MS Drug Developments: Utility of CD20-Targeted B-Cell Therapy for Relapsing Multiple Sclerosis

Jonathan L. Carter, MD, is an associate professor of neurology at the Mayo Clinic Alix School of Medicine, Phoenix/Scottsdale, Arizona. With more than 20 years of experience, his clinical research interests include multiple sclerosis (MS), transverse myelitis, neuroimmunology, and neurophysiology.

What is the anti-CD20 pharmacotherapeutic landscape?

The 2 FDA-approved anti-CD20 medications for treating MS are ocrelizumab and ofatumumab. Rituximab, the parent drug of both derivatives, is also prescribed off label for the treatment of MS. Ocrelizumab was the first anti-CD20 agent approved, both for the relapsing–remitting MS (RRMS) and primary progressive forms (PPMS), based on the results of the pivotal OPERA and ORATORIO trials (ClinicalTrials.gov Identifiers: NCT01247324 and NCT01194570, respectively).^1,2 These therapies have also been reclassified by the FDA as approved for active secondary progressive MS (SPMS).^3,4
 
Rituximab was never submitted to the FDA for approval for treating MS, despite the phase 2 rituximab trial that showed evidence of efficacy.⁵ Ocrelizumab, a humanized version of rituximab, was carried forward as a new drug for the phase 3 trial.

What is the mechanism of action of anti-CD20 therapies?

These drugs target B-cell populations from the pre-B-cell lineage all the way up to the mature cell population—but they do not affect plasma cells, in terms of impacting antibody formation. Although there can be a diminished antibody response to vaccines, for example, the anti-CD20 response doesn’t target plasma cells to the extent that one would typically see a significant drop in antibody levels.
 
This group of compounds was developed mainly for hematologic malignancies; when they were applied to the treatment of MS, the MS community was a little surprised by their efficacy. We had been looking through the lens of MS being a T cell-mediated disease, and most clinicians hadn’t given much attention to a potential B-cell mechanism. 

How are anti-CD20 therapies being utilized in MS?

For RRMS, the consensus in the MS community is that ocrelizumab and ofatumumab are considered to be in the higher tier of efficacy. Ocrelizumab was compared against interferon beta-1a, and demonstrated superior effect, in the 2 pivotal trials that led to FDA approval.^1,2 Ofatumumab was significantly more effective than teriflunomide, an oral therapy, when the 2 treatments were compared (ClinicalTrials.gov Identifiers: NCT02792218 and NCT02792231),⁶ leading to FDA approval.
 
Both these agents have higher efficacy than first-generation injectables and teriflunomide, which is in the lower tier of efficacy. They have not been compared directly with any of the sphingosine 1-phosphate-receptor modulators, such as fingolimod, or with any of the fumarate compounds, so we don’t know for sure what their efficacy is relative to those therapies.

Has the advent of these agents altered the goals of MS therapy?

The MS community as a whole is moving toward more complete suppression of disease activity—so-called “NEDA” [no evidence of disease activity], which is talked about a lot as an outcome measure in MS trials. We’re really not at the point at which NEDA is achievable with agents we have, but that’s the goal. We are also looking at quality-of-life measurements, in addition to more traditional outcome measures, in clinical trials.

How are anti-CD20 agents implemented in practice, in terms of efficacy? 

Anti-CD20 inhibitors are often considered first-line therapy for MS. Guidelines for their positioning in the first line are not worked out yet; however, a patient who has an unusually aggressive early course of MS, an unusually severe first attack, or risk factors for more severe disease might be selected to receive anti-CD20 therapy initially, just as they would any other induction or high-efficacy therapy, including other monoclonal antibodies, such as alemtuzumab and natalizumab, which are used in more aggressive early cases. Of course, anti-CD20 treatment is also used frequently as an escalation therapy.
 
So, for patients who have had an inadequate response to other agents, anti-CD20 agents are attractive because they offer a different mechanism of action than the therapy that the patient might have been receiving previously.

Is there a significant difference in adverse effects between ofatumumab and ocrelizumab?

Not really. Ofatumumab is administered by subcutaneous injection, and patients can get a reaction to the injection. In fact, labeling recommends that the first injection be given in a healthcare provider’s office.⁷ Typically, injection reactions occur most often with the first dose.
 
The other significant adverse effect is infection; risk is increased with anti-CD20 therapy. The FDA recently added a recommendation to labeling of the drugs regarding checking immunoglobulin levels at least once a year, because some patients can have a drop in the immunoglobulin M (IgM) level and, more importantly, in the IgG level. Some patients who have had recurrent infection with these agents have had a low IgG level; for them, the recommendation is to supplement anti-CD20 therapy with intravenous immunoglobulin or consider switching to a different agent.

Is the risk of infection higher with anti-CD20 therapy than it was with earlier generations of MS drugs?

Probably not. All immunomodulatory therapies increase the risk of infection. That increase in risk varies from drug to drug, depending on what was shown about risk during the clinical trials.
 
The risk of infection becomes more of an issue in treating progressive disease. In studies of ocrelizumab for PPMS, the population that was treated was older; there was a higher infection rate than in RRMS patients.⁸ Postmarketing surveillance has shown that, as older patients are being treated with these agents, the risk of infection does go up significantly, just because of the effect of normal aging on the immune system and diminished immunocompetence. The 1 case of progressive multifocal leukoencephalopathy reported with ocrelizumab monotherapy was in a very elderly patient who had a low lymphocyte count before being treated. Certainly, immunosenescence increases the risk of these adverse events in older patients with MS.

