired of hearing about ‘the real MS’ or smouldering MS, but the study below provides you with some hope. A post-hoc analysis of the natalizumab secondary progressive or ASCEND trial shows that chronic MS lesion activity is associated with disability worsening. This is not a novel finding and builds on other evidence that chronic active lesions, which include slowly expanding lesions (SELs), cause tissue destruction and predict poor outcomes.

Smouldering coals - image from Wikipedia

What is a new finding is that natalizumab has an impact, albeit small, on these chronic active lesions, including SELs, and indicates that natalizumab is a potentially effective treatment for smouldering MS. It is also telling me that a component of smouldering MS, possible a large component, is still being driven by inflammation from the periphery and that by blocking the trafficking of lymphocytes into the central nervous system you slow down the process. So why then is natalizumab not licensed for people with progressive MS?

The short answer the ASCEND study was poorly designed and Biogen shot itself in the foot. Their study was too short or the primary outcome was inappropriate for a 2-year read-out. I did try to get Biogen to change their study design and extend it by a year, but my appeals fell on deaf ears.

What was the ASCEND study negative?

Worsening disability in someone with progressive MS in the short to intermediate term, say over the next 2 years, is primed by inflammation from the past, i.e. over the last few years. Suppressing inflammation today, therefore, will have little, or potentially no, impact on worsening disability over the next one to two years as the damage priming progression over this time has already occurred. Therefore, all anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS.

The population of pwSPMS in the ASCEND trial were very advanced with more than 60% needing a walking stick (EDSS 6.0 or 6.5). As the majority of the trial participants were almost off their feet and had markedly reduced reserve in the neuronal pathway supplying their legs it is difficult to show a treatment response in 2 years, because the inflammation priming this worsening has already happened.

Sadly, as predicted, the ASCEND study was negative on lower limb function (EDSS and timed-25 foot walk), but positive on upper limb function (9-hole peg test) at 2 years. As predicted from therapeutic lag the study was positive at 3 years in the extension study. These results are consistent with MS being a length-dependent central axonopathy; the longer the central nerve fibres are the more likely they are to get hit multiple times by MS lesions and the sooner they degenerate. The nerve fibres supplying the legs are about twice as long as those supplying the arms, which is why smouldering MS becomes apparent sooner in relation to walking/running compared to arm and hand function.

Another interesting observation from the ASCEND trial is the data showing that natalizumab-treated pwSPMS were more likely to have a confirmed disability improvement compared to placebo-treated and a significant lowering of blood neurofilament levels in the 2-year period of blinded observation. Could natalizumab’s impact on peripheral blood NFL levels and chronic active lesions, including SELs, allow a reversal of the neurodegenerative pathology and allow some neuroregeneration and recovery of function? It is a real pity we don’t have spinal fluid from the ASCEND trial participants it would be fascinating to look at regenerative biomarkers, i.e. is there any evidence of axonal sprouting and synaptogenesis on natalizumab?

What these post-hoc analyses are telling us is that so-called non-relapsing advanced MS is still inflammatory, i.e. not inactive and that this inflammation is modifiable by a highly effective DMT such as natalizumab.

I am convinced that natalizumab is an effective treatment for SPMS. If I was Biogen I would do an ASCEND-2 or ASCEND-HAND trial of natalizumab in advanced MS only this time extending recruitment into pwMS in wheelchairs, similar to what we are doing with the ORATORIO-HAND (ocrelizumab in PPMS) or CHARIOT-MS (cladribine in progressive) studies.

Another potential option is a randomised withdrawal study. The latter could be done in the UK, where we are forced to stop DMTs in pwMS who have become SPMS or wheelchair-bound. The idea is to randomise pwMS having to stop DMTs to placebo or natalizumab with the primary outcome being time to relapse or evident disease activity using MRI and serum NFL levels. Some of you may ask, what about PML? Yes, what about PML? This can potentially be derisked using the current tools including extended interval dosing (EID). Please be aware that both JCV and PML are biological problems and sometime in the future we will have effective treatment for JCV infections. This is why we shouldn’t give up on natalizumab and other anti-trafficking DMTs.

The implications of the therapeutic lag and length-dependent axonopathy are that MS is an asynchronous progressive disease for want of a better term. You may have progressive MS in your legs and still be relapsing in your arms and brain stem. It is clear we have been designing, and doing, trials in progressive MS incorrectly. More importantly, these concepts challenge the so-called therapeutic window. It also means that instead of writing someone off with progressive MS because their so-called therapeutic window has closed is that we can now focus on the other therapeutic windows that are still open, i.e. hand and arm function, cognition, speech and swallowing...

It has never made sense to me not to be able to prescribe a DMT to pwMS simply because they needed a wheelchair as a result of a devastating spinal cord relapse. What about their upper limb, cognitive and cerebellar function? Do we simply write these systems off because one, or two, systems are severely damaged? I personally think the therapeutic lag and asynchronous progressive MS hypotheses give pwMS hope; hope for treatments that can at least preserve the function of pathways with reserve capacity, whilst we work on remyelination and neurorestorative strategies. This will at least buy us time and spread hope!

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Article

Beynon et al. Chronic lesion activity and disability progression in secondary progressive multiple sclerosis. BMJ Open Neurology https://neurologyopen.bmj.com/content/4/1/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. However, the relationships between SELs, acute lesion activity (ALA), overall chronic lesion activity (CLA) and disability progression are not well understood. 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: CLA 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 ALA at baseline and on study, 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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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.

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