Emerging evidence suggests that B lymphocyte (B cell)-depletion therapy represents a breakthrough in slowing the progression of disability in relapsing–remitting multiple sclerosis (RRMS).1 The overall goal in multiple sclerosis (MS) treatment is to modify disease progression and disability and to prevent new lesions on magnetic resonance imaging (MRI).2 The primary pathogenesis of MS comprises focal inflammatory demyelination and degeneration; disease-modifying therapies (DMT) address the inflammatory component.3 In the United States, approximately 1 million people have MS, and many of these people reside in the northern region of the country, a pattern that is seen in the rest of the world.4,5



Neuroimmunology of B Cells in MS

Previously, T lymphocytes (T cells) were thought to be the primary driver of disease in MS.6 Recent clinical trials of the anti-CD20 monoclonal antibody ocrelizumab for RRMS, and subsequent US Food and Drug Administration approval of the drug, have led researchers to investigate more possibilities for disease modification with other CD20 monoclonal antibodies.6 Recognition that B cells produce antibodies against immunoglobulin G (IgG) oligoclonal bands found in the cerebrospinal fluid of most patients with MS further supports targeting B cells in RRMS.1

B-cell Depletion Therapies in Later-Phase Trials

Ocrelizumab, a humanized monoclonal antibody, was compared with interferon β-1a (IFN beta-1a) in the double phase 3 trials OPERA I (N=821) and OPERA II (N=835) in patients with RRMS (ClinicalTrials.gov Identifiers: NCT01247324 and NCT01412333, respectively).7 In these 96-week identical trials, the primary end point was the annualized relapse rate (ARR)7:

• 0.16 for ocrelizumab and 0.29 for IFNB-1a in OPERA I; a 46% lower ARR for ocrelizumab (P <.001)
• 0.16 for ocrelizumab and 0.29 for IFNB-1a in OPERA II; a 47% lower ARR for ocrelizumab in OPERA II (P <.001).  

Compared with IFNB-1a, ocrelizumab was associated with better outcomes as measured by ARR, suppression of new inflammatory lesions, progression of disability, and new formation of enlarged plaque.8
 
Neoplasms occurred in 0.5% of patients who received ocrelizumab compared with 0.2% of those who received IFNB-1a. Serious infection was more common in patients who received IFNB-1a (2.9%) than in those who received ocrelizumab (1.3%).7
 
Ofatumumab,a human antibody initially indicated for chronic lymphocytic leukemia, has shown promise in double phase 3 trials in patients with RRMS. The ASCLEPIOS I (N=927) and ASCLEPIOS II (N=955) trials9 (ClinicalTrials.gov Identifiers: NCT02792218 and NCT02792231, respectively) compared ofatumumab with teriflunomide, an oral inhibitor of pyrimidine synthesis that reduces T- and B-cell activation in patients with RRMS or secondary progressive MS.
 
The primary end point in these trials was the ARR, which was lower with ofatumumab (0.11) than with teriflunomide (0.22; P <.001) in ASCLEPIOS I and, comparably, 0.10 and 0.25 (P <.001), respectively, in ASCLEPIOS II.7
 
For 3 secondary end points — deteriorating disability at 3 months and at 6 months and disability improvement at 6 months — ofatumumab compared favorably with teriflunomide (10.9% and 15.0% [P =.002], 8.1% and 12.0% [P =.01], and 11.0% and 8.1% [P =.09], respectively).9
 
The adverse event profile in the ASCLEPIOS trials included occurrences at least 100 days after final administration of the trial drug.9 Events that occurred in at least 10% of patients receiving ofatumumab included injection reactions, nasopharyngitis, headache, upper respiratory tract infection, and urinary tract infection. Events that occurred in at least 10% of patients receiving teriflunomide included nasopharyngitis, injection reactions, alopecia, and upper respiratory tract infection.9
 
Rituximab,an IgG1 subclass of IgG chimeric-human monoclonal antibody against CD20, was initially approved for treating non-Hodgkin lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis.1 Rituximab was among the first B cell-depleting therapies used off-label to treat RRMS, for which the drug’s anti-CD20 depletion ability was revealed to have a lasting effect on T cells.10
 
Researchers foresee not only a DMT in B-cell depletion but also a way to reduce the number of reinfusions that reduce disease activity.11 Such was the case in an uncontrolled, open-label study of 102 patients treated with rituximab for a mean of 2.4 years.11 In the dual-site study by Novi and colleagues, patients were reinfused with rituximab 375 mg/m2 based on a prespecified percentage of memory B cells and not on an every-6-month schedule, as had been the standard approach.11 A year before the start of rituximab therapy, the ARR was 0.67; 3 years after initiating rituximab therapy, the ARR decreased to 0.01.11
 
