Case study
My MS clinical nurse specialist has suggested I switch from ocrelizumab to ofatumumab. She reckons ofatumumab is safer than ocrelizumab. Apparently, it will make me more independent of the increasing problem of finding suitable NHS infusion slots as I can self-administer the drug myself in monthly injections. I have been on ocrelizumab for close to three years. Two quick questions. Firstly, is she correct; is ofatumumab safer than ocrelizumab? Secondly, I note that on the MS-Selfie Infocards, ofatumumab scores higher than ocrelizumab on relapses. Does this mean it is also more effective than ocrelizumab?
Prof G’s opinion
Is ofatumumab safer than ocrelizumab?
On balance, ofatumumab may be safer than ocrelizumab in the short term, but by an amount that, in my opinion, is not clinically relevant to my MS practice or at least not yet. I need more data.
As you know, ofatumumab is not given by an infusion and hence is not associated with an infusion reaction due to rapid B-cell lysis (bursting of cells). This means we can avoid using relatively high doses of steroids to prevent infusion reactions and hence the associated complications of high-dose steroids. You need to be aware that the infusion reactions associated with ocrelizumab from cell lysis are only a problem with the first (Day 1), second (Day 15) or possibly third infusions (month 6). After this infusion reactions are not a problem because most pwMS on ocrelizumab are B-cell depleted, and hence there are very few B-cells to lyse with subsequent infusions. As a result, many centres have stopped using steroids after the third infusion, a practice which was accelerated during the COVID-19 pandemic. The latter is a safety issue as high-dose steroids increase your risk of severe COVID-19.
It seems that ofatumumab is less depleting than ocrelizumab regarding the deep tissues (lymph nodes, spleen, bone marrow and other non-blood compartments), and B-cell repopulation occurs more quickly after stopping ofatumumab treatment compared to when stopping ocrelizumab. The data for this latter conclusion is based on relatively short-term studies and a different cut-off for defining B-cell reconstitution. I am not convinced that long-term ofatumumab dosing, over many years, will not result in more deep tissue depletion like that with ocrelizumab. Hence over time, ofatumumab B-cell repopulation kinetics will get closer to that of ocrelizumab. This is relevant when interpreting the lower short-term incidence of hypogammaglobulinaemia and associated infections currently seen with ofatumumab. Hence the incidences of both these complications may increase with the duration of ofatumumab treatment. The same applies to vaccine responses; I suspect the longer you have been on ofatumumab, the more blunted your antibody responses to new vaccines will become.
If you look at the SmPCs (summary of product characteristics) for both ofatumumab and ocrelizumab, they tell a different story around B-cell repopulation kinetics.
The fact that ofatumumab uses 40 B-cells/µl and ocrelizumab 80 B-cells/µl to define the lower limit of normal (LLN) means the reported kinetics are not comparable. It is like comparing Granny Smith apples with Golden Delicious apples; they may both be varieties of apples, but they look and taste very different.
Please be aware that ocrelizumab was also tested in primary progressive MS (Oratorio study), with a study population that was older, more disabled and more likely to have comorbidities than relapsing-remitting populations. The older primary progressive MS population had more adverse events, which makes ocrelizumab look less safe. However, regarding the relapsing populations in the Opera 1 & 2 studies, the safety profile is not too dissimilar to ofatumumab. The corollary is that if ofatumumab were trialled and used in pwPPMS, a similar safety profile would emerge to that seen with ocrelizumab in the PPMS population.
Another factor that needs to be considered is that this patient is switching to ofatumumab from ocrelizumab. In this scenario, ocrelizumab is likely to have induced a state of profound B-cell depletion. As ofatumumab, another anti-CD20 therapy, would maintain the B-cell depleted state, why would this patient's safety profile change? Ofatumumab will keep this patient in a B-cell-depleted state and not allow B-cell repletion. This means safety in terms of B-cell depletion (infection risk, immunoglobulin levels and vaccine responses) is unlikely to change.
