Tuesday, 17 March 2015

ATX-MS-1467 myelin to control MS

Heather B. Streeter, Rachel Rigden, Keith F. Martin, Neil J. Scolding, and David C. Wraith, Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS Published online March 12, 2015 doi: 10.1212/NXI.0000000000000093Neurol Neuroimmunol Neuroinflamm June 2015 vol. 2 no. 3 e93

Objective: The study was designed to test the efficacy of ATX-MS-1467 in a relevant preclinical model and to assess its safety for the treatment of patients with secondary progressive multiple sclerosis (SPMS).
Methods: ATX-MS-1467 was tested for its ability to suppress experimental autoimmune encephalomyelitis (EAE) in the (Ob x DR2)F1 mouse both before and after disease onset. Safety was assessed by clinical assessment, MRI analysis, and the measurement of immune responses to self- and nonself-antigens in patients with SPMS.
Results: ATX-MS-1467 displayed a dose-dependent inhibition of EAE and was more effective than glatiramer acetate in the treatment of ongoing disease in humanized mice. A phase 1 open-label dose-escalating study demonstrated that ATX-MS-1467 was safe and well-tolerated in a group of 6 patients with SPMS, up to a dose of 800 µg.
Conclusions: The results of this study support further development of ATX-MS-1467 in a clinical trial powered to investigate the immunologic and clinical benefits of treatment in relapsing-remitting MS.
Classification of evidence: This study provides Class IV evidence that ATX-MS-1467 is safe and tolerated in a group of 6 patients with SPMS.

I am really pleased that Prof David Wraith has got his science to clinic. His approach is the result of studies stretching back into the 1980s, unfortunately I wonder if the approach has been too slow and they may have missed the real therapeutic boat.

The problem with all current drugs are their side effects, so the treatments that we desire are ones that only target the disease causing cells. This is easily done in animals where the autoimmune target is known. In MS the precise target is not known so you may want something that causes bystander suppression, so it suppresses immune responses by producing an immune inhibitory molecule called interleukin 10. This can work in EAE. Can it work in humans? Let's hope so.

In this study they inject a mix of myelin basic protein peptides (A chain of 10-15 amino acids) and it inhibits EAE in a mouse with human major histocompatibility complex, which is the part of the body involved in immune recognition.

The logical choice is in Relapsing MSers because the EAE models they use reflects Relapsing MS and not progressive MS. But can new studies be done in RRMS?

Is it ethical to put people on placebo? The answer should be no, but Pharma still do it, time and time again. 600 people on placebo in one ongoing trial.

Pharma find places where MS drugs are not available so the option is nothing or go on a trial and get nothing or the chance of drug. Is this what will happen? I suspect so.

Once gilenya comes off patent will prices of MS drugs drop? If they do, RRMS will be less attractive for pharma to develop new treatments. Time will tell. Its still a few years away

Will there be a further trial be in SPMS? Will it work?. This is one of the major unmet needs so companies convince themselves to use their anti-immunologicals in primary or secondary progressive MS. They follow the view that progressive MS is a T cell problem. To date myelin basic protein specific tolerance in SPMS has failed, T and B cell depletion with antibodies has failed and replacement of the immune system has failed. So will immune tolerance work in progressive MS?

Yes maybe in those with active relapsing progression,

The basic science idea was built around delivering the peptide via the nose or intravenously, which is an immunological tolerising route. However, this carries risks of anaphylaxisis, so when the approach originally when to clinical trials the subcutaneous route was used. This is a sensitizing route. Hopefully ATX-MS-1467 wont make MS worse as subcutanous injection of MBP peptides in the past has augmented MS. Will an MBP peptide mix stop disease that is targeted to other antigens. Lets hope so.

However we need to remember that copaxone is delivered by this route. It is interesting that this study also shows that subcutaneous Glaterimer Acetate does not work in EAE . Is this validation of the model as GA failed in progressive MS, or does it show that GA is not very good at treating EAE, when it is not mixed with the immunizing antigen? Because if you read the published literature this how it works best in EAE.

19 comments:

  1. Looks a very weak approach give the current push for early / highly effective therapies. Another example of how slow MS research is - ideas from the 80s only now being tested.

    Will Prof Mouse ever deliver an effective treatment? "time will tell" ��

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    1. The approach was developed during the 1990's and the 00's. I think it shows you how long it takes academics to develop treatments from scratch. It was only in the 00s when pharma investment was made. The Approach of Dr Miller from Chicago has likewise been developed over a similar lime frame. Antigen-specific therapy is the only future to treat immune problems, if you don't want side effects. So the idea is not weak at all..

      As to highly effective.....if done right it is disease wipe out end of story if started early enough. We have shown this with a transient T cell depletion and intravenous delivery of antigen. But which antigens to use in MS. Will the approach work in humans maybe it already has.

