Case study: ocrelizumab or ofatumumab, which would you choose?

This patient with active relapsing-remitting MS has been offered ocrelizumab or ofatumumab. Prof G discusses his views on these two DMTs and explains how to differentiate between the two.

Photo by Possessed Photography on Unsplash

Case study

I am a 24-year old woman who received my diagnosis of MS three weeks ago. I probably had my first attack when I was 18 years old after starting college; I had a numb left leg that cleared up after 5 or 6 days. Four weeks ago I lost vision in my right eye. I noticed a smudge in the centre of my vision when I closed my left eye while I was putting on my make-up. I thought I simply had a dirty contact lens, but over the next three days, the smudge enlarged until I could not see anything except for a grey rim of light around the edge. I was seen in the eye clinic and was diagnosed as having optic neuritis. I was referred to a neurologist and after having an MRI I was diagnosed with relapsing-remitting MS. My neurologist thinks that I have probably had MS for several years because I have a large number of lesions on my scan. I have been recommended to start on an anti-CD20 treatment and have been given a choice between ocrelizumab and ofatumumab, which would you recommend? 

Prof G’s opinion

This lady lives in the US and many of the issues she raised about reimbursement and co-pay I can’t address. So I am going to respond to her clinical question as if she is being treated on the NHS and there are no issues around reimbursement. 

As with all newly diagnosed patients with MS, I will make sure my basic set of questions are addressed.

What is multiple sclerosis (MS)?

This patient has to know what MS is and be aware of the prognosis of both untreated and undertreated MS.

Am I sure that I have MS?

I will review her diagnosis. She has not had a lumbar puncture and I would recommend this. Analysing the CSF not only helps exclude MS mimics, it helps confirm the diagnosis and also provides prognostic information. Does this lady have oligoclonal IgG bands in her spinal fluid? If not, that is a good prognostic factor and would steer me away from using an anti-CD20 therapy. I have no data in hand about how effective an anti-CD20 therapy is OCB-ve pwMS. I would also like to know if her CSF neurofilament levels are raised; a high level is a poor prognostic factor and may nudge her towards higher efficacy therapies.

What type of MS do I have?

Based on her history this patient has relapsing-remitting MS.

What prognostic group do I fall into?

I simply don’t have enough information to be able to say with any confidence what prognostic group this patient falls into. However, as she seems to have a high lesion load and has been told by her neurologist that she has had MS for several years she probably falls into the intermediate or poor prognostic group. The fact that her neurologist is recommending an anti-CD20 therapy first-line suggests he/she is worried about this patient. 

What is the risk of not being treated with a disease-modifying therapy (DMT)?

I don’t believe in pulling punches and this young lady needs to be told how bad MS can be if left untreated or under-treated. I would recommend she reads our ‘Brain Health: Time Matters’ policy document to get an understanding of how MS is being treated in the modern era. 

Do I have active MS?

This patient has active MS. She has had a recent relapse. I would be interested to know if her MRI had any enhancing lesions and if her CSF had raised neurofilament levels. These may shift her from the active to the highly active MS category and open up other treatment options, for example, alemtuzumab or oral cladribine.

Am I eligible for treatment with a DMT?

Yes, she is eligible for treatment with one of our platform therapies, i.e. interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate, ocrelizumab and ofatumumab. However, it sounds like she may not have highly active MS as she has only had one relapse in the last 12 months and she doesn’t know if she has Gd-enhancing lesions. Don’t you think her neurologist should have told her if she had active lesions or not? 

What is the difference between a maintenance/escalation DMT and an IRT (immune reconstitution therapy)?

In an ideal world, this topic should be discussed at this stage, but as she is not eligible for an IRT it may complicate things. It is great pity we could offer this patient an IRT as they have distinct advantages when treating MS over maintenance treatments such as an anti-CD20 treatment. I would spend time explaining to this patient about long term immunosuppression, poor vaccine responses, the risk of hypogammaglobulinemia, infections and possibly secondary malignancy associated with anti-CD20s.

I would probably not bring up the issue of end-organ damage or brain volume loss at this stage. The latter is only an attribute you need to discuss if you were comparing anti-CD20 to other high efficacy treatments. As she is going to start an anti-CD20 this is not, in my opinion, a differentiator between ocrelizumab and ofatumumab. 

Do I understand the difference between short-term intermittent and long-term continuous immunosuppression?