Learning point: the immunological effects of sequencing from ocrelizumab to ofatumumab will differ significantly from being treated with ofatumumab from the outset.
Apart from avoiding high-dose steroids to prevent infusion reactions (which may not be necessary), I am not convinced that this patient's nurse’s claim that ofatumumab is safer than ocrelizumab is correct.
Switching for efficacy reasons
As ocrelizumab is not a completely humanised monoclonal antibody, there is a small risk (~1%) of anti-drug antibody (ADA) development, which may neutralise the action of ocrelizumab and prevent B-cell depletion. Therefore, ocrelizumab may fail the patient because of ADAs, an obvious indication to switch to ofatumumab.
ADAs to ocrelizumab can be looked for by assessing peripheral B-cell counts and checking for ADAs using specialised assays. In comparison, if someone has breakthrough disease activity on ocrelizumab without ADAs and good B-cell depletion, it makes little sense to switch to ofatumumab. In this situation is important to review the diagnosis of MS to make sure it is correct and then switch to another class of DMT or consider AHSCT.
Please note that ofatumumab is a humanised monoclonal antibody; hence, the chances of developing ADAs on ofatumumab are very low (<0.1%).
Switching for convenience
Yes, this is a valid reason for switching from ocrelizumab to ofatumumab. Some pwMS would rather self-inject once a month than spend at least half a day every six months coming in for an infusion. We have a small number of patients at our centre making the switch for this reason. There is, however, a push at many UK MS centres with a shortage in NHS infusion capacity for patients to make this switch. I have no problem with this policy, provided they make their patients aware of the reasons for recommending the switch and giving the patient a choice.
A potentially more significant issue is not offering pwMS a choice between ocrelizumab and ofatumumab upfront when they start an anti-CD20. As ofatumumab does not require an infusion, initiating ofatumumab is easier and quicker than ocrelizumab. This is particularly relevant to district general hospitals where they don’t have large MS infusion units. This may not be bad in that pwMS will probably get onto a highly effective DMT earlier by bypassing the various hurdles the NHS puts in the way of infusion therapies. My only concern with this approach is that we still have not sorted out whether ocrelizumab or ofatumumab offer better outcomes in relation to smouldering MS.
Venous access
Finding a suitable vein and then cannulating it can be a problem in some patients. If this is a recurrent problem, switching from an IV formulation to a subcutaneous formulation may be worth considering.
Relapses vs smouldering MS
Unfortunately, there have been no direct comparisons between ocrelizumab and ofatumumab regarding their relative effectiveness. When you do network analyses, ofatumumab does slightly better than ocrelizumab regarding its impact on relapse reduction. This is why ofatumumab scores more highly than ocrelizumab on the MS-Selfie Infocards because the information on relative efficacy is taken from network analyses. To be honest, the difference between these agents on relapse reduction is so small it is unlikely to be clinically significant.
I am influenced more by the potential CNS effects of these agents, i.e. do they get into the brain and spinal cord and impact smouldering pathology?
Ocrelizumab is given at a higher dose than ofatumumab and probably explains its greater effect on deep tissue B-cells. The half-life of circulating monoclonal antibodies is partially determined by its circulating concentration vs the amount of CD20 it targets on B-cells. The more circulating antibody around, the longer their half-life. The more target antigen around, i.e. CD20+ B-cells, the lower the so-called half-life of the antibody because the antigen (CD20) binds to and removes the antibody from circulation. Following B-cell depletion, the steady state of ofatumumab's half-life is 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 mentioned above. For ofatumumab, B-cell counts reach the lower limit of normal in at least 50% of patients 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? 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.
It is hypothesised 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 and others 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, 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.
Dose-response relationships in biology are often S-shaped. I suspect the intrathecal effects of ofatumumab based on body weight are on the flat part of the S-curve. Compared 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 image below). We are currently investigating this hypothesis by doing detailed CSF studies comparing what happens in the spinal fluid of patients on ocrelizumab high-dose vs ocrelizumab standard dose.