How are adverse effects of anti-CD20 therapy managed?

A severe infusion-related reaction was reported in 2.4% of patients treated with ocrelizumab compared with 0.1% who received interferon beta-1a in OPERA, and in 1.2% of patients treated with ocrelizumab compared with 1.7% given placebo in ORATORIO.⁹ These reactions can usually be mitigated by slowing the infusion rate and giving additional medications, such as antihistamines, if an infusion reaction occurs. Infusion reactions are most common with the first or second dose of ocrelizumab.

Is there a difference between the 2 agents in activity against PPMS? If so, what are the implications of that difference?

Ocrelizumab is approved for PPMS; the other drug that specifically approved for progressive MS is siponimod, which is one of the sphingosine 1-phosphate-receptor modulators that carries an indication for SPMS. I think most of us in the MS community think that PPMS and SPMS are not fundamentally different, and that the rate of worsening, once you get to a certain point on the disability scale, is similar. So, I tend to approach them as basically the same group of patients.
 
The other point to make about PPMS is that the effects of anti-CD20 therapy are quite modest. The ORATORIO trial of ocrelizumab showed an approximate 25% slowing of the rate of progression.¹⁰ In a post hoc analysis, ocrelizumab delayed the time to becoming wheelchair-bound by approximately 7 years—an Expanded Disability Status Scale score of 7 or higher. Ocrelizumab did delay progression but, compared with the treatment of RRMS, in which we sometimes see sustained improvement in disability on anti-CD20 therapy, goals of treatment with progressive MS are a lot more modest. That’s where patient selection becomes important.
 
By that, I mean that if I’m a clinician whose patient is aged 70 years and has had pretty stable MS for the past 10 years, I have to consider that they are not going to show a recognizable response to anti-CD20 therapy because they’re not progressing rapidly—yet they would incur all the risk of the adverse effects of these drugs, including infection. 

Are there ways to stratify patients to determine whether to give or not give them anti-CD20 therapy?

Yes. In the ORATORIO trial, in which ocrelizumab was compared to placebo in patients with PPMS, the cutoff age was 55 years; their mean age was 45 years; and, going into the study, approximately 25% had an active magnetic resonance imaging scan with gadolinium-enhancing lesions.² They also had shorter duration of disease. So these were patients who were earlier on the PPMS spectrum, had more active disease, and might be expected to respond better to immunomodulatory therapy. They would be prime candidates for ocrelizumab therapy.
 
On the other hand, somebody in their 60s who has very, very slow progression year to year and a nonactive magnetic resonance imaging scan would probably not be a good candidate to start anti-CD20 therapy.

Do all these therapies signal potential to arrest progression?

Any therapy that is highly active in a younger group of patients with active MS could potentially stabilize disease. Data from the OPERA trials in RRMS looked at sustained improvement in disability in a post hoc analysis and showed that such improvement did happen in some patients. I would expect similar findings with ofatumumab because the molecules are very similar. If you look at any patient with active disease who is put on a highly effective therapy, you would expect sustained improvement or a halt to progression of disability.

What can clinicians do to optimize these therapies?

Two things: Patient selection and managing patients’ expectations become important when you’re treating progressive types of MS.

Disclosure

Jonathan L. Carter, MD, reported affiliations with Sanofi Genzyme, MedDay Pharmaceuticals, and Lundbeck.

References

1. Hauser SL, Bar-Or A, Comi G, et al; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-234. doi:10.1056/nejmoa1601277
 
2. Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220. doi:10.1056/nejmoa1606468
 
3. FDA approves new drug to treat multiple sclerosis. US Food & Drug Administration. Press release.. www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-multiple-sclerosis. Published March 29, 2017. Accessed April 21, 2021
 
4. FDA approves Novartis Kesimpta^® (ofatumumab), the first and only self-administered, targeted B-cell therapy for patients with relapsing multiple sclerosis. News release. Novartis; August 20, 2020. Accessed May 4, 2021.
www.novartis.com/news/media-releases/fda-approves-novartis-kesimpta-ofatumumab-first-and-only-self-administered-targeted-b-cell-therapy-patients-relapsing-multiple-sclerosis
 
5. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. 2013;8(7):e66308. doi: 10.1371/journal.pone.0066308
 
6. Hauser SL, Bar-Or A, Cohen JA, et al; ASCLEPIOS I and ASCLEPIOS II Trial Groups. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020;383(6):546-557. doi:10.1056/nejmoa1917246
 
 7. Bar-Or A, Grove RA, Austin DJ, et al. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis. Neurology. 2018;90(20):e1805-e1814. doi:10.1212/wnl.0000000000005516
 
 8. Hawker K, O’Connor P, Freedman MS, et al; OLYMPUS Trial Group. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol. 2009;66(4):460-471. doi:10.1002/ana.21867
 
9. Mayer L, Kappos L, Racke MK, et al. Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies. Mult Scler Relat Disord. 2019;30:236-243. doi:10.1016/j.msard.2019.01.044
 
 10. Mulero P, Midaglia L, Montalban X. Ocrelizumab: a new milestone in multiple sclerosis therapy. Ther Adv Neurol Dis. 2018;11:1756286418773025. doi:10.1177/1756286418773025

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