This patient needs to know about the potential consequences of starting on a long term immunosuppressive therapy such as an anti-CD20. She will need to be told that an anti-CD20 therapy increases your chances of getting COVID-19 and severe COVID-19 and its impact on the COVID-19 vaccine and other vaccine responses. I would tell her about hypogammaglobulinemia and how as of yet we don’t know how to deal with this problem apart from stopping the treatment and switching her to another DMT. The big downside to an anti-CD20 therapy is long term immunosuppression, simply because the risks increase with time. 

With an IRT the risk is frontloaded and the immunosuppression short-lived. Once the immune system has reconstituted vaccine responses are normal.

Do I understand the concept of treat-2-target?

I would explain to her what our treatment target is and how we aim to achieve this aim and the monitoring requirements. This patient will need to have a rebaseline MRI at 6 months and then annual scans thereafter.

What are the attributes of the specific DMTs?

I would spend a lot of time with this patient explaining what MS is and how anti-CD20 therapies work. It is important for pwMS to not only understand their disease but how DMTs are thought to work. At the moment I don’t think there is enough data on the differences between ocrelizumab and ofatumumab to differentiate them. For example, ofatumumab is probably more potent than ocrelizumab in how it kills B-cell and because it is given subcutaneously and gets into the body in a different way it may have different effects on the different B-cell compartments; for example, lymph node vs. bone marrow. One issue I will mention is the potential difference in relation to penetration into the brain and spinal cord. 

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. Ocrelizumab is given at a fixed dose of 600 mg intravenously every 6 months compared to ofatumumab, which is given at a dose of 20 mg subcutaneously every month. Does this make 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 smouldering MS or PIRA (progression independent of relapses). When you compare ocrelizumab to ofatumumab using a method called a network analysis ofatumumab looks to be superior in terms of suppressing relapse activity. However, the differences are small and I would be hard-pressed to say these differences are clinically meaningful; in other words, I would not necessarily recommend choosing ofatumumab over ocrelizumab because of its small advantage in terms of relapse reduction. 

It seems 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 its circulating concentration vs. the amount of CD20 its target on B-cells. The more circulating antibody around, the longer its 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 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.

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 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.

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). We are currently investigating this hypothesis by doing detailed CSF studies comparing what happens within the spinal fluid of patients on ocrelizumab high-dose vs. ocrelizumab standard-dose. 

I do think ofatumumab is a low-dose anti-CD20 therapy and ocrelizumab is a higher-dose anti-CD20 therapy and is one of the reasons we are comparing standard dose ocrelizumab (600mg) with 1,200mg and 1,800mg in a clinical trial (NCT04544436). The reason why I am mentioning this here is that I think this patient would be an ideal candidate to participate in this trial. I would definitely offer her the option of being screened for this study. 

How can I derisk or reduce my chances of getting certain adverse events on specific DMTs?

We have a well-defined protocol for derisking anti-CD20 therapies, which includes baseline blood tests for infection screening and vaccine review. This will need to be done before she can start treatment.

What about timing? 

Apart from making sure this patient has been vaccinated, which will include COVID-19, pneumococcal and possibly mumps, measles, rubella, HPV and other travel vaccines. I see no reason not to start her treatment ASAP. 

Other factors? 

As she is a young woman it would be appropriate to discuss how we would manage her treatment in the event of her wanting to start a family. We would need to stop her anti-CD20 therapy at least three months before she decides to start trying to fall pregnant.

What would I recommend?

I would leave this up to her to decide. Apart from the high vs. low dose issue mentioned above, I don’t think there is any daylight between ocrelizumab and ofatumumab when it comes to their anti-inflammatory effects. Ocrelizumab may have the edge in terms of CNS penetration, but the higher dose comes with greater peripheral B-cell depletion and longer B-cell reconstitution, which may increase its infection risks.

There is little doubt that self-administered subcutaneous ofatumumab has the advantage in that this patient will not need to attend hospital for infusions, will have a lower risk of injection or infusion-like reactions and will not need steroids to prevent these reactions. As ofatumumab is prescribed as an outpatient therapy it will save the NHS money as there is no added VAT for outpatient therapies. In comparison, ocrelizumab as an inpatient infusion therapy will have VAT added and is more expensive and labour intensive for the NHS. At a population level, ofatumumab has the potential to change the way MS is managed; i.e. it will bring a very high efficacy treatment to local and community-based hospitals and HCPs.  The latter cannot be under-estimated at a healthcare system level. Ofatumumab will also free up staff at hospitals to get on with other potentially more important things than giving infusion to optimise MS outcomes.

So I am going to sit on the fence and let her make the choice herself. However, before doing this I will offer her the option of being screened and randomised to the high-dose ocrelizumab study (NCT04544436). 

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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 advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.