It is worth pointing out that ocrelizumab significantly impacted brain volume loss in clinical trials compared to interferon-beta (relapsing cohort) or placebo (primary progressive MS). In contrast, there was no difference between ofatumumab and teriflunomide on brain volume loss in the two relapsing MS trials. Is this telling us that ofatumumab has minimal impact on the end organ? Possibly, which is why we need to wait for real-life data comparing ofatumumab to ocrelizumab, particularly in relation to brain volume loss and other markers of smouldering MS.
I consider ofatumumab a low-dose anti-CD20 therapy and ocrelizumab a higher-dose anti-CD20 therapy. This is one of the reasons we are comparing the standard dose of ocrelizumab (600mg) with 1,200mg and 1,800mg in a clinical trial (NCT04544436). I am mentioning this because this patient may want to wait for the read-out of these trials before switching from ocrelizumab to ofatumumab.
High-dose vs low-dose anti-CD20 therapy
To move our treatment target beyond NEIDA (no evident inflammatory disease activity), the new focus has to be on preventing end-organ damage and the processes driving smouldering MS, i.e. stopping disability progression, normalising brain volume loss, flattening neurofilament levels, stopping slowly expanding lesions from getting bigger, clearing the CSF of oligoclonal IgG bands and if possible promoting repair and recovery of the nervous system.
What good is it to be free of relapses and focal MRI activity if you get worse? This is why the concept of using low-dose anti-CD20 therapy is so flawed. Trial participants exposed to lower doses of ocrelizumab in the phase 3 trials, due to body size, do as well as those exposed to higher doses in relation to relapses and MRI activity, but not in relation to worsening disability or smouldering disease.
The phase 3 ocrelizumab trials used a fixed dose of 600mg of ocrelizumab intravenously every 6 months. By doing this, smaller pwMS got a larger dose of ocrelizumab than larger people. For example, someone weighing 60 kg will get 10mg/kg of ocrelizumab 6-monthly compared to 5mg/kg for someone with MS weighing 120 kg. Trial subjects can be divided into four groups or quartiles representing four dosing levels by measuring drug concentrations. Despite no difference between these four groups concerning the treatment effect of ocrelizumab on relapses and MRI activity, those subjects who received higher doses and had more significant B-cell depletion were less likely to progress (see paper below). This higher-dose treatment effect on smouldering MS, i.e. beyond NEIDA, was seen in both the relapsing and primary progressive populations.
From these post-hoc analyses of the phase 3 ocrelizumab trials, it is clear that you need higher, and not lower, doses of anti-CD20 therapy to tackle smouldering MS. At the moment, these observations only apply to the initial two years of treatment. Hence, you may only need higher doses as an induction strategy to purge the various B-cell compartments of pathogenic (disease-causing) cells.
I have hypothesised that the deep tissue compartments house memory B-cells, which may be an important sanctuary for latent EBV and/or the highly autoreactive population of B-cells that drive and maintain the MS disease state. This population of cells may reside in the deep tissues and/or the central nervous system, which can only be reached with higher doses of anti-CD20 therapy or other CNS penetrant anti-B-cell strategies, for example, ixazomib, cladribine, BTK inhibitors, etc. This is why we need higher doses of anti-CD20 therapies, not lower doses, to go beyond the peripheral B-cell target.
Once you have purged these compartments after two years of anti-CD20 treatment, you may not need to maintain pwMS on such high doses of anti-CD20 therapy, which will continue suppressing normal B-cell biology and immune responses with long-term complications. This is why I have proposed using high-dose ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment or maintenance therapy, such as teriflunomide, leflunomide, IMU-838 (vidofludimus) or ASLAN003 (selective second-generation DHODH inhibitors), HAART (highly active antiretrovirals), famciclovir or another anti-EBV viral agent, or BTKi’s.
