Repopulating B cells after B cell depleting therapy. Ofatumumab seems quicker than Ocrelizumab


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.

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!

In the European Label we have

“B-cell repletion
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
treatment discontinuation”.

In the American label we have

“B-cell Repletion
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.

CoI: Multiple

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.

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  • What is the data ‘ modeling’ based off of phase 3 clinical trial data ??? One of the bugbears of research in medicine is that phase 3 clinical data is supposed to be ‘available upon request’ but it is a smokescreen for holding the data back. I have tried it myself multiple times through clinical trials websites with zero results.

    For instance if anyone wants to drill down into PML data at the individual patient level they will find nothing!!!

    • Biogen has signed up to Vivli. Inc trial data sharing site but they have no duty to provide data from before 2012 and you are after post-marketing data. I have done the data request and the ocrelizumab data access is essentially done. You have to first sign their legal agreement and then you get access to the trial data…however, when it arrives it is not what you ask for, it is everything and you get no key to where the data is and where the data you want is. For example, you want 5 rows of data for each person but that is somewhere in 20 files then there are 100 columns and in the column you are really interested in contains a million rows. You do the data analysis but you cant have access to the data even when it contains NO patient identifiers, you have generated unless it is the sumarizing table and once you are kicked out of the system that anlaysis is gone to you. This is all monitored by external policing so it is not the companies refusing you. However, they set the rules that the data-nazis adhere too. They monitor what you do when you access the data and if you dont go in enough they shut you down. This is not free access to data. It should be deposited with the regulators at the time of licensing requests and once the licence is granted data should be made freely available.

  • Nothing about the ofatumumab data repopulation data seems clear or transparent. This from the Figure 2 legend of the ofatumumab phase II MIRROR study, Neurology 2018 …

    “Pharmacodynamic response showing dose-response depletion of CD19 B cells and repletion kinetics
    (safety population). The median time to repletion based on Kaplan-Meier estimates was ≈11 months for the ofatumumab 3 and 30 mg every 12 weeks groups and ≈14 months for the ofatumumab 60 mg every 12 and 4 weeks groups.”

    Approximately 14 months, or 60 weeks, for the higher doses (neither the currently approved dose it should be noted) studied in the trial; well over a year after a short exposure and relatively small cumulative dose of ofatumumab. So you can choose from less than half a year based on a low LLN cut-off, modelling indicating around 36 weeks or 40 weeks as cited in the SmPC, or up to 60 weeks if you take the data for the actual recovery time as reported in the phase II trial for the higher cumulative dose cohorts. An embarrassment of data riches, but precious little clarity

  • This has been one of my biggest frustrations in Covid – Roche/Genentech (ocrelizumab maker) continues to be super opaque about vaccine-related data. I called their patient access line multiple times with questions, and they couldn’t even point me to the disclosures buried in their prescribing label. Now I’ve started calling them monthly to let them know I’m delaying my next dose while I monitor my B cell repletion and reconsider my MS treatment options, hoping enough others do the same that they’ll be more proactive helping us navigate the Covid vaccine environment.

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