Acute remyelination of MS lesions

A big thank you to innovators and risk takers behind the anti-lingo development programme. #MSBlog #MSResearch

"Should we be excited about yesterday's announcement by Biogen-Idec of the results of their anti-lingo trial yesterday? Their study took subjects with acute optic neuritis and treated them within 4 weeks to see if anti-lingo, a drug that blocks one of the inhibitors of remyelination, could improve visual outcome at 24 weeks. Although Biogen-Idec are claiming the trial is positive my interpretation is more guarded; I think it is negative. Why? The primary outcome is speed of conduction a marker of myelination; the results were borderline positive. However, if the drug was truly remyelinating the optic nerve fibres it should also protect some of vulnerable fibres from dying, or degenerating, and hence the retinal nerve fibre thickness should have been thicker on anti-lingo compared to subjects treated with placebo. Therefore, I am not convinced that this study is positive. My other concerns relate the the study design. We have always promoted the concept of a therapeutic pyramid in MS; i.e. anti-inflammatory to stop ongoing damage (not really relevant in this trial as the lesion had already developed), neuroprotection to keep the axons and nerves alive, remyelination of the surviving nerves and finally neurorestoration. No attempt was done to build a pyramid in this study."

"We have also shown in our animal model that neuroprotection in acute focal inflammatory lesions has to occur in a very narrow window; the so called inflammatory penumbra. In our animal model this is 3 days and correlates with the duration of blood brain barrier leakage. When we extrapolate this to MS we think the window is from 7 to 21 days; i.e the duration an acute MS lesion enhances with gadolinium on MRI. If you give a drug beyond this time window it will probably be too late and the axons that need protecting are probably too damaged and hence there will be nothing to remyelinate. This study does two things wrong; (1) it does not use a neuroprotectant and (2) it had a treatment window of 4 weeks, which according to our modeling is too long.  I think anti-lingo needs to be combined with a neuroprotectant (e.g. a sodium channel blocker) and needs to be given within a therapeutic window of  2 weeks. Anti-lingo is an antibody and hence is quite a large molecule; by giving the drug when the blood-brain-barrier is still open will allow it to cross and engage its target. Biogen-Idec will be able to do a post-hoc analysis to see if subjects treated within 2 weeks of symptoms onset did better than those treated in the 2-4 week window. We are currently testing the inflammatory penumbra concept with our phenytoin in acute optic neuritis trial and have set the treatment window at 14 days; this trial is now complete and the results will be presented in April this year."

"I am at a meeting with a large number of MS colleagues. At dinner last night the anti-lingo trial results dominated the conversation. One colleague made the comment that we neurologists know little about the significance of the results; he suggested that a much better indicator of whether the anti-lingo results are meaningful or not is what the markets think. He made the point that the market integrates information from many sources and hence it would be a better indicator than our opinions. The following share price plot shows Biogen-Idec share dipping slightly; I think the market's interpretation is compatible with my analysis."

"Whatever your interpretation of the trial results are I must congratulate Biogen-Idec for not being risk adverse and for taking on this study. Doing this study took guts and shows what a bold, brave and cutting-edge company Biogen-Idec is. Pharma companies who don't take risks, like Biogen-Idec have done with anti-lingo, shrivel and die. The only game in town is innovation and risk taking. To innovate you have to invest in R&D  and then translate your R&D into drugs that address the unmet needs of patients. Lingo and anti-lingo biology was discovered and pioneered by Biogen-Idec scientists. Biogen-Idec have then invested heavily in the clinical development of anti-lingo and in so doing are pioneering a new therapeutic strategy for MS. Every study is an experiment and we will all learn from this experiment. It is clear that anti-lingo programme needs to go forward; the unmet need, particularly in progressive MS, is still there. Finally, a big thank you to all the clinicians and people with optic neuritis who volunteered for this study; without their participation we would not be having this discussion."

CoI: multiple

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