Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Giovannoni G, Cutter G, Pia-Sormani M, Belachew S, Hyde R, Koendgen H, Knappertz V, Tomic D, Leppert D, Herndon R, Wheeler-Kingshott CA, Ciccarelli O, Selwood D, di Cantogno EV, Ben-Amor AF, Matthews P, Carassiti D, Baker D, Schmierer K. Mult Scler Relat Disord. 2017 Feb;12:70-78. doi: 10.1016/j.msard.2017.01.007. Review.
Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.
ProfG was recently at his debating Society and lost.
But in fact it is you who have lost, because the argument that ProfG was making, was falling on deaf-ears.
He said we should not simply see MS, as a two stage disease, one stage relapsing disease and the second stage progressive disease, but as a continuum.
However, the two stage disease has been winning the vote meaning people are buying-in to doing nothing, once frank progression starts.
You lose because their is no ambition to make a Treatment for all.
This was the tennet for ProfGs Ig Nobel prize and a few papers contribute to this view.
However, it should not be all doom and gloom because the data is there.
It is clear that one stage does not suddenly materialize. The inflammation starts from the get-go and persists in some guise and likewise the neurodegenerative component occurs from the word-go and persists in progressive MS.
So everyone can gain some benefit from curbing inflammation, with would be even better if we stopped inflammation and saved nerves and promoted repair.
If you have been reading the blog, the content of this paper should come as no surprise.
This is because the take-home message is that we should be aiming to preserve what we can preserve and aim to give “Treatment for All”.
If your legs have gone, let’s aim to save your arms, and if your arms go let’s save the head. We have focused too long on the legs and this has meant no treatments for people with progressive MS and no treatments for people in wheel chairs..
Had we focused on the arms, some form of treatment could have been available years ago.
However, this paper has taken 2 years to surface, as it was submitted in March 2015. So there is some resistance within the community to maintain the blinkered view.
The other cause of tardiness may have been down to profG:-(
Blinkers mean slow progress.
- The longer the nerve pathway.
- The more likely is that it will be affected by MS lesions.
- Therefore disability will become more noticeable in these pathways.
The longest nerve pathways are to the toes and so it is surprising that loss of movement is one of the major systems affected.
So studies focus of mobility and the EDSS. This paper suggests that there may be a hierarchy of the speed in which systems are affected.
This leads to the Asynchronous Progressive Disease model.
Each nerve pathway has some reserve capacity to compensate for damage, but this reserve gets exhausted at different rates, so system breakdown starting with the bladder and lower legs on the whole become affect first….there are always exceptions to the rule.
Let’s imaging that the nerves are like sparklers and once lit they will burn until they finish, and once started they are hard, but not impossible to put out. Once you have sparklers they are going to be lit one by one until the packet is finished
However, it is easy to stop the next sparkler being lit. This is what current DMT do, and whilst their use may be too late to stop progression in something that is already programmed to be damaged, it may not be too later to stop the next nerve pathway accumulating so much damage it becomes a sparkler.
This can be achieved with some current MS drugs, but it we focus on our legs it may be too later to stop the progression. So trials fails and you have no treatment. However
Then you may be able to save lost function. Ocrelizumab saved leg function but saved even more of hand function. Focus on hands as a outcome and you would already have a treatment available.
But this has proved difficult to show and this is because it takes time for the benefit to show itself. If the trials are too short, they may be too short to see a benefit, because it is masked by the worsening due to the sparklers burning.
This is the therapeutic Lag
How do you disprove this, one of the best ways, is to do a well planned trial
Maybe the authors have the power to do this.
However ProfG’s view
“This paper is Treacle to Read”
Maybe DrK or ProfG can explain betterer
So what is the significance of all this
Well have a look at the Poster from the up and Coming
AAN Meeting in Boston in April 2017
(Abstracts are online Now…What’s interesting to You)
I’m surprised that ProfG isn’t on this one
because he has been banging on about it for enough time
i.e. Think-hand and focus on hand function.
