All clear on the disability progression?

A

Confirmed Disability Progression (CDP):
Measures the increase in a patient’s EDSS score that is sustained over a pre-determined time period, which means a patient’s physical disability has increased
.

As more more drugs enter the MS market, the line between what drugs are used where (RRMS vs progressive MS) has begun to blur. This matter is further complicated by most of us not understanding the clinical trials that have preceeded these decisions. Moreover, some of our antipathy towards logically considering the wherefore and the what not’s of treatments is illogically hampered by the launch of MS drugs timed to the nearest international conference.

Dr Avasarala, from Lexington USA uses the example of the launch of different Sphingosine-1-phosphate (S1P1) modulators for different types of MS to nicely frame this lack of understanding.

Fingolimod, a first generation S1P1 modulator is licensed for RRMS, whilst Siponimod a follow on drug, but with a similar mode of action is licensed for CIS, RRMS (FDA approved) and active SPMS. FREEDOMS1 clinical trial of fingolimod with an entry level of MS participants at a low disability level (EDSS score of 2.0), had a reduced risk of CDP at 3 months and 6 months. Whilst, FREEDOMS2 clinical trial, similarly using fingolimod, doesn’t demonstrate a statistically significant effect on CDP at even the low EDSS ranges (EDSS score 2.0-2.5). The EXPAND trial using siponimod, on the other hand with MS participants with EDSS scores of 3.0-6.5, clearly has a statistically significant effect on the 3 month (21% risk reduction) and 6 month (26% risk reduction) CDP.

What really is going on here?

Your guess is good as mine.

I leave you with Dr Avasarala’s concluding remarks: At a time when more FDA-approved drugs are entering the market for MS patients, clarity concerning disability data are urgently needed since there is accumulating evidence that disability in MS probably begins at the time of diagnosis, even as early as the clinically isolated syndrome. Unless we untangle the maze of divergent data on disability, having availability of more FDA-approved drugs alone might not translate into successfully addressing disability concerns in patients. How the MOA of any drug addresses disability will likely drive treatment choices but that in turn depends on what specific patient phenotype that the drug was studied in.

Abstract

Mult Scler Relat Disord. 2020 Sep 28;46:102529. doi: 10.1016/j.msard.2020.102529. Online ahead of print.

Discordant disability data in multiple sclerosis phase 3 studies among sphingosine-1- receptor modulator drugs

Jagannadha Avasarala

Fingolimod, Siponimod and Ozanimod are all sphingosine-1-phosphate (S1P1) receptor modulators, FDA-approved for use in multiple sclerosis (MS). Additionally, siponimod and ozanimod are sphingosine-1-receptor 5 (S1P5) receptor modulators that have better cardiac side-effect profile(s) than fingolimod. All 3 drugs have potential anti-inflammatory and immunomodulating activities and selectively target and bind to S1PR1 on lymphocytes, causing transient receptor activation followed by S1PR1 internalization and degradation. This results in the sequestration of lymphocytes in lymph nodes. By preventing egress of lymphocytes, these drugs reduce both the amount of circulating peripheral lymphocytes and the infiltration of lymphocytes into target tissues. The drugs are all classified as small molecules, have the ability to penetrate the blood-brain-barrier and are highly protein-bound. As to why the drug effects on disability are different between the drugs when their mechanism of action (MOA) is fundamentally similar remains unknown. Contributors to disability in MS patients, among others, include sub-pial lesions in the brain seen best using 7T MRIs, age of patient, involvement of the cord/infratentorial areas/brainstem, male gender, # of relapses in the first two years since diagnosis, and incomplete resolution of relapses. Of the 3 drugs, only siponimod is approved for the treatment of secondary progressive multiple sclerosis (SPMS) while all of them are approved for ‘relapsing forms of MS’. All 3 prevent lymphocyte egress from lymph nodes, central to their efficacy in MS. Since all 3 drugs have the same MOA except for cardiac side-effects which have no direct bearing on disability measures, what is it that separates one from each other in producing differential disease outcomes ?

About the author

Neuro Doc Gnanapavan

14 comments

  • I have a suspicion we will need a substantially more granular and holistic disability measure than EDSS for better insights to emerge.

