Bad Drug?…..Bad Idea? Remyelination Trial accepts the Null Hypothesis

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The orginal title was changed read the comments

Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial.Cadavid D, Mellion M, Hupperts R, Edwards KR, Calabresi PA, Drulović J, Giovannoni G, Hartung HP, Arnold DL, Fisher E, Rudick R, Mi S, Chai Y, Li J, Zhang Y, Cheng W, Xu L, Zhu B, Green SM, Chang I, Deykin A, Sheikh SI; SYNERGY study investigators. Lancet Neurol. 2019 Jul 5. pii: S1474-4422(19)30137-1. 

BACKGROUND: Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis.

METHODS:

We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18-58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov, number NCT01864148.

FINDINGS: Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment.

INTERPRETATION:Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose.

They say its safe, yes I say….but it didn’t work

Are we surprised. Is the idea rubbish?…I don’t think so (but see below, but there is evidence that this molecule can promote myelinating cells, but as for the application to solve the problem. I am not convinced

I really don’t understand why we are using a large protein that is not going to get into the brain very well to target a process that is going on in the brain. They say that about 0.01% gets into the CNS and thats enough but why make it as hard as possible to show a positive effect?

It makes them give loads of antibody. A 100mg/kg is about 1-2g of antibody. Just as well the high dose didn’t work compare to placebo where there is no antibody because this dose is in the “intravenous immunoglobulin” territory (Antibody against nothing in particular just the antibody content of a alot of donors). So one could say any benefit is not specific.

They did see a subgroup responding I think and so it is not quite dead, but hoping for local blood brain barrier dysfunction to get antibody to where it is needed is either genius or there was probably not enough thought made before chucking millions done the toilet.

We wouln’t use an CNS-excluded drug to treat a CNS disease would we..Em! Don’t blame the scientist for that one! Should there be surprise when it doesn’t work.

However they may say the animal work was so clear.

Yes, but this is just a crutch that helps you spend the millions, as the models of a few days that will repair if you don’t do anything, have very little similarity of how the antibody was used in this study.

That is one thing but the other more pressing thing is are the animal models sending you down the garden path.

Last week I was at the MS frontiers meeting and one of the lectures was on remyelination. It was a masterclass of animals are wonderful, but there was a bit of horrible human stuff that was swept under the carpet as irrelevant. I piped up as “an advocate of old Nick” and asked what about the Swedish study that suggest that humans repair differently, which gave some support for the “dust swept under the carpet”. The guest speaker didn”t answer the question, like some politician. However, the chair who had a vested interest, came out with the human work was rubbish. When DrK asked something I got an new name for the Chair as DrHyde.

I am willing to believe that the human work is rubbish, but I am also willing to accept the animal work is wrong, too. I don’t have a career balancing on the fact, but I have been there and don’t spend my life defending EAE when its wrong. Indeeed the EAE data supporting the anti-LINGO effect was to my mind “too good to be true” and suggested an anti-inflammatory effect rather than a repair effect in my mind. We did anti-NOGO in the same scenario and it did nothing as I would expect. That’s another story of data interpretaton. However, it is an important fact and rather than take the “Science Opinion leader approach” of ignoring stuff you dont like, it needs to be addressed. If the samples were not remyleination, as claimed simply supply blinded samples containing bone fide remyelination and ask them to repeat the work. They can’t repeat it and that should be it. Sadly it never is. I know of a few examples where the opinions leaders idea was put to the sword..eg. you say this happens…here are some samples where is it.

It is not always easy however to publishe stories where you are wrong. I have had this experience so I know.

Indeed the animal modellers seem frightened to do the difficult experiment where they take animals with chronic disease, stop the disease from getting worse and then see if the treatment of interest makes things better.

Likewise there is a problem with the MS Community, who is stuck on monotherapies when they need to think #combi. They keep throwing away potentially useful drugs because they given then a task that the treatment can’t answer. The immunosuppressive DMT can’t do the repair, but the repair agent can’t do the immunosuppression and without this the disease continues and wipes out any benefit your hopeful candidate has. By the time you eventually get it and decide to do the combi (combination) you have thrown away all your best candidates and you are left with the dregs.

Sad but true (Metalica)…innit (with rap:-)

In this study people were excluded if they treated fingolimod or natalizumab within 3 months of baseline; treatment with alemtuzumab, ocrelizumab, or rituximab within 6 months of baseline. There’s your foot here’s a gun, go on shoot it!.

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28 comments

Leave a Reply to DJ Hartt Cancel reply

  • To be honest, doing trials like this despite the long-known and minutely-described presence of the blood/brain barrier ( worked on by yours truly many moons ago) which is designed to keep molecules like antibodies out of the brain, displays a level of intellectual bankruptcy that I can only marvel at.

  • Another trial failure – do any succeed in the neuroprotection, remyelination or neuro restoration space?

    At least you guys can slag off the trial design, choice of drug….. and then you can do a trial (anti-ebv, anti-spasticity …) and other researchers can slag off your trial design and choice of drug…

    PLEASE can one MS researcher pick a good drug candidate (based on robust research), design a defensible trial and deliver a positive result which will benefit MS patients. I’m fatigued by all the MS research failures. Even the drugs which get licensed are pulled (dacluzimab, Alemtuzumab). The researchers must get a good salary as you can’t be in this business for job satisfaction (which I would fine as improving the lives of MSers through safe and highly effective treatments).

    • Hindsight is a wonderful thing, and if you dont try you can’t win.

