This post is for your interest, but it is all useful for doctors nurses and pharma
At the moment we have been talking about the possibilitiy of delaying anti-CD20 to allow your B cells to repopulate to increase your COVID-19 vaccine response. Obviously you need to consider the risks or lack of risks from such a delay and it is not my job to advise but I can help and supply relevent information.
How quickly do B cells come back after depletion?
The ususal way is to talk about the time to reach the Lower Limit of Normal (LLN). If we talk about the lower limit of normal for B cells in many peoples eyes this level is 80 B cells/microlitre (e.g. Aguis et al. https://doi.org/10.1177/1352458517740641).
Now the problem I see is that this can get used in the Label (FDA) or summary of medical product characteritistics (EMA) without definition. This we OK if we all stick to the same definition!
The lower limit of normal for oocrelizumab is not defined in the FDA label or the European Summary of Medical product characteristics (SpMC) for ocrelizumab (Maybe I missed it).
The Europrean (SpMC) it says
“In the Phase III studies, between each dose of Ocrevus, up to 5% of patients showed B-cell repletion
(> lower limit of normal (LLN) or baseline) at least at one time point.
The longest follow up time after the last Ocrevus infusion (Phase II study WA21493, N=51) indicates
that the median time to B-cell repletion (return to baseline/LLN whichever occurred first) was
72 weeks (range 27 – 175 weeks). 90% of all patients had their B-cells repleted to LLN or baseline by
approximately two and a half years after the last infusion”
This in my mind uses the definition of LLN= 80 B cells/microlitre and fits with what I see on graphs produced by the manufacturer.
Now what does it say for ofatumumab well the depletion data has just been published ( Bar Or et al. 2021) and they say “
“Patients who did not enter the extension study (n = 3) were followed up every 3 months for at least 9 months or until B-cell repletion (i.e. until levels returned to baseline values or to the lower limit of normal (LLN, 80 cells/µL), whichever came first) after study-drug discontinuation. Further information on B-cell repletion following cessation of ofatumumab treatment will be collected as part of the ongoing ALITHIOS study”.
Furthermore they say “By Day 14, B-cell counts were below the LLN (80 cells/µL) for all patients with available data (n = 273) who were receiving ofatumumab”.
Great so we can compare one with another. The above suggests that they aren’t going to talk about repletion yet but they do talk about repletion in the labels SpMC in Europe
They say “The median time to B-cell recovery to the lower limit of normal (LLN, defined as 40 cells/µl) or baseline value is 24.6 weeks post treatment discontinuation based on data from phase III studies”
Wow 25 weeks (ofatumumab) verses 72 weeks (ocrelizumab) thats a big difference and what would one expect one uses 20mg and the other 600mg, but hang-on the general definition of LLN is not 80 cells but 40 cells!
Data from RMS phase III clinical studies indicate a median time to B-cell recovery to LLN or baseline
value of 24.6 weeks post treatment discontinuation. PK-B cell modelling and simulation for B-cell
repletion corroborate this data, predicting median time to B-cell recovery to LLN of 23 weeks post
Data from RMS clinical studies indicate B-cell recoveries over the LLN in at least 50% of patients in 24 to 36 weeks post-treatment discontinuation. Modeling and simulation for B-cell repletion corroborates these data, predicting median time to B-cell recovery of 40 weeks post treatment discontinuation”.
They do not define what LLN, so are they using 80 cells/microlitre
So whilst the manufacturers ponders on this is and think how the repletion data is reported, so that you can get an idea of the differences between ofatumumab and ocrelizumab.
The repopulation data of ocrelizumab has been reported in a different way
Gibiansky E, Petry C, Mercier F, Günther A, Herman A, Kappos L, Hauser S, Yamamoto Y, Wang Q, Model F, Kletzl H. Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO. Br J Clin Pharmacol. 2021;87:2511-2520
Aims Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20‐positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS were assessed.
Methods A population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation.
Results The ocrelizumab serum concentration vs time course was accurately described by a 2‐compartment model with time‐dependent clearance. Body weight was found to be the main covariate. The area under the concentration–time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing <60 kg and 21% lower for patients weighing >90 kg when compared with the 60–90 kg group. The terminal half‐life of ocrelizumab was estimated as 26 days. The extent of B‐cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure.
Conclusion The pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B‐cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B‐cell depletion was greater with higher exposure.
In the text they say
“However, repletion data from the Phase II study show that, following the final infusion of 600 mg ocrelizumab, median time to B‐cell repletion was 72 weeks (range 27–175), with LLN defined as 80 cells/μL. Sensitivity analyses of different LLN definitions showed median repletion times between 53 (LLN = 40 cell/μL, range 27–145) and 86 (LLN = 107 cells/μL, range 27–222) weeks”.
So it takes 25 weeks for oftaumumab to repopulate to 40 cells per microlitre and 53 weeks (range 27 to 145 weeks) for ocrelizumab to do this.
Now the question. Will be is this true after significant time on ofatumumab and in terms of COVID-19 vaccination.
If you are part of BartsMS and are planning on using ofatumumab then you should get your COVID-19 vaccination and Booster before starting treatment.
General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.