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.
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!.