We have made a suggestion that cladribine, alemtuzumab and anti-CD20 depleters work in the same way and this would suggest that if you dose 3 times (i.e. a year) then you may be able to “watch and wait” just like you do with alemtuzumab and cladribine. This study asks what happens when you stop ocrelizumab.
Before I read on, I would think that it is inconcievable that some people will not show disease activity. With alemtuzumab this approach only inhibits disease in about 50% of people so should we expect anything less?. Cladribine does abit better than alemtuzumab so now I read on…….
Wow it is better than I thought there is no difference between those on drug verses who stopped taking drug and the time off drug was 24-28 months. I suppose this doesn’t surprise me as we showed that an 18 month break did not noticeably increase risk of disease break through based on the phase II extension trial data. Cladribine has data for a 3year period so 36months. However, there seemed to be activity after more than 32 months this is two and a half years which is more than enough time to have a drug free-pregnancy.
So why isn’t this a priority to sort out!
The problem is that it is not in the interests of companies to do this as they sell less drug, but maybe they will sell more because they will be go-to drugs It has been suggested that there are few go-to drugs that should be tried first and if they fail them we can think of the twenty or so other agents. It becomes simpler not more complex. With a bit of monitoring drug could be restarted if lesions show themselves. With current B cell depleters we know they deplete within 1 day and so should be active very quickly (other anti-CD20 don’t have the data before about 2 weeks). Other MS drugs may not work that fast.
Companies don’t want people to stop using their products but if it was considered safe to have a drug free pregnancy and supported by a company…Surely it would be the go to reagent or class of agent for family planning. Now I say drug free-period and here I say well not really. 30 months and that is because we know that when you give 600mg of ocrelizumab there is plenty circulating months later to deplete B cells. With ocrleizumab there is clear data showing 20mg doses gets rid of B cells but with 600mg and a half-life of about a month at one month you have 300mg worth of drug at 2 months 150mg worth of drug, at 3 months 75mg of drug at 4 months 37.5mg worth of drug and at 5 months 18.75mg worth of drugs at 6 months you have 9.375mg worth of drug. These calculations are a bit simple but you get the point. with the 6 month dosing and stop it takes a median of 62-72 weeks to get to 80 cells per microlitre and 53 weeks to get to 40 cells per microlitre. In this current study it was 12 months so maybe 6 months after the antibody is gone. With ofatumumab it takes about 24-25 weeks after stopping to get to 40 cells per microlitre.
With alemtuzumab another bash of the drug seems to stop further disease activity in about 75% of people, so we should not despair if there is a need to have more antibody.
They say
“For clinically stable patients, ocrelizumab withdrawal after about 30 months may be a safe short-term strategy, potentially reducing long-term risks such as hypogammaglobulinaemia and influencing health economics by lowering treatment costs. These findings support individualised treatment strategies and highlight the need for monitoring beyond 2 years off-treatment to detect delayed reactivation”.
They show that “following ocrelizumab discontinuation, six patients (10%) experienced clinical relapses, of them one without development of new T2L and five with development of a total of seven new T2L. In four patients (7%), isolated disease activity in MRI with a total of eight new T2L was observed”
This means that more than 80% continue to do OK so it is better than alemtuzumab. Staying on the drug led to relapse “Among continuers, 26 patients (11%) presented clinical relapses, of them 21 without development of new T2L”
“Infection rates were similar comparing discontinuers and continuers and remained stable after discontinuation of ocrelizumab treatment”
This is what we suggested could occur about a decade ago…there are more trials in progress but it sort of suggests trial of extended dosing intervals trials less than 24 months are doomed to give us anything we haven’t seen already.
Did we get a mention? Well no…But I’m not bitter
Konen FF, Axhausen F, Wolff S, Mühlenbrock P, Gingele S, Jendretzky KF, Nay S, Grote-Levi LM, Schwenkenbecher P, Meuth SG, Skripuletz T, Pfeuffer S. Discontinuation of ocrelizumab in multiple sclerosis: reoccurrence of disease activity. J Neurol Neurosurg Psychiatry. 2026 Jan 20:jnnp-2025-337944.
Background: The optimal strategy after discontinuation of B-cell depleting therapies like ocrelizumab in people with multiple sclerosis (pwMS) remains uncertain, particularly regarding delayed disease reactivation, disability progression and required treatment duration before cessation.
Methods: In this prospective two-centre observational cohort study with propensity score-matched (PSM) analysis, we evaluated recurrence of disease activity and disability worsening after ocrelizumab discontinuation. PwMS fulfilling the 2017 McDonald criteria were enrolled between January 2018 and December 2023 at two German MS centres. Participants received ocrelizumab for ≥12 months with no inflammatory activity in the preceding 12 months. Of 655 eligible patients (continuers, n=578; discontinuers, n=77), 290 were included after 4:1 PSM. The primary exposure was discontinuation, mainly due to infection concerns during COVID-19 (81%) or hypogammaglobulinaemia (16%). Main outcomes were time to combined inflammatory activity (CIA) and progression independent of relapse activity (PIRA). Receiver operating characteristic (ROC) identified optimal treatment duration.
Results: After median follow-up of 28.5 months, there was no significant difference in CIA risk between groups (HR: 0.91, 95% CI 0.08 to 10.79) or for PIRA (HR: 4.8, 95% CI 0.38 to 60.2). Beyond 24 months after discontinuation, disease activity remained stable, with a numerical rise that did not reach statistical significance. ROC analysis suggested no further reduction of activity beyond 29-30 months of therapy, but increasing reactivation risk after >32 months off-treatment.
Conclusions: For stable pwMS, ocrelizumab discontinuation after about 30 months on-treatment appears safe short-term, though vigilant monitoring is warranted beyond 2 years off-treatment due to potential delayed reactivation.
Disclaimer> My views alone
Source: multiple-sclerosis-research.org