Targeting B cells Slows Progressive MS…..Wakey, Wakey People monotherapy is so last century.

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In the News today CD20-Depletion appears to have benefit is SPMS…

But what does it say to me?


Time to start learning and acting on the knowledge!
Naegelin Y, Naegelin P, von Felten S, Lorscheider J, Sonder J, Uitdehaag BMJ, Scotti B, Zecca C, Gobbi C, Kappos L, Derfuss T.

JAMA Neurol. 2019 Jan 7. doi: 10.1001/jamaneurol.2018.4239. [Epub ahead of print]

IMPORTANCE:

Therapeutic options for patients with secondary progressive multiple sclerosis (SPMS) are limited.

OBJECTIVE:

To analyze disability progression in patients with SPMS treated with rituximab compared with matched control patients never treated with rituximab.

DESIGN, SETTING, AND PARTICIPANTS:

This retrospective cohort study analyzed data obtained from patients with SPMS at 3 multiple sclerosis centers located in Basel and Lugano, Switzerland, and Amsterdam, the Netherlands, from 2004 to 2017. Patients were included for analysis if they had received a diagnosis of SPMS, were treated (57 eligible; 54 included) or never treated (504 eligible; 59 included) with rituximab, and had at least 1 follow-up visit. The variables used for propensity score matching were sex, age, Expanded Disability Status Scale (EDSS) score, and disease duration. Follow-up duration was up to 10 years, with a mean (SD) of 3.5 (2.6) years for rituximab-treated patients and 5.4 (2.4) years for controls in the total cohort and a mean (SD) of 3.5 (2.7) years for rituximab-treated patients and 4.8 (2.2) years for controls in the matched cohort.

EXPOSURES:

Comparing EDSS score progression in patients with SPMS (treated with rituximab vs not treated with rituximab) using propensity score matching.

MAIN OUTCOMES AND MEASURES:

The primary end point was progression of EDSS score after baseline, and the secondary end point was time to confirmed disability progression.

RESULTS:

After 1:1 propensity score matching, 44 matched pairs (88 patients) were included in the analysis. At baseline, patients treated with rituximab had a mean (SD) age of 49.7 (10.0) years, mean (SD) disease duration of 18.2 (9.4) years, and mean (SD) EDSS score of 5.9 (1.4), and 26 (59%) were women, whereas controls had a mean (SD) age of 51.3 (7.4) years, mean (SD) disease duration of 19.4 (8.7) years, and mean (SD) EDSS score of 5.70 (1.29), and 27 (61%) were women. In the covariate-adjusted analysis of the matched set, patients with SPMS who were treated with rituximab had a significantly lower EDSS score during a mean (SD) follow-up of 3.5 (2.7) years (mean difference, -0.52; 95% CI, -0.79 to -0.26; P < .001). Time to confirmed disability progression was significantly delayed in the rituximab-treated group (hazard ratio, 0.49; 95% CI, 0.26-0.93; P = .03).

CONCLUSIONS AND RELEVANCE:

In this study, patients with SPMS treated with rituximab had a significantly lower EDSS score for up to 10 years of follow-up and a significantly delayed confirmed progression compared with matched controls, suggesting that B-cell depletion by rituximab may be therapeutically beneficial in these patients. A prospective randomized clinical trial with a better level of evidence is needed to confirm the efficacy of rituximab in such patients.

Ocrelizumab has been licensed for the treatment of progressive MS, so the chances are that rituximab, which also depletes CD20-B cells will work too.

So in this study they looked at people who were treated with SPMS who had been treated with rituximab and those people who had been followed up for some time. They then matched people up who had not been given the antibody and saw where they got to.

In this study they examine what was the effect of treating (54 pwMS) with people with SPMS with rituximab (CD20-B cell depleting) verse not treating people with MS (59pwMS).  As the people on rituximab were younger (a good feature known to favour a response to rituximab), they then went back and matched the people on rituximab with people who had not had rituximab and got 44 pairs of people.

