Freedman MS, Bar-Or A, Oger J, Traboulsee A, Patry D, Young C, Olsson T, Li D, Hartung HP, Krantz M, Ferenczi L, Verco T; On behalf of the MAESTRO-01 Investigators. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS.Neurology 2011;77:1551-1560.
MBP8298 (also known as dirucotide) is a synthetic peptide that is similar to myelin basic protien (MBP). This peptide can react with a molecules that are associated with recognition of infections by the immune system, which are important in rejection of organ transplants. Two types of these molecules namely DR2 and DR4 have been linked to the development of MS. Notably the DR2 type in Northern Europeans and DR4 in Southern Europeans. When MBP8298-like molecules are administered intravenously to animals with MS-like disease induced by MBP then they have the potential to inhibit the development of disease. This only inhibits MBP specific cells and so should have a good efficacy without side-effects
Could this be used to treat autoimmunity in MS?
OBJECTIVE: To evaluate the efficacy and safety of MBP8298 in subjects with secondary progressive multiple sclerosis (SPMS) who express human leucocyte antigen (HLA) haplotype DR2 or DR4 (DR2(+) or DR4(+)).
METHODS: This multicenter randomized 2-year, double-blind, placebo-controlled study included 612 subjects with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) score of 3.5-6.5, stratified according to baseline EDSS score (3.5-5.0, or 5.5-6.5) and HLA haplotype (DR2(+) or DR4(+), or DR2(-)/DR4(-)). Upon entry of 100 DR2(-)/DR4(-) subjects, further study enrollment was limited to DR2(+) or DR4(+) subjects. Subjects were randomly assigned to either 500 mg MBP8298 or placebo, given by intravenous injection once every 6 months for 2 years. The primary outcome measure was time to progression by ≥1.0 EDSS point (or 0.5 point if baseline EDSS was 5.5 or higher), confirmed 6 months later. Secondary outcomes included mean change in EDSS, mean change in Multiple Sclerosis Functional Composite, MRI changes, annualized relapse rate, and quality of life.
RESULTS: There were no significant differences between treatment groups in either the primary or secondary endpoints. MBP8298 was well tolerated in all treated subjects with no safety issues identified.
CONCLUSION: In the population studied, treatment with MBP8298 did not provide a clinical benefit compared to placebo. Classification of evidence: This study provides Class 1 evidence that MBP8298 is not effective in patients with SPMS who are HLA DR2(+) or DR4(+).
This trial was doomed to fail on so many levels and is a waste of a drug and peoples expectations.
(a) Prof G may argue that there is no good evidence that MS is a problem of autoimmunity. The only way to prove this is to stop autoimmunity and hope that disease goes away.
(b) Although T cells drive the disease in animal models, again the evidence for the importance of T cells during MS has not been compellingly shown.
(c) There is no good evidence that myelin basic protein is a target for autoimmunity in MS. In my opinion MBP has recieved undue attention as a target in MS because it is easy to make, unlike other myelin protiens and is water soluble unlike other myelin protiens. Therefore it is easy to work with, but is a poor candidate target. It is not central nervous system restricted unlike MS and autoimmunity to this protien can induce a peripheral nerve disease. There are much better candiates, but it does not need to be the same target in everyone with MS.
(c) Without a transient immunosuppresssion, intravenous antigen is not that that effective at preventing established disease from developing further.
(d) IMPORTANTLY. Progressive MS does not respond to immunosuppression!!!, so even if it were the best drug since sliced bread then it would still be doomed to failure. In my opinion some Neuros/Companies are still convinced that all problems of MS are due to autoimmunity, but this is like having your head in the sand!!!. The data no longer stack up to support that view…….so yet another failure. Company making the drug down the tube!
On the plus side it shows that putting myelin peptides into MSers is safe, so when they select a more realistic target it has more chance of success.