Thursday, 22 March 2018

The Phoenix has risen: the era of disease modification in progressive MS has truly arrived

The EXPAND study first positive study in people with secondary progressive MS and marks a new landmark in the treatment of MS.

Please note that I am a co-author on this paper and I sit on the trial steering committee. I am clearly conflicted and therefore you may not want to read or hear what I have to say about the trial's findings. 

If we #Thinkhand we would have another treatment for Progressive MS.

Kapoor R, Ho PR, Campbell N, Chang I, Deykin A, Forrestal F, Lucas N, Yu B, Arnold DL, Freedman MS, Goldman MD, Hartung HP, Havrdov√° EK, Jeffery D, Miller A, Sellebjerg F, Cadavid D, Mikol D, Steiner D; ASCEND investigators. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis(ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 2018 Mar 12. pii: S1474-4422(18)30069-3.

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, 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.

In a week where we have had the suggestion of guest authors on trials, I scan through the authors to see some familiar faces, but I am surprsied to see that this paper does not have ProfG as one of the lead authors. 

Why...he has been saying that if we use the EDSS as the primary outcome, we are throwing treatments for progressive MS away. He also argued that the original ACSEND trial was not long enough to see an effect on progression. 

We are so focussed on the legs as an outcome with the EDSS However, we should be focussing on upper limb and head function as it will have more reserve in the system to save by treatment.

As can be seen by this study, if you focussed on hand function you would have had a positive trial, as the Nine hole peg test showed a signficant treatment effect. The  effect on the lower limbs did not.

The regulators and neuros need to wake up and get rid of their EDSS-tinted tunnel vision.

Wednesday, 21 March 2018

Is it not time to extend the diagnosis of MS into the asymptomatic phase?

At a continuing medical education (CME) meeting I co-chaired in Vienna, a concept emerged that is silently gnawing away at my consciousness and has changed my thinking.

The concept concerns how we deal with the problem of the radiologically isolated syndrome (RIS) or asymptomatic MS.

Monday, 19 March 2018

Cladribine selectively depletes B cells and induces long term depletion of memory B cells

Last year we suggested that all agents that currently are used to inhibit MS, all target memory B cells.

The agents that are highly-effective deplete memory B cells well and those that are not highly-effective don't.

We didn't have the data on whether cladribine depletes memory B cells, but as cladribine is highly effective in treating relapsing MS.
It suggests that they should be depleted.

The hypothesis can be tested, as we have been using cladribine off-label.

If you want to know the on

MS in the News HSCT poster doing the rounds

"Game changing" HSCT data is being reported in the media.

This is in response to data being presented at a meeting, which we commented on a few weeks ago.. I saw Roumen Balabanov last week and he wasn't aware that the abstract below was published.

We made a post where the authors had complained about Social media as inaccurate, but I made the point that the authors are happy to take the benefits of Social Media.

This story is being circulated by Social Media.
If you want to read the abstract

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. 

Saturday, 17 March 2018

Charcot 3: does an anti-viral inhibit MS?

Does an anti-viral inhibit MS? Charcot 1 is still not published (nudge, nudge) but it didn't work but that didn't surprise me as the treatment agent prevented virus integrating into the DNA, which was targeting a virus that had already integrated.

However there was anecdote of disease remission after taking the drug. It has happened again:

Friday, 16 March 2018

Guest Authors: The alternative view

Earlier this week a piece was published in the Annals of Neurology reporting how certain authors are on clinical trials and implying that they could be "guest authors"; celebrated “key opinion leaders” who do not contribute to trial design or execution, or manuscript drafting, but whose name lends gravitas to the study.

Today Prof A gives a response to this.

Thursday, 15 March 2018

Can interleukin-4 save nerve cells?

Untreated inflammation is bad for the brain. Over time, repeated bouts of inflammation predispose to the gradual loss of nerve cells from the brain and spinal cord. This gradual degenerative process is what we can quantify with brain atrophy and measurements of neurofilament. Loss of nerve projections (axons) begins very early in the inflammatory process, occurs both within and distant from lesions, and is probably the main driver of disability.