The pwMS group had a score of 5.9 and a similar control group had a score at 5.7 and disease duration was about 18 years. The results indicate that disability progression over a mean of 3 years (some people were followed for up to ten years) was reduced by about 50% P<0.001) and time to worsening was delayed by about a half too.

This sounds great.

However we have to say, we are not told the basis of why people were treated with rituximab and furthermore MRI was only available for about 2/3 of the people and so the samples were not matched for potential lesion activity. However, of the people with MRI (26%) of 27/44 had active lesions verses 0 (0%) of 23/44 of the none-treated group. We know that lesion activity is a marker of response to rituximab, based on results in PPMS as shown in the phase II trial, and would have a biasing effect. Furthermore the people in the control group has recieved less DMT in the previous years in the run-up to the analysis and may suggest that thier disease was less active. 

You would also say that the study was very small (Look at the figure and the number of people at 3 years follow up is very small). So to get an effect on EDSS is amazing. Just think what may have happened if hand function had been monitored? 

Sadly they were not imaged and we can not say anything about brain atrophy as this imaging was not available.

Furthermore, the statistical analysis section was about as long as the results section indicating that a lot of juggling was done to get the final figures. 

The other problem is we have no idea how long people were treated for. Rituximab is usually given every 6 months. How many doses were given. I suspect that you do not have to give every 6 months to get long-term benefit. If true it has safety and cost-benefit implications

Now our Friends in Sweden (where Rituximab is commonly used) should be able to do this study to replicate the results, but I think the replication data, or was it the initial data as it, was presented at the AAN about 2 years ago from work done in the USA. This showed that not as big an effect as there was a big slowing down of worsening (about 20%)
Neurology April 18, 2017; 88 (16 Supplement) The safety and efficacy of Rituximab Use in Secondary-Progressive Multiple Sclerosis (SPMS) at UMMHC: five years follow up data (P5.408)
Idanis Berrios Morales, Evdokia Eleftheriou, Louise Maranda, Letterio Politi, Carolina Ionete

Objective: Goals of our study were to: (1) assess the safety and tolerability of Rituximab in patients with SPMS with no relapse previously treated with DMT’s (2) measure the efficacy of Rituximab in delaying progression of disease using Extended Disability Status Scale (EDSS) (3) assess the effect of Rituximab on MRI measures such as T2 lesion burden, T1 hypointensities and contrast enhancing lesions.
Results: Patients in Rituximab group (n=40) had good tolerability with mild to moderate adverse effects, most commonly being urinary tract infection compared to controls (n=29). EDSS in the Rituximab group had a decrease probability of worsening compared to controls (HR= 0.787, [0.366–1.737] p=0.533). The Rituximab group had an increase probability of improving the EDSS compared to the control group (HR=2.836 [0.261–30.82] p=0.392). MRI metrics are currently under evaluation.
Conclusions: This study demonstrates the possibility of Rituximab as a DMT for SPMS without relapses due to its good safety profile and ability to reduce disability progression as seen in EDSS.
What does this suggest

We need a trial to test it
The idea that progressive MS does not respond to current DMT is untenable. So for the ostriches out there who think this…you know who you are!…Get your head out of the sand!!!.

To not do this will destine some pwMS to do worse
The question of whether it is cost-effective is another matter and it you have a low cost option and you do not have to give it forever the answer is surely going to be yes… However, do we have to wait for patents to end. and hope the price drops to make it cost effective (it took about 30-35 years for copaxone patents to end and the cost went up and up and up and the generics are not much less) or go off-label? In socialized medicine where high-cost options may be restricted it will have to be off-label or nothing. Do we have the jajce? 

However before we (neuros) start patting ourselves on the back and say how ace we all are, perhaps we need to look at the data, because the effect of monotherapy of DMT does not look good enough…We need combinations.

You can see that the proportion of people with worsening disease increases with time, suggesting that disability is getting worse and it is the majority of people who are getting worse. 

