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.

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