      So now to the snipe...will we ever deliver a treatment...,,,Yes. However strictly speaking it is pharma and only pharma that have delivered effective treatments to MS. Academics are bit players.

      Do your reading. Basic scientist create ideas and an evidence base that neurologists take to show they work in trials and pharma develop them. Nobody has the skills to take things all the way. All we have to do is get an idea to translate to benefit in humans and then its job done.

      I look forward to hearing your apologises Anon 8:03

      Will I deliver what I really want to deliver....as Least I'm trying:-(

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    2. P.S.
      Our trial (placebo controlled yep pharma does this again) in symptomatic control in spasticity starts in two months will you sign up?
      Our progressive trial proximus has already started, will you sign up. Recruitment has been very slow...the balls in your court

      NB. We terminated our immune-tolerance trial because of new circumstances and importantly because you wouldn't sign up. So we now have success with n=1.....this answers your question already, so you don't have to wait........but this is meaningless with this sample size, so it's back to the drawing board and another 10 years wasted...cheers:-)

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    3. Prof M - I offer my apologies.

      "At Least I'm trying" = Prof G said you can be very trying at times.

      I will be signing up to the spasticity trial. Please can I suggest a third arm to the trial. This is where Mouse gets a years supply of Special Brew and I am guaranteed to get the real drug (no placebo). Why aren't you trailling your drug against an existing anti spasticity drug e.g. gabapentin? I really want this trial to be a success - for me and for you ($$$$).

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    4. PPS Re Placebo controlled trial in spasticity above....people with spasticity who are not recieving treatment because your neuro does want to give you the side-effects of current anti-spasticity are the people that we are interested in particular because we have learned from the Sativex experience. The study on lasts a few weeks and it will be study failed or onwards and upwards

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    5. Why not trialling against existing. This is a phase II. First question is it safe...it is in non MSers but in MS more is going to get in the brain. I am not worried given the safety margin animals but we need to be cautious. Next the comparison is really within the individual before and after The worry is the placebo effect which is what we have to factor in. We would expect Gabapentin to work so we would need a non inferiority trial. We do not think it will be more anti-spastic but we hope it has a better tolerability.In phase III it will be a different design costing many more millions. Sativex struggled to show an effect because it was put on an existing therapy.

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    6. I was hoping it would be more effective than current drugs (which aren't great).

      I see that Barts has gone into special measures! Prof G goes on a long holiday, leaves the Mouse Doctors in control, and this is the result! As the saying goes "you pay peanuts..."

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    7. in an ideal world we would put drug into a few people to see if it works in an open label fashion. however this could be commercial suicide if you don't the obvious right answer, so we decided to do it properly.

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    8. Anon 11.23
      Well we won't know until we do the trial.
      No monkeys here ;-)

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    9. I'm ashamed to say that for years and years I suffered with spasticity. a long time ago I was told to learn to live with MS and didn't dream of mentioning it to my neurologist., why would I? I didn't go to the cinema or theatre because it was so uncomfortable. I used to wrap my legs around the legs of my office chair to keep them still. One day I thought I'd mention it and my neurologist said "we can do something about that". I suppose I was getting on with my life, had no clue what was going on in the MS world.

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  2. They surely aren't proposing to do a trial in SPMS? Good on 'em for getting this far but I think the boat has long since sailed.

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  3. The objective states: "to evaluate the safety in SPMS" while in the conclusion: "the results support the development of a clinical trial to assess the immunological and clinical benefits in patients with RRMS" Is this drug being studied for SPMS or RRMS? It seems to lack focus.

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    1. I suspect it's being tested in SPMS to determine safety but the obvious ultimate application would seem to be RRMS.

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    2. The paper clearly states "for the assessment of safety in the TREATMENT of SPMS" and then in the conclusion "support for the development.....in the TREATMENT of RRMS". I wonder why they would use SPMSers for safety determination if the drug will be used in RRMSers?

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    3. How do you get ethics to test a drug in RRMS when there are ten options available, so it is back to yesteryear when they were tested in SPMS however will you get the right immunological signal from looking at SPMS vs RRMS. There is absolutely little logic in trying the approach in SPMS in real SPEAE I suspect this approach would not work. Will it get tested there....maybe

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  4. If you try the IL-10 route, I think BCG vaccination is far more promising. All parasites connected with the hygiene hypothesis use IL-10 to evade host immune responses. I think this is how they protect from autoimmune disorders. Why would you try new drugs if you already have one at hand that has been perfected over millions of years? These attenuated mycobacteria really deserve a lot more attention.

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    1. I've missed this. What's going on with BCG vaccinations?

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    2. BCG vaccination to inhibit MS it was big a while ago. Most of UK used to be vaccinated with BCG and we are MS central go figure:-)

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    3. I had the bcg twice as they decided i didn't have enough of a scar from the first. It clearly had no preventative effect for me! Anecdotal evidence only though :-)

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