Does the progression flatline..No.

Now you can ask if therapeutic lag is important and they perhaps should have rebased lined at 6 months to give time for the ocrelizumab to work, however it does suggest to me that.

Now you can say that the effect of the DMT is not good enough so we should find a neuroprotective that gives a better effect. 

This is the view of some academics, where the grass is greener elsewhere, However, look at the effect of statins, look at the effect of ibudilast, look at the effect of the anti-lingo etc. and the benefits of these monotherapies are incremental and not that great either.

Any future academic trial that does not have a DMT at the bottom of the pack, is wasting time and your brain!!!!  
The jobbing academics are happy to do monotherapy trials because it is easy and it get the results that are easier to interpret and they can publish in a good journal (if it works..even if the effect is incremental as shown here) and do another trial (lasting 5 years?) in 6-7 years..then retire:-(. 

In the 12 years you are waiting to see progress what has happened to your brain health. Won’t be good for some.

Will I be here in 12 years time saying the same thing?

Honestly I can say “no” to this.

I’ll be long gone I suspect, but the sad thing is I may be somewhere else thinking the same thing

To me it shows that we don’t read and assimilate knowledge! 

The charities and other funders should not pander to this and if they have vision they need to be bold and say “Enough is enough people! Design the more complicated studies”.
However, will they?. I’m not so sure for two reasons.

1. Cost. As you have to buy the bottom of the ladder (DMT) for the trial. Nothing is licenced for this indication. However, they could go to company and ask them to supply drug for a study or be bold and use a generic. If they have to be larger the trials get more expensive too.

DrK has been struggling to get the costs down of his Wheelie Trial (#ChariotMS #ChariotX), which puts cladribine at the bottom of the pile. Although I am biased and conflicted, surely someone out there should see that this can be a ground-breaking opportunity and should chuck him a few “bob” and say “Add another arm and do cladribine + neuroprotective/repair agent or even be bolder  and have cladribine + neuroprotective & repair agents). If it works and there is benefit, you can do another study knowing that people benefit and they you change cladribine for another DMT on the bottom, which may be better such as rituximab, ocrelizumab, HSCT or alemtuzumab another generic or perhaps siponimod (Although in my mind immune-reconstitution therapies have more merit, it can be debated)

2. They (we) are simply not “thinking and learning” and advisors may be working to their own agendas and mind-sets (Is understanding the mechanism more important than developing treatments that benefit pwMS?). 

I have been on a search party looking for neuroprotective agents that could be used in progressive MS. I spent some time preparing documents to support the logic and preparing the list of different B cell depleting agents that could be used. They were all dismissed and didn’t make the cut. The selection committee who got the reports appeared happier to pick agents that had absolutely no evidence that they could be of benefit in SPMS, but maybe had a sexier mechanism, than something that works in MS.


I guess that I am no different, as I am writing, or is it ranting, here from my own mindset. I believe it is a sensible view point based on my current view of the reality. Maybe I am living in a different world to everybody else as I don’t have rose-tinted glasses, is my face going blue?. 

CoI: Multiple but none relevant..except perhaps after this tirade, I won’t be on any of the search parties 🙁

About the author

MouseDoctor

28 comments

  • Targeting B cells Slows Progressive MS…

    Does the efficacy not depend on how much / what type of inflammation a person has? You don't take the burden of possible severe side effects into account? E.g. cancer risk in those who have had deaths to cancer in the family? The age of a patient – starting B-cell depletion late? I hope that one day, there are truly effective therapies which are a little more intelligent, refined than partial immune system destruction. And this toxic pyramid / cauldron sounds hellish to me.

    • Does the efficacy not depend on how much / what type of inflammation a person has?

      Yes probably-This is why it is clear that efficacy is beeter in people with gadolinium + lesions.

      You don't take burden of severe side effects…Yes I would you have to look at each individual and do risk benefit analysis.

      The age of a patient and starting late…Yes we know that age is a factor, but should we withhold treatment based on age…no but it happens every day.

