This is a debate close to my brain and the pros and cons have been debated in an MS journal. You know I’m biased and believe that studies should be done by the makers of anti-CD20 depleting antibodies, but what do other people (in blue saying no) think and say.
“Anti-CD20 MS drugs are highly effective in treating relapsing MS in their current approved treatment regimens (ocrelizumab in a 6-monthly intravenous dose of 600 mg and ofatumumab in a 4-weekly subcutaneous dose of 20 mg). Rituximab is used off-label in 6- to 12-month intravenous doses of 500–1000 mg and has shown comparable efficacy to the other anti-CD20 therapies in observational trials”.
Should we extend extended interval dosing (EID) to B-cell depleting therapies?
The primary aim of EID should be retaining maximal drug efficacy. Although data on EID of anti-CD20 therapies is expanding, all (mostly retrospective) cohorts have short durations of follow-up and lack control groups. Furthermore, these studies investigated various strategies of EID, some investigating a set interval extension and others only re-dosing based on percentage or absolute number of CD19+ or CD27+ B-cells. Even though these cohorts are valuable and indicate a growing initiative of EID of anti-CD20 therapies in MS, the evidence is insufficient regarding efficacy of EID of anti-CD20 therapies.
So more evidence, evidence, evidence is needed…but here’s the but
In contrast, unpublished data of the phase-II and III studies of ocrelizumab, suggest that higher drug concentrations, leading to longer complete B-cell depletion, was associated with a risk reduction of confirmed disability progression in relapsing and progressive MS without an increase of safety issues (Kletzl, presentation AAN 2019). This finding has led to two ongoing trials initiated by Hoffman-La Roche, the manufacturer of ocrelizumab, studying higher doses of ocrelizumab in relapsing remitting MS patients (ClinicalTrials.gov Identifier: NCT04544436) and primary progressive MS patients (ClinicalTrials.gov Identifier: NCT04548999). Results from these studies are expected in 2029.
So the thought that EID may not affect MS progression could cause a decade delay in EID research….I have to say, I’ll be gone by 2029 (dead or retired..but, the first bit will be complete at 2023-2024), if we have to wait for the DoDo of ToDo trials to finish. They are double and triple dose ocrelizumab trials. Let’s say they show an effect on progression, the question is what does this say against EID?
The idea for the effect on progression came from the view that small people don’t progress compared to big people because ounce for once or grammme per gramme big people get less antibody when you used a fixed 600mg dose. For example a 150kg man is going to get a lot less antibody than a 40kg female ie. 0.6g/40kg = 15mg/kg verses 0.6g/150kg = 4mg/kg. So let’s give a bigger fixed dose of 1200mg ((less than 75kg) or 1800mg dose (more than 75kg) for everybody as occurs in the trials above. I wonder, if it would be more scientific to dose people according to their actual size so the 150kg person would need 2250mg if everyone gets 15mg/kg (in the example used,). This is how rituximab is used in rheumatoid arthritis.
However, does the antibody have to be given every 6 months even if a triple dose is used. A triple dose will mean the drug hangs around for an extra 2 months because it will take about two months to get rid of the extra antibody if half of it takes about a month to disappear. Maybe all you need is for a big enough dose to do its job and you don’t need to give it all the time and it can then have an effect on progression.
In 2018, the RIDOSE-MS study (ClinicalTrials.gov Identifier: NCT03979456) started randomizing relapsing MS patients or patients with a clinically isolated syndrome between 500 mg rituximab 6 or 12 months with long-term follow-up, results will follow in 2025. I predict that brain atrophy will be inhibited to a level as good as alemtuzumab in contrast to that seen in ocrelizumab phase III trials. If this prediction is true, will we have to wait until someone does the trials for people to believe it happens with ocrelizumab or ofatumumab?
We should also be aware that infusion-related events decrease with subsequent ocrelizumab doses, a decrease that might not be as present when applying EID. Another prevalent clinical observation is the wearing-off phenomenon, in which patients describe increase of MS symptoms prior to their next infusion of monoclonal antibodies. A recent study showed that 61% of MS patients on ocrelizumab experienced this phenomenon during treatment.(Gibiansky et al. Br J Clin Pharmacol 2021; 87:2511) EID could increase duration or severity of these symptoms in a proportion of patients.
Finally, when considering EID for anti-CD20 therapies, a relative over-treatment should be suspected. Even though we know that B-cell depletion in most ocrelizumab-, rituximab-, and ofatumumab-treated patients exceeds the approved infusion interval and ocrelizumab likely has prolonged clinical effects after discontinuation, we are unsure what biomarker to use for pharmacodynamic treatment effect of anti-CD20 therapies in MS. Should we mainly look at CD19+ B-cells altogether, focus on CD27+ memory B-cells or maybe on CD20+ T-cells? Until we better understand the basis of the therapeutic effect of anti-CD20 therapies, we have no designated biomarker to guide EID.
In conclusion, although EID of anti-CD20 therapies is of interest and could decrease costs and possibly complications, we should be cautious of re-emerging disease activity and disability progression when considering interval extension of these therapies. Until a randomized controlled trial is executed investigating EID of anti-CD20 therapies in MS patients, extending intervals between infusions of anti-CD20 therapies can pose unnecessary risks for MS patients. https://doi.org/10.1177/13524585211065711
So the view is that we need trials and I would agree with that if we preach evidence base...the question is who will do such a study as it is not in the interests of pharma to do this. Who will do it?
Don’t look at me you need a clinician…maybe it will get done in rituxiland
Manuel Escobar J, Cortese M, Edan G, Freedman MS, Hartung HP, Montalbán X, Sandbrink R, Radü EW, Barkhof F, Wicklein EM, Kappos L, Ascherio A, Munger KL. Body mass index as a predictor of MS activity and progression among participants in BENEFIT. Mult Scler. 2022:13524585211061861.
BENEFIT was a beta interferon trial that looked at the conversion from a clinically isolated syndrome (CIS) to multiple sclerosis (MS). This study looks at size and progression and doesn’t really find the BMI is a predictor of worsening, suggesting in the ocrelizumab studies drug dosing was important
Results: No associations were observed between obesity BMI ⩾ 30 kg/m2 and normal weight as 18.5 ⩽ BMI < 25. patients for conversion to clinically definite MS, sustained progression on EDSS or magnetic resonance imaging (MRI) outcomes
Disclaimer. The views are those of the authpur and not any institution