Underpinning the induction-maintenance strategy is the hypothesis to allow B-cell reconstitution after anti-CD20 therapy in the presence of an antiviral agent to prevent EBV reactivation and reinfection of new memory B cells. Induction maintenance will also derisk the long-term immunosuppression associated with anti-CD20 therapies and prevent the development of hypogammaglobulinemia, allowing patients to respond to vaccines and deal with infections as the follow-on maintenance anti-viral therapies are not immunosuppressive treatments.
What are low-dose anti-CD20 therapies?
Please note that lower dose anti-CD20 therapies are a moving target and should not be equated with peripheral B-cell counts, which are a poor surrogate for what is happening in the deep tissues and CNS. We need better and more accessible biomarkers to study these compartments. Receiving ocrelizumab less than the licensed 6-monthly dose, rituximab, or ofatumumab could be classified as low-dose anti-CD20 therapy.
Please remember in the Swedish MS cohort, rituximab had less impact on brain volume loss compared to interferon beta (Fredrik Piehl, personal communication), and despite ofatumumab being vastly superior to teriflunomide in suppressing relapses and MRI activity, it was not superior to teriflunomide at slowing down brain volume loss in year two of the ASCLEPIOS I and II clinical trials (NCT02792218 and NCT02792231). Please pause here and ask yourself why? Another fundamental question you should ask yourself is whether or not you would choose your MS to be treated with low-dose or high-dose anti-CD20 therapy.
I am sure you have many questions about the issues raised in this Newsletter. If you are a regular reader of this newsletter, most of the points I cover in this Newsletter should be familiar to you.
Research paper
Background and objectives: Ocrelizumab improved clinical and MRI measures of disease activity and progression in three phase 3 multiple sclerosis (MS) studies. Post hoc analyses demonstrated a correlation between the ocrelizumab serum concentration and the degree of blood B-cell depletion, and body weight was identified as the most influential covariate on ocrelizumab pharmacokinetics. The magnitude of ocrelizumab treatment benefit on disability progression was greater in lighter vs heavier patients. These observations suggest that higher ocrelizumab serum levels provide more complete B-cell depletion and a greater delay in disability progression. The current post hoc analyses assessed population exposure-efficacy/safety relationships of ocrelizumab in patients with relapsing and primary progressive MS.
Methods: Patients in OPERA I/II and ORATORIO were grouped in exposure quartiles based on their observed individual serum ocrelizumab level over the treatment period. Exposure-response relationships were analyzed for clinical efficacy (24-week confirmed disability progression (CDP), annualized relapse rate [ARR], and MRI outcomes) and adverse events.
Results: Ocrelizumab reduced new MRI lesion counts to nearly undetectable levels in patients with relapsing or primary progressive MS across all exposure subgroups, and reduced ARR in patients with relapsing MS to very low levels (0.13-0.18). A consistent trend of higher ocrelizumab exposure leading to lower rates of CDP was seen (0%-25% [lowest] to 75%-100% [highest] quartile hazard ratios and 95% confidence intervals; relapsing MS: 0.70 [0.41-1.19], 0.85 [0.52-1.39], 0.47 [0.25-0.87], and 0.34 [0.17-0.70] vs interferon β-1a; primary progressive MS: 0.88 [0.59-1.30], 0.86 [0.60-1.25], 0.77 [0.52-1.14], and 0.55 [0.36-0.83] vs placebo). Infusion-related reactions, serious adverse events, and serious infections were similar across exposure subgroups.
Discussion: The almost complete reduction of ARR and MRI activity already evident in the lowest quartile, and across all ocrelizumab-exposure groups, suggests a ceiling effect. A consistent trend of higher ocrelizumab exposure leading to greater reduction in risk of CDP was observed, particularly in the relapsing MS trials, and was not associated with a higher rate of adverse events. Higher ocrelizumab exposure may provide improved control of disability progression by reducing disease activity below that detectable by ARR and MRI, and/or by attenuating other B-cell-related pathologies responsible for tissue damage.
Classification of evidence: This analysis provides Class III evidence that higher ocrelizumab serum levels are related to greater reduction in risk of disability progression in patients with multiple sclerosis. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in the open-label extension.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your own healthcare professional, who will be able to help you.
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