Barts-MS rose-tinted-odometer: ★★★ (gray Friday; overcast and miserable #3a3b3c)
It was not easy writing this blog post; I hope it makes sense. I was asked the other day ‘what defines a low versus a high-dose B-cell depleting anti-CD20 therapy?’.
Unlike with small molecules the dose of monoclonal antibodies is not necessarily about drug/antibody levels, but how much of the target gets inhibited or depleted and then how long these effects last. So when I compare ocrelizumab (600mg intravenously every 6 months) with ofatumumab (20mg subcutaneously every month) is there a difference? Yes and no; it depends on whether or not you take into account the potential CNS effects of these agents.
No in the sense that both of these doses are likely to keep circulating peripheral B-cell numbers very low and seem to have similar effects when it comes to suppression of inflammatory MS activity, i.e. relapses, focal MRI lesions, relapse associated-worsening and possibly even a component of PIRA (progression independent of relapses).
It is clear that ocrelizumab is a higher dose and is having a greater effect on deep tissue B-cells. The half-life of circulating monoclonal antibodies is partially determined by the circulating concentration vs. the quenching effect of the target antigen. The more circulating antibody around, the longer its half-life. The more target antigen around, i.e. CD20+ B-cells, the lower half-life of the antibody because the antigen binds to and removes antibody from the circulation. Following B-cell depletion, the half-life at steady state for ofatumumab is estimated to be approximately 16 days (FDA ofatumumab prescribing information) compared to 26 days for ocrelizumab (FDA ocrelizumab prescribing information).
Other differences supporting the low vs. high dose differences relate to B-cell repopulation kinetics. For ofatumumab B-cell counts reach the lower limit of normal in at least 50% of patients in 24 to 36 weeks after stopping treatment, which equates to a median time to B-cell recovery of ~40 weeks post-treatment discontinuation (FDA ofatumumab prescribing information). For ocrelizumab, the median time for B-cell counts to return to either baseline or the lower limit of normal is 72 weeks (range 27-175 weeks) (FDA ocrelizumab prescribing information).
Based on the above there is little doubt that ocrelizumab is higher-dose than ofatumumab. Is this relevant? I think it may be if part of the mode of action of B-cell depletion therapies is to target B-cells and B-cell follicle-like structures within the CNS of pwMS. The amount of antibody that crosses the blood-brain barrier is roughly 0.5% of what is circulating in the periphery; as steady-state levels are higher with ocrelizumab more of it is likely to cross the blood-brain barrier and affect CNS and meningeal B-cells.
We are only one of many groups that hypothesise that the intrathecal or CNS B-cells, plasma cells and antibodies (oligoclonal bands) are pathogenic in MS and are driving some of the smouldering pathologies we see in MS. This is why we are exploring therapies such as proteasome inhibitors (ixazomib), cladribine, BTK inhibitors and high-dose ocrelizumab to see if we can scrub the CNS clean of OCBs. So yes, based on this hypothesis I think the dose of ofatumumab may be too low to affect intrathecal B-cells. A clue to this is that there was no dose effect, based on body size, on disability progression noted with ofatumumab compared to that seen with ocrelizumab. Why?
Dose-response relationships in biology are often S-shaped. I suspect the intrathecal effects of ofatumumab based on body size is on the flat part of the S-curve. In comparison with the higher body-size based doses of ocrelizumab, the intrathecal/smouldering MS effects are on the linear part of the curve and hence why there is a clear signal (see dosing imaging below). There is a way to investigate this hypothesis involves doing detailed CSF studies comparing what happens within the spinal fluid of patients on ocrelizumab high-dose vs. ocrelizumab standard-dose vs. ofatumumab standard-dose. I hypothesize there will be a clear ladder on the impact on CNS B-cell biology. At the same time, we can ask what is the impact of this anti-CD20 dosing tier is on meningeal B-cell follicle-like structures, slowly expanding lesions, subpial cortical lesions, brain volume loss, CSF NFL levels, etc.?
So yes, I do think ofatumumab is a low-dose anti-CD20 therapy and ocrelizumab is a higher-dose anti-CD20 therapy. This explains why I helped push/nudged Roche-Genentech to design and run their own version of our proposed DoDo (double-dose) ocrelizumab study. The good news is that these high-dose ocrelizumab trials are recruiting rapidly and we should have an answer to some of these questions in the next 3-4 years.
Based on the above I am also against low-dose rituximab dosing in MS. I think we need high-dose CNS-penetrant anti-CD20 therapies; at least initially. Once you have purged the CNS of B-cells and B-cell follicle like structures the dose can probably be reduced.
Please, let me know if this post makes sense? Thanks.
CoI: Please note I sit on the steering committee of Roche-Genentech’s high-dose ocrelizumab programme.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni 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.