The treatment of multiple sclerosis (MS) remains challenging despite the great efforts made in the development of novel therapies. Driven by the growing knowledge of the immunopathogenesis of the disease, a plethora of new pharmacological agents have been developed and tested in clinical trials. However, the therapeutic advantages and positive clinical trials of some of these agents are outweighed by studies of promising agents that either failed due to negative or inconclusive results or had to be withdrawn because of serious unexpected adverse events. Most failed clinical trials did not lack a well-considered pathophysiological rationale, but concepts from experimental models were proven wrong in humans. Lessons learned from these discrepancies help to optimize future study design and, potentially more importantly, provide further insight into the immunopathogenesis of MS. Here, we summarize trials on MS treatments since 2010 that failed or were interrupted, identifying potential underlying reasons for failure or inconclusiveness.
Kleinschnitz C, Meuth SG, Wiendl H.The trials and errors in MS therapy. Int MS J. 2008;15(3):79-90.
This paper explores trials that did not meet expectations and provides a nice list of human failings as it relates to MS. Whilst it is nothing to shout about, it is important that we learn from the lessons.
Such lessons developed a successful trial for PPMS. Had that trial been designed based on no knowledge of failures, I would bet that the Ocreluzimab in PPMS study would not have shown a signficant effect. This is because rituximab failed in the same type of experiement but that informed the ocrelizumab study in how to load it for success.
Many neuros will be bleating that it just goes to show that animal models are rubbish and this delivers a fair amount of material for EAE beating, but in contruary it may show that it is them who are the rubbish ones.
Baker D, Amor S.Experimental autoimmune encephalomyelitis is a good model of multiple sclerosis if used wisely. Mult Scler Relat Disord. 2014;3(5):555-64
I get chastised about saying such things in public as it is is not news through rose-tinted glasses.It is an admission that we make mistakes.
Sure there is indeed a load of rubbish EAE experiments (some done by the people viewed as being the best and published in the best journals) out there and this should not be defended…. but stamped out!…..some people may say this is harsh. Some experiments will never repeat in another lab let alone a human.
If there is a side-effect issue we can move on and design ways to avoid side-effects and get the same outcome, this is what we are trying to do. But, if the idea gets chucked away because of a perceived failed trial then the research avenue is dead and an oppertunity to do something is wasted..