I have had another email from a US colleague who is worried about the risk-benefit ration of ocrelizumab in PPMS. He/she is worried about the risk of secondary malignancy with ocrelizumab and is therefore going to ‘continue prescribing off-label Rituximab instead’. I pointed out to him/her that the safety data on Rituximab-treated PPMSers in real life is too small to assume it is safe in PPMS and that he/she is prescribing a therapy that has been shown to be ineffective in PPMS. Because Rituximab is effective in RRMS does not mean we can extrapolate the RRMS rituximab data to PPMS and assume it will be effective in PPMS as well.
It is interesting to see how the mind works and that someone is prepared to extrapolate efficacy data from RRMS to PPMS, despite the rituximab PPMS trial being negative and ignoring the fact that the ocrelizumab PPMS trial is positive.
Could there be an efficacy difference between rituximab and ocrelizumab that explains the results? I have recently learnt that ocrelizumab is a much more potent B-cell depleter than Rituximab, i.e. ~10x as potent. Could this explain its therapeutic effect in PPMS? A 600mg dose of ocrelizumab is therefore ~6x more potent than 1,000mg dose of rituximab. The large punch provided by ocrelizumab may explain and efficacy difference particularly if we are targeting the hard to get to meningeal and intrathecal B cells? Let’s hope an ocrelizumab CSF biomarker study is done to explore this possibility. Another way of looking at this is to see what impact ocrelizumab has on cortical gray matter atrophy and B cell follicles using imaging. We think some of the gray matter atrophy that occurs in MS is due to the meningeal B-cell infiltrates.
I also pointed out to my colleague that to assume that ocrelizumab increases his/her patient’s risk of secondary malignancy may be premature; the ocrelizumab malignancy signal at the moment could be a false positive signal. We really need to wait for more data to emerge through post-marketing surveillance to clarify this issue. We have the same issue with oral cladribine; the only way to assess secondary malignancy risks with DMTs is with long-term follow-up studies.
It is interesting to see the spectrum of opinions about ocrelizumab treatment of PPMS. On the one hand some neurologists are saying it is not effective and hence they are not going to prescribe it for their patients, on the other hand some are saying they don’t think it is safe and therefore they will prefer to prescribe a treatment that has not been shown to be effective in PPMS and yet others accepting the results and agreeing that their patients should receive ocrelizumab. In reality all these options are right and it simply reflects the complexities of clinical decision making that lead to variable adoption rates of new innovations.