Sunday, 18 March 2018

#Thinkhand - Natalizumab preserves upper limb function in advanced disease

Most people with MS will have discrete episodes of disability - relapses - from which they get better. Unfortunately over time, many people gradually accumulate disability and stop having clear relapses. This shift is often labelled as a shift from 'relapsing' to 'progressive' disease, and once in the second phase people are often given the label 'secondary progressive MS'. While this label may not necessarily be that helpful - it make be more useful just to distinguish early from advanced MS - it is still widely in use. 


The evidence for using DMTs once people enter the 'progressive' phase is far less good than for people in the 'relapsing' phase. This has really affected what treatments people with advanced disease can get access to. As many readers may be aware, there is a case to be made that this lack of evidence is all to do with how the trials have been run. Most trials in advanced disease have focussed on measures of disability that are heavily weighted towards lower limb function. While this is obviously incredibly important, there are many aspects of advanced MS that affect people's lives but have nothing to do with the lower limbs - upper limb function, cognition, bladder and bowel function are the clearest examples. Upper limb function is a particularly interesting measure because it may be easier to protect than lower limb function and has obvious important real-life implications for how people can maintain independence and have a good quality of life.  

The ASCEND trial was a large international trial which asked whether natalizumab (tysabri) has an effect on disability in the progressive phase of the disease. We knew already from the AFFIRM study that natalizumab is really effective for both relapses and disability during the relapsing phase of the disease

People with MS were randomised to receive placebo or natalizumab injections every four weeks over a two year period. After that period, there was an open-label extension during which people in the placebo arm were invited to start natalizumab.

To be included in the study, you had to be aged 18-58, have had a diagnosis of 'secondary progressive' disease for at least 2 years, have had disability progression without relapses for at least a year, had no relapses in the 3 months prior to enrolment, have an EDSS from 3 - 6.5 and not have had natalizumab in the past.

They managed to recruit 889 people. To measure disability, the authors used three outcomes: the timed 25 foot walk test, EDSS, and the 9 hole peg test. They also used a combined measure taking into account all three of these tests.

Natalizumab treatment was not associated with any benefit in terms of EDSS or T25FW, but it reduced the proportion of people who got worse at the 9HPT. This is a staggering result, as it shows that natalizumab has an impact on upper limb disability over a two year period without affecting lower limb disability.

This result implies that people who have been labelled as having progressive disease can still derive benefit from natalizumab treatment. While it did not have a statistically significant effect on lower limb function, it was beneficial for preserving upper limb function, as measured by the 9HPT.

What does this mean?It bolsters the case for using more sophisticated outcomes in advanced MS trials. While restoring and protecting lower limb function is a holy grail, it is much more difficult to achieve at present, and focussing solely on EDSS and walking speed leads to people in wheelchairs generally being excluded from trials, and lead to potentially helpful drugs being discarded due to negative trial results.

The ASCEND trial also shows us that people who have been labelled with progressive disease still have ongoing inflammation in the brain. Around 1 in 4 participants had Gd-enhancing lesions at baseline, which implies active lesion formation, despite these participants not having been diagnosed with relapses. To explain how natalizumab works in advanced disease you can either invoke a new mechanism of action, or you can argue that it is probably working in the same way it does for relapsing disease: by preventing lymphocytes from getting into the CNS. 


I think the simplest explanation for ASCEND is that people with 'secondary progressive' disease have ongoing CNS inflammation which can be stoppered by preventing immune cells from getting in. Unfortunately the authors don't present an analysis of whether the number of Gd-enhancing lesions at baseline could predict response - it seems from the results that there is not much difference between people with and without Gd-enhancing lesions, but you can't glean this from the paper as is. Intuitively I would suspect that the more Gd+ lesions you have the better your chance of response to natalizumab. If true, this would add weight to the idea that natalizumab is working here by reducing CNS inflammation rather than another effect.  

In short, the idea that people in the progressive phase cannot benefit from therapies which limit inflammation is a myth.

This study is really important as it drives home the message that:

- People with advanced MS can benefit from treatment
- Tysabri is an example of an effective treatment for preserving upper limb function in advanced disease
-  Preserving upper limb function is an important and achievable goal in advanced MS trials
- There is a dissociation between upper and lower limb disability: here tysabri had no effect on the latter

This study definitely reinforces the #ThinkHand message and trashes the idea that relapsing and progressive disease are separate entities to be treated in a totally separate way. 

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Abstract

Background

Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.

Methods

ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.

Findings

Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.

Interpretation

Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.

3 comments:

  1. Why wait for trials to help ppms patients. Why not reclassify them as rrms and start them on natlizumab. You will get your trial results and save this untreated populatuon suffering from continuous progression. But you need big boy pants to mmake such stand.

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  2. So this will likely take >5 years, which many of us do not have, to run and implement results from a trial. This trial "might" be able to "slightly" slow the ultimate progression of the disease? So we may be able to squeeze out a little more time before the inevitable. There has to be a better answer than than putting weight behind more neuroinflammatory trials that have NEDA less than 50% at best in RRMS, let alone progressive MS.

    Is the goal of these trials to preserve function or actually improve function? I would prefer to back a trial that actually improves function. Something that actually remyelinates, effectively prevents neurodegeneration and promotes neurorestoration.

    I think MD and MD2 have expressed many great ideas on this blog that prevent neurodegeneration. Something other than neuroinflammation that works on hot microglia, A1 astrocytes and neuron protection. Why are these not being promoted and trialed by Barts MS research group concurrently?

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  3. As a PwPPMS, I am really disappointed with this blog's continued insistence on partial immune system destruction being the go to solution for all presentations of MS. I have sustained injury from MS, no question, but I do not wish to add a nobbled immune system to that for the sake of a _possible_ couple of years' leeway. I appreciate, for example, being able to tend to my flowers without worrying about being infected by a common garden fungus, and not having issues with UTIs, PML or added malignancy risk.

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