      Until you find a good design that works they are all bad but importantly there is lack of common sense.

      • Time to pass the baton to cancer researchers. They have 200 diseases and are making huge strides. MS researchers have one disease and are stumbling along.

        • They also have a shit load more money. A cancer researcher isn’t going to bring a neuroprotectant to the table, which is where we need to be going next in combination with effective DMTs. That we aren’t further along with this is certainly not the fault of the researchers, many of whom have existed on fumes when it comes to funding for decades.

          • Now do you wonder why,MS patients are forced to take risky unproven treatments?

            How many years before add on therapies come to fruition when studied sequentially instead of collectively?

            The treatment pyramid will be be so long, confusing, ineffective and expensive that researchers will be retired and MS patients will be dead and broke.

            Not enough money for research is simply not true. It should be stated not enough money is in the hands of the innovative, altruistic non-conflicted researchers.

            40 billion + per year is currently generated for partially effective treatments that work on a downstream reaction that have minimal effect on progression of the disease.

            That being said, I think MD and MD2 have some great ideas with respect to trial designs, CNS penetrant drugs and causes, like EBV laden B-cells in meningeal follicles of the CNS possibly triggering hot microglia, inefficient oligodendrocytes and neuronal death through possible HERV activation.

            The current treatment pyramid is not viable and would not be needed if a cause of MS was found.

          • 1. The cause is autoimmunity due to a chance infection at certain age in a genetically prone individual who has perfectly normal genes in a certain combination creating a response that is different in indivdiuals by something we are immune to. So how does this inform on a universal treatment. Of course this is one scenario.
            2.
            The treatment pyramid is not viable. Why not. You have people taking poly pharmacy for symptomatic treatment. You need a DMT like cladribine or may be ocrelizumab or alemtuzumab on the bottom and cheap neuroprotectant on top or a cheap DMT on the bottom once their patent life has gone and an expensive neuroprotectant on top or two cheap agents where a patent always them to be expensive and pharma are interested but until you get the cheap DMT on the bottom pharma won’t be interested. It is about patent cycling and profits. Maybe a daily DMT with neuroprotectant and abit of anti- inflammatory neuroprotective.

            It is only as impossible as the ambition of the neuros and importantly the funders.

            Is there was such ambition in the MS societies who called for funding, someone would do it

            At present in UK it would be possible to do it if you used a standard of care + a neuroprotectant.

            In other countries it may be difficult if you have to pay for both drugs. The resistance perhaps that this is best suited for a study in early MS where standard of care is approved and you have more chance of success because there is more neurological reserve.

            I know the community want later treatments so be bold and fund an extra arm for Dr K as well.

            Come on benefactor with big pockets come out of the wood work and fund such a trial rather than a building. The Ozzy Osbourne trial, the iron maiden trial the Harry power trial the Joe blogs trials

            PS I have to thank some people for doing this to get us where we are with MS chariot

            We have blown money on vitamin D trials worm trials microbiome trials which have in my opinion a low probability of success. Here you have an idea that is common sense.

            Be bold. I hope PROXIMUS will change you mindset that we have to do this now even it is just to shut me up and show me I am wrong.

  • I’m confused 2 years ago. Why r u reporting on this now. Or has the affinity trial failed? I remember u guys being excited by the subgroup responders. How is this new news if you pardon the punn.

    • Why….It was in pubmed today.
      But you are right it is old news, shows how you get the ews before itspublished
      Excited thats Prof-Glass half-full-G

      • Ahh OK. That’s like saying who won the fight before watching the match. Surely since endpoints weren’t meant why r all the readers getting excited? The real drug that could be a game changer is the repurposed drug Cambridge is working on remylination.

        • Which one? There are loads.

          If their recent animal data is correct the trial may now fail for the wrong reasons.

          Let’s see.

          The drug will have off target side effects as the receptors are all over the place. So maybe good for pulsed therapy.

          Many of these drugs are anticholinergics which may not be the best idea.

  • Great and helpful commentary, but ur headline: No no no!! Clinical trials are designed to resolve a hypothesis. The only time a trial “fails” is when it under-accrues, there are irregularities in data, or there is some problem with conduct. Trials “succeed” when they bring greater precision to a prior estimate (even if that new estimate does not refute a null).

    This study succeeded, it seems. It gave a clear result. It is the drug development plan that failed.

    The phrasing of your headline encourages people to look at negative results as uninformative, hence less important to publish… or to read. It also inadvertently demeans the value that patients who volunteered for those studies contributed to medical science. Please reconsider your concept of “trial failure!”

    • Nice to see you are glass half full. The MS-SMART team pat themselves on the back on how well they did to recruit and do the trial, but as you say the null hypothesis (There is no difference) was accepted and there was no difference between the three drug tested compared to placebo…Im my mind the trial failed because it did not find a useful treatment. But I will change the title from trial failed to give it a more PC title. See what you think. However, in this case yes it failed because the hypothesis is that targeting LINGO-1 promotes remyelination. The methodology was in my opinion not up to the ability to answer the question properly.

      Should we pick three differnt treatments and do the same again for MS-SMART2? You can say the treatment selection was wrong, but what in the experimental design could be imporoved..we keep using whole brain atrophy when it is fraught with problems for example.

      • Are you permitted yet to write a post about the upcoming Sizomus trial using the myeloma drug Ixazomib? Thankyou.

        • NDG or ProfG probably will write a post soon as they aim to be recruiting soon. The tiral detail is in the public domain
          on clinical trials.gov NCT03783416

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