      Truly effective therapies…I agree. The best one at present is to deal with the condition early and aim to stop SPMS developing.

      Toxic pyramid/cauldron sounds hellish…I guess if your head is in the ground hell is a bit closer:-).

      There many people who are happy to nothing that is your choice…but at the moment those that do want something have little or no choice.

    • Thanks MD.

      "Yes I would you have to look at each individual and do risk benefit analysis."

      That's hopefully a good approach.

      Surely – for most PwMS at least, as opposed to GPs, neurologists – it is not a case of "being happy to do nothing" but of making the best choice available for the individual. We are all different in so many different ways and for some the choices are by no means black and white.

      Current treatments don't impress me much, but if you're trying to tell me my head is in the sand, you are very wrong. I've had PPMS for going on two decades, and I've never been afraid to look truth in the eye. 😉

    • I agree you make the best choice available and my rant is squarely aimed at my colleagues.

      I agree…they don't impressa me much either and that is why we need to strive to make what little benefit we have better

    • "Alemtuzumab or HSCT; the choice is becoming clearer."

      Why stop the whole disease at once, when you can be on a bunch of different drugs your whole life and still have leaks of your suppressed disease?

      MD's zeal and luck of imagination is Pharma's dream.

    • Which DMT would I take…we need to have some secrets 😉

      It is a shame we will not get to know for alemtuzumab as a trial is unlikely and as for a trial of HSCT probably no time soon in SPMS also.

    • The question shouldn't be simply "if you were a person with SPMS what disease modifying therapy would you take?". More correctly, the question should be "if you were a patient with SPMS and enhancing lesions what DMT you take", and/or "if you are a question without enhancing lesions what DMTs would you take?"

      Seems to me that all of the available info points to the fact that all of the available disease modifying therapies (including HSCT) see their efficacy drop dramatically in patients who do not display enhancing lesions. Patients without active inflammation are effectively left without any good treatment options.

      This leaves the vast majority of patients with PPMS completely in the lurch. We remain the orphans of the MS community. Clearly, there are other disease mechanisms at work that need to be investigated, found out, and addressed. Once we get at these as yet unknown mechanisms, the dominoes will fall and all other forms of MS will see dramatic improvements in treatment modalities…

    • "Alemtuzumab or HSCT; the choice is becoming clearer"

      Coke or Pepsi..?

      Alemtuzumab the choice of a new generation..as the old ad slogan went

    • MD's zeal and luck of imagination is Pharma's dream.

      I am guessing that is lack…however dont be so sure I am Pharmas dream

    • Dear WK

      "Clearly, there are other disease mechanisms at work that need to be investigated"

      I couldn't agree more and the whiff of activity of ocrelizumab and siponimod may not be a blessing as it will make innovation into this area harder. You point about activity is well taken too but lesions only enhance for 2-4 weeks so if you have a scan once a year there are 48 weeks when a lesion can come and ggo and if you dont leave a T2 signal it will go unnoticed.

      However you are correct to point out the issues that surround the "fudge". In Europe they didnt buy it like in the US and so ocrelizumab has a more restrictive licence

  • Sadly, MD, this nightmare will never end.

    Researchers, because of funding and steering committees, will never attempt the treatment pyramid and continue to study single treatments of MS, which is currently the immunosuppressant only approach.

    This approach will see a progressive patient worsen but just slightly less than placebo. This will be of statistical significance but not noticeable to the patient themselves clinically whatsoever.

    A meaningful treatment to the progressive MS that not only stops progression but reverses and returns function to a progressive MS patient is decades away.

    • The immunosuppressive only approach. I disagree we have had only statin, only ibudilast, only floxitine, only lamotrigine, only riluzole, only clemastine, only beroxatine.

      Reverses and returns function in humans is some way off…sadly I agree until the effective phase II surfaces then we have to wait for phase III and licencing. It will be some time I am sorry to say too.