Because the Novi study did not have a comparator, adverse events could not be compared. However, the researchers conjectured that, after initial induction therapy, reinfusing patients based on the peripheral blood mononuclear cell level, rather than on a 6-month schedule, might reduce the number of treatment-related adverse events and thus provide a template for personalized medicine.11
 
Although no phase 3 trials of rituximab for RRMS have been published, the RIDOSE-MS study (ClinicalTrials.gov Identifier: NCT03979456), based on a Swedish registry of patients with RRMS, is underway.12,13 This prospective, randomized study will compare 2 regimens of rituximab: 500 mg dosed at 6- and at 12-month intervals. The primary end point is no evidence of disease activity. Results of the 3-year RIDOSE-MS study should be available in 2025.12
 
Ublituximab, which also demonstrated promise in a phase 2 trial as a B cell-depleting therapy for RRMS, is undergoing phase 3 trials (ULTIMATE 1 and ULTIMATE 2 [ClinicalTrials.gov Identifiers: NCT03277261 and NCT03277248, respectively]).14-16

B Cell-Depletion Therapies in Later-Phase Trials

Therapeutic Approaches for Targeting B Cells

No one treatment algorithm governs B cell-depletion therapy for RRMS due to its heterogeneity and the difficulty in pinpointing the underlying process of disease progression.3 Because MS therapies have varying levels of toxicity, neurologists attempt to minimize long-term safety risks by initiating treatment with the safest but least effective agents.3 The problem with this approach is that the therapeutic window for some patients might close before they receive the most effective therapy.3

Management Challenges and Risk Assessment

While B cell-depletion therapy might be a breakthrough treatment for some patients with RRMS, it does come with caveats. Because B cell-depletion therapy can cause infection, as reported in 57% to 60% of patients with RRMS treated with ocrelizumab compared with 53% to 54% of patients who received IFNB-1a, patients need to be screened carefully before starting therapy.20 They should be tested for tuberculosis,  hepatitis B and C virus infection, and HIV infection.20 During treatment with B cell-depletion therapy, patients need to avoid live vaccines.20
 
Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with ocrelizumab. However, most of these patients had been treated previously with fingolimod or natalizumab. In trials with rituximab and ocrelizumab monotherapy, no patients were reported to have developed PML.20
 
In the phase 3 trials OPERA (I and II) and ORATORIO (ClinicalTrials.gov Identifier: NCT01194570), malignancies occurred in, respectively, 0.5% and 2.3% of patients who received ocrelizumab compared with 0.2% and 0.8% of patients taking interferon and placebo.20 Rituximab, for which there is longer-term data than for ocrelizumab, does not appear to increase the risk of cancer in patients with MS.18

Ocrelizumab adverse effects
Flip
Ocrelizumab adverse effects
Adverse effects most commonly reported include upper respiratory tract infection and infusion reactions.

Rituximab adverse effects
Flip
Rituximab adverse effects
Adverse effects most commonly reported include urinary tract infection, sinusitis, and infusion reactions.

B Cell-Depletion Therapy in Specific Populations

To determine the benefit of B cell-depletion therapy among subgroups of patients with RRMS (defined by age, sex, body mass index, and disability status measured by the Expanded Disability Status Scale score), Turner and colleagues analyzed data from the OPERA I and OPERA II phase 3 trials that compared ocrelizumab and IFNB-1a.8 They found that the treatment effect of ocrelizumab was consistent in most subgroups for all end points, including ARR, progression of disability, and MRI findings.8
 
The evidence base is small regarding the safety of B cell-depletion therapy during pregnancy,1 which represents a challenge when treating women during reproductive years, who constitute much of the MS population.1 Although the literature is scant, peripheral lymphocytopenia has been reported in infants born to mothers who received B cell-depletion therapy.1 Primate studies have reported renal toxicity, testicular toxicity, lymphoid follicle formation in the bone marrow, and perinatal death in offspring with severe B-cell reduction.1
 
One possible strategy is to provide B cell-depleting therapy before pregnancy, which would still offer protection to the mother but not risk harm to a fetus.1 Women of childbearing potential are advised to use contraception during B cell-depletion treatment and for as long as 6 months after the last infusion.1
 
Lactation studies among B cell-depleting therapies are lacking; more definitive evidence is needed to guide treatment for nursing mothers.16 In one of the few studies of B cell-depleting therapies, a rituximab case study revealed the level of rituximab in breast milk to be 240 times lower than in maternal serum, signaling that B-cell therapies might have potential to be used safely in lactating patients.21
 
Refer to the full Prescribing Information for additional details about Ocrevus®, Kesimpta®, and Rituxan®.