  • NDG,

    Thanks for your post.

    “there is accumulating evidence that disability in MS probably begins at the time of diagnosis“

    Since my diagnosis some 18 years ago, MS has been many things: autoimmune, inflammatory, neurodegenerative, inside – out, outside-in, 4 diseases, 1 disease….

    In 2020, the so called experts and MSologists still haven’t got a clue how this disease starts and how it progresses. The approach has been to use drugs (usually used for other conditions such cancer) and see what happens. Surely a better approach would have been to fully understand the disease processes and then design therapies to properly address them. The clamber for treatments such as CCSVI really highlighted how MS research and the understanding of the disease is still in the dark ages.

    2020 has been a write off for MS research (ACTRIMS/ECTRIMS was a damp squib of epic proportions) and advances in treatments to address disability progression have not been delivered. The only thing an MS patient wants from a therapy is to stop disability progression in its tracks, yet no therapy is proven to do this.

    Fingolimod, Siponimod and Ozanimod… are just more examples of moving the deckchairs on the deck of the Titanic. Until a research team can map out this disease ie what starts it, what drives it…. we remain in this mad world where the number of MS treatments options keeps increasing, yet the therapy to stop patients becoming more disabled remains elusive. Something needs to change as it’s just Groundhog Day for MS patients.

    • Hi Sid,

      Thank you for your comments. I agree there is still a way to go. We are slowly starting to see granularity in trials, the inclusion of other biomarkers, such as NFL (neurofilaments) in trials now tells us that there is a biological readout. We also know that highly active treatments work quickly using these read outs. There is also increasingly inclusion of cognitive measures and patient reported outcome measures e.g. fatigue, mood etc. MS physicians do look at these results and utilise them in treatment decisions. I definitely do when I’m advising patients on therapies. My belief is that the drug development needs to be sped up, using the biological readouts a Phase 2 study depending on the activity of the drug in 3months – why wait for the full two years when really you should be able to proceed to phase 3 after you know the drug is efficacious? We’re now in the realm of technology- everyone is counting their steps and you can check how mobile a person is just using that. There is no need for EDSS monitoring in this day and age.

  • A lot of it is study design, picking the right endpoint definitions. FREEDOMS 2 had a fault in its definition of disability progression at low range, if I remember correctly; there is a lot of noise at EDSS 0-1.5, so the definition needs to pick that out by only counting relatively large increases in disability at the low range. A post hoc analysis using different criteria fixed it, but it was too late by then. EXPAND was event-driven to improve power, but maybe got lucky with a high event rate, which had scuppered INFORMS in PPMS (and alemtuzumab in CARE-MS 2). There are other factors of course, but appropriate surrogates for what is really being measured, permanent loss of neuronal function, are really important when it’s very hard to measure that in amongst everything else that is going on.

    • Event rates, 2:1 design are all helpful. We know clinically that what we’re interested in is long-term outcomes. The drop out rates in studies is high and databases in centres are too poorly maintained to be able to answer this. The proof is in the 10year studies.

  • I was hoping you could find a way to incorporate more parameters in your definition of “disability “. The physical disability is only one aspect of disability. To me, disability became a slippery slope of fatigue, overwhelming inability, sick days from work, can’t take another step. The emotional roller coaster. Questions, is it Me? Am I shirking my responsibility? Everyone I work with is my age. Why can’t I keep up? Easy to measure a timed 25 foot walk. Not so easy to tease out the dark side of our days, especially when we might say “I’m fine”.

    • I know what you mean, I can run 5K (more if I trained a bit harder, but maybe not Prof G’s marathon 😄). Most people I know complain about how fast I walk (the faster I walk/run the better – standing is harder) I can kill a 25 foot walk, but some days I am so tired it is all I can do to stay awake and follow a conversation (let alone a discussion on Zoom!). Definitely not so easy to tease things out.

    • Gosh Mary this is really well put!
      Basing everything on the flimsy parameter that is EDSS is plain silly!
      Except perhaps for the likes of Alem and HSCT it can appear as if the rest are beginning to resemble a jar of coloured Smarties and those with PPMS and PIRA/SPMS are left like kids with their noses pressed against the shop window.

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