Do trials for Longer than 2 years.
Do this and you have a drug (Natalizumab) that impacts
on progressive disease!
Maybe no poster publication but he can feel snug
with the “I told you So”
ASCEND Phase 3 Trial Open-Label Extension Study Results: Natalizumab May Delay Disability Progression in Secondary Progressive Multiple Sclerosis (SPMS) Hans-Peter Hartung , Douglas Arnold, Mark Freedman , Eva Havrdova , Douglas Jeffery, Raju Kapoor , Aaron Miller , Finn Sellebjerg , Haihong Li, Nisha Lucas, Diego Cadavid, Nolan Campbell, Pei-Ran Ho, Deborah Steiner10
Objective: To investigate long-term (>2 years) effects of natalizumab treatment in the ASCEND open-label extension. Background: During ASCEND’s 2-year randomized treatment period, natalizumab did not delay disability progression in SPMS patients with advanced disease (so the TRIAL FAILED) assessed by the primary composite endpoint (Expanded Disability Status Scale [EDSS], Timed 25-Foot Walk [T25FW], and 9-Hole Peg Test [9HPT]), but did slow progression on the 9HPT (upper-limb) component. (If Hand Function was main outcome the trial would have been positive)
Design/Methods: Patients who completed the 2-year, randomized, placebo-controlled treatment phase and entered the extension phase received open-label natalizumab (The trial was extended for more than 2 years to 3 years). Original treatment assignments remained blinded to investigators and patients throughout the extension. Disability progression was assessed for up to 3 years using the primary composite endpoint.
Results: Of 888 randomized, dosed ASCEND patients, 566 (63.7%) participated in the open-label extension (switched-from-placebo: n=274, median follow-up=156.9 weeks; natalizumab-continuers: n=292, median followup=160.4 weeks). Baseline characteristics and disease history were similar between groups and consistent with the overall ASCEND population. Fewer natalizumab-continuers than switched-from-placebo patients were composite endpoint progressors (52% vs 61%; adjusted odds ratio [OR]: 0.67; 95% confidence interval [CI]: 0.47- 0.94; P=0.02). Natalizumab reduced 9HPT progression (19% natalizumab-continuers vs 28% switched-from placebo; adjusted OR: 0.59; 95% CI: 0.39-0.88; P=0.01). (Benefit was still seen when hand function was analysed) T25FW and EDSS progression comparisons favored natalizumab (T25FW, adjusted OR: 0.80; 95% CI: 0.57-1.12; P=0.20; EDSS, adjusted OR: 0.73; 95% CI: 0.48- 1.10; P=0.13). Not quite a positive for saving leg function but indications start to appear maybe trails need to be 4 years long
Conclusions: The ASCEND open-label extension showed clinically meaningful benefits of natalizumab on disability progression in advanced SPMS patients. Consistent with 2‑year results, the largest treatment benefit was seen on preserving upper-limb function (9HPT), but preservation of ambulatory function (T25FW and EDSS) was also observed, leading to overall benefit on the primary composite endpoint. (When all issues are compared benefit is seen that may have lead to success) These results suggest that, while some benefits are evident after natalizumab initiation, full benefits on disability progression, particularly lower-limb function, in advanced SPMS patients may not be evident until after longer treatment duration.(Study Supported by: Biogen)
This suggests progressive MS trials need to be longer than 2 years or we have to swap primary endpoint outcomes. These are consistent with the ideas from the paper above.
This is retrospective analysis.
Why don’t we do some perspective analysis and test out whether we can control loss of hand function in people with advanced MS?
We should aim for treatment for all across the whole EDSS spectrum.
What do you think?
Can we do a DMT trial for People in wheelchairs?
(Somewhere in the World?)
p.s. I know Hannah does not have MS, but let’s use the paralympic spirit and say
“Yes I(we) can” (click) Let’s go for it