References

1. Gelfand JM, Cree BAC, Hauser SL. Ocrelizumab and other CD20+ B-cell-depleting therapies in multiple sclerosis. Neurotherapeutics. 2017;14(4):835-841. doi:10.1007/s13311-017-0557-4
2. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology [published correction appears in Neurology. 2019;92(2):112. doi: 10.1212/WNL.0000000000006722]. Neurology. 2018;90(17):777-788. doi:10.1212/WNL.0000000000005347
3. Smith AL, Cohen JA, Hua LH. Therapeutic targets for multiple sclerosis: current treatment goals and future directionsNeurotherapeutics. 2017;14(4):952-960. doi:10.1007/s13311-017-0548-5
4. Patz A. Strength in numbers. Momentum. National Multiple Sclerosis Society.
https://momentummagazineonline.com/strength-in-numbers/. Accessed November 12, 2020.
5. The Multiple Sclerosis International Federation, Atlas of MS. 3rd ed. https://www.msif.org/wp-content/uploads/2020/10/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf Accessed November 12, 2020.
6. Greenfield AL, Hauser SL. B‐cell therapy for multiple sclerosis: entering an eraAnn Neurol. 2018;83(1):13-26. doi:10.1002/ana.25119
7. 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
8. Turner B, Cree BAC, Kappos L, et al. Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosisJ Neurol. 2019;266(5):1182-1193. doi:10.1007/s00415-019-09248-6
9. Hauser SL, Bar-Or A, Cohen JA, et al; ASCLEPIOS I and ASCLEPIOS II Trial Groups. Ofatumumab versus teriflunomide in multiple sclerosisN Engl J Med. 2020;383(6):546-557. doi:10.1056/NEJMoa1917246
10. Nissimov N, Hajiyeva Z, Torke S, et al. B cells reappear less mature and more activated after their anti-CD20-mediated depletion in multiple sclerosis. Proc Natl Acad Sci U S A. 2020;117(41):25690-25699. doi:10.1073/pnas.2012249117
11. Novi G, Bovis F, Fabbri S, et al. Tailoring B cell depletion therapy in MS according to memory B cell monitoring. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e845. doi:10.1212/NXI.0000000000000845
12. ClinicalTrials.gov. RItuximab long-term DOSE trial in multiple sclerosis – RIDOSE-MS (RIDOSE-MS) [ClinicalTrials.gov Identifier: NCT03979456]. https://clinicaltrials.gov/ct2/show/study/NCT03979456. Accessed November 17, 2020.
13. Wood H. Targeting B cells leads to breakthrough therapy. Nature Research website. https://www.nature.com/articles/d42859-018-00030-8. December 10, 2018. Accessed November 17, 2020.
14. Fox E, Lovett-Racke AE, Gormley M, et al. A phase 2 multicenter study of ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, in patients with relapsing forms of multiple sclerosisMult Scler. Published online April 30, 2020. doi:10.1177/1352458520918375
15. ClinicalTrials.gov. A phase 3, randomized, multi-center, double-blinded, active-controlled study to assess the efficacy and safety/tolerability of ublituximab (TG-1101; UTX) as compared to teriflunomide in subjects with relapsing multiple sclerosis (RMS) (ULTIMATE 1). https://clinicaltrials.gov/ct2/show/NCT03277261. Accessed November 12, 2020.
16. ClinicalTrials.gov. A phase 3, randomized, multi-center, double-blinded, active-controlled study to assess the efficacy and safety/tolerability of ublituximab (TG-1101; UTX) as compares to teriflunomide in subjects with relapsing multiple sclerosis (RMS) (ULTIMATE 2). https://clinicaltrials.gov/ct2/show/NCT03277248. Accessed November 12, 2020.
17. Ocrevus. Prescribing Information. Genentech, Inc; November 2020. Accessed November 16, 2020. https://www.gene.com/download/pdf/ocrevus_prescribing.pdf
18. Kesimpta. Prescribing Information. Novartis AG; August 2020. Accessed November 16, 2020. https://www.novartis.us/sites/www.novartis.us/files/kesimpta.pdf
19. Rituxan. Prescribing Information. Genentech, Inc; August 2020. Accessed November 16, 2020. https://www.gene.com/download/pdf/rituxan_prescribing.pdf
20. Milo R. Therapies for multiple sclerosis targeting B cellsCroat Med J. 2019;60(2):87-98. doi:10.3325/cmj.2019.60.87
21. Myhr KM, Torkildsen Ø, Lossius A, Bø L, Holmøy T. B cell depletion in the treatment of multiple sclerosisExpert Opin Biol Ther. 2019;19(3):261-271. doi:10.1080/14712598.2019.1568407

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Neurology Advisor had no role in this content’s preparation.

Reviewed February 2021