    • Why in the world are the above name drugs that show neuroprotection or remyelination studied independently or sequentially instead as an add on therapy/concurrently to already partially "successful" existing immunosuppressant therapy?

      The hashtag #TIME IS BRAIN is almost laughable when it comes to the way that trials are currently run in the MS research world.

    • Entirely agree, it's a waste of time looking at a neuroprotectant for instance on its own rather than as an add on to an existing effective DMT. We bang on about this endlessly but the powers that be aren't listening. It HAS to be the correct approach but the can't do attitude prevails.

  • I would love to see head to head trial of ocrezulimab vs rituximab.

    They would likely have the exact same outcomes and save MS patients and taxpayers millions of dollars by neurology prescribing rituximab instead of ocrezulimab.

    Ocrezulimab is just another example of another recycled/redesigned drug with inflated costs designed to pad the wallet of Pharma's shareholders and not improve the innovation or outcome in MS patients.

    I am sure if one designed a proper selection biased trial using rituximab instead of ocrezulimab, the outcomes would have showed an identical reduction of <25% in disease progression above placebo if rituximab was used.

    This seems like one big elaborate scheme designed to make money off ill patients. Is there any other B-cell therapies used against cancer, like lymphomas or leukemias, that we can expect to be recycled or redesigned then remarketed with astronomical prices for MS patients?

  • I agree MS is a cash cow, but that is why new agents appear. We struggled with our anti-spastic drug as the potential investors thought that the price would not get price of a DMT but a cheap as chips baclofen substitute and so they didn't want to invest.

    As for efficacy of rituximab I think there is a massive literature from our friends in Sweden who have treated thousands of PwMS. There is a PECORI study ongoing

    The ocrelizumab trial was designed based on the rituximab data and so benefitted from rituximabs failure. It was made to exploit the lack of patent life of rituximab. Yes a head to head trial will show they are the same beast with some subtle differences such as rituximab causing more anti-drug responses and maybe the infections wont be the same but in the same ball park. I would like to see ocrelizumba repeated infusion verses ocrelizumab as a pulsed therapy.

    As to 25% difference, that was for lower limb function for upper limb function the difference was 45%

  • I respectively disagree that there are any "new" agents are appearing in the MS world. Pharma is repurposing drugs from other medicine fields, usually from the treatment of oncology, dermatology or rheumatology patients. Innovation is severely lacking.

    Pharma buys/owns a patent from a pre-existing drug and lets it expire. It then re-markets it or may make a very slight biochemical change to it using R&D as an excuse for the astronomical pricing. There is no innovation.

    This includes Ocrevus, Mavenclad, Lemtrada, Gilenya, Aubagio and Tecfidera.

    If you want to strike it rich then buy an expired patent of an anti-B-cell therapy used in another field, like oncology.

    Pharma is no different than the immoral convicted hedge fund felon and American businessman Martin Shkreli that bought a previous HIV drug's expiring patent and then marked up prices by 5000% for vulnerable HIV patients.

    PS: I am sorry your anti-spastic drug failed. Baclofen is a horrible excuse of a drug with multiple bad adverse reactions. I would pay a much higher cost for a drug with less adverse reactions.

  • It'll let pharma defend their position on their innovation aspect…but MS is chicken feed for what the big companies are interested in and we are lucky to have them around if you compare MS withother neurological conditions.

    • Always very humbling and sad to see and hear of folk suffering even worse neurological diseases like incurable Motor Neurone Disease. I would encourage everyone to read up about this ghastly condition and support the MNDA charity who do so much to provide support and advice.

  • Re the Treatment Pyramid graphic:
    (Which is easy to understand)

    Are any neuroprotection options available for someone who is past the bottom rung?
    Meaning, for someone who already has a good anti-inflammatory (rituximab)

    Another question: is it sort of accurate to say that anti-inflammatories convert you from RRMS to slow PPMS?
    Where RRMS and PPMS are just labels for points on the gradient of MS presentations

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