Multiple Sclerosis Research Repository

Dear FDA, Office of Scientific Investigations, Office of Compliance, CDER: 

I’m writing this letter to express the following concern about how adverse events were reported in this trial: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2415988(“Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis” by Robert J. Fox, M.D., et al)

In this trial, it appears that only “Increase in ALT level to >3x ULN.”  I am concerned that increase in ALT levels to >2x ULN does not appear to have been assessed.  I believe that the FDA should require information about ALT levels >2x ULN in trial participants before considering approving tolebrutinib.  I find it both concerning and suspicious that the authors/investigators did not assess and/or report increases in ALT levels >2x ULN among trial participants.  It also seems to be the case that increase in ALT levels equal to 3 was not assessed and/or reported either.  

Interestingly enough, though, the following adverse event was assessed and reported in the trial report: “ALT level >3x ULN and total bilirubin level >2x ULN.”  I am curious as to why the investigators assessed total bilirubin levels at >2x ULN but did not assess ALT levels at >2x ULN.  

My understanding is that the FDA will likely soon consider tolebrutinib for approval for nonrelapsing secondary progressive multiple sclerosis, with approval possibly anticipated by the end of this year.  Before undertaking consideration of tolebrutinib for possible approval (it showed a very minimal treatment effect, with NNTs of around 10 and 11 for very small absolute risk reductions for 6-month and 3-month CDP, respectively), I am requesting that the FDA obtain information about how many trial participants had increases in ALT level >2x ULN and equal to 3x ULN and review this information before making a decision about approval.  

Respectfully Submitted: