Introduction
The global pandemic outbreak of coronavirus disease (COVID-19) impacted the well-being of both healthy individuals and people with underlying health conditions [
1]. More than 231 million people worldwide have been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in more than 4.7 million deaths (2.1%) as of September 25, 2021, the data cut-off for the current study. As of January 17, 2022, 326 million cases and 5.5 million deaths worldwide have been reported [
2]. Vaccine breakthrough COVID-19 constitutes a small percentage (up to 1.5%) of all fully vaccinated cases [
3,
4] but is expected to rise as COVID-19 vaccine effectiveness is waning over time and new SARS-CoV-2 variants emerge.
People with multiple sclerosis (MS) are at an increased risk of serious infections due to concomitant comorbidities or immunosuppressive treatments [
5‐
8]. A recently published pooled analysis reported a 24% increased risk of death from COVID-19 in patients with MS after age standardization as compared with the general population [
9]. The hospitalization rate reported due to COVID-19 in people with MS (general/with or without disease modifying therapy [DMT]) varied between 15.5% to 36.5% and the mortality rate from 1.97% to 10.3% [
1,
9‐
13]. Several publications suggest that there is no increased risk of contracting COVID-19 in people with MS compared with the general population [
13]. However, several factors such as older age, presence of comorbidities, elevated body mass index (BMI), MS-related disability, progressive MS phenotype, type and duration of DMT, and recent corticosteroid treatment may affect the severity and outcome of COVID-19 in patients with MS [
1,
9,
10,
14,
15].
Anti-CD20 monoclonal antibodies (mAbs) deplete B cells, an action that may compromise immune responses and lead to a higher risk of severe COVID-19 [
16]. Opinions were published during the COVID-19 pandemic recommending delayed dosing for B-cell–depleting therapies based on a perception of increased risk of COVID-19 [
14,
17,
18]. In addition, some studies have observed that B-cell therapies impact humoral responses to COVID-19 vaccination [
19‐
21]. Although much was learned since the start of the pandemic, healthcare professionals (HCPs) continue to face uncertainties in the management of patients with MS in routine clinical practice and are concerned with potential reinfections, waning effect of vaccination, and vaccine breakthrough infections. More evidence from clinical studies and post-marketing settings regarding the impact of COVID-19 in people with MS treated with B-cell–depleting therapies is needed [
13].
Ofatumumab is a fully human anti-CD20 mAb that induces B-cell depletion and is approved for the treatment of relapsing MS (RMS). Ofatumumab received marketing authorization in the US on August 20, 2020, which was in the midst of the COVID-19 pandemic—declared by the World Health Organization (WHO) on March 11, 2020 [
22]. The present analyses aimed to describe the characteristics of COVID-19 cases, COVID-19 vaccination status, and breakthrough infections in people with RMS receiving ofatumumab in the ongoing open-label ALITHIOS study and from post-marketing reports reported spontaneously to the Novartis Global Safety Database.
Discussion
The data presented herein are reassuring in the sense that most MS patients with COVID-19 reported in the open-label ALITHIOS study and the post-marketing setting had non-serious COVID-19 disease and the majority recovered despite being treated with ofatumumab, which depletes circulating B cells.
Of 245 patients recorded as COVID-19 cases in ALITHIOS, fewer than 10% were serious or resulted in hospitalization with only two deaths. Fatal outcomes (2/245 or 0.8%) due to COVID-19 in ofatumumab-treated patients were lower than those reported in the general population (2.1%) [
2], overall MS general population (1.97%) [
9], and MS patients with DMTs (1.4–5.9%) [
1,
11,
12] and without DMTs (10.3%) [
12]. The two ALITHIOS patients with a fatal outcome were unvaccinated and had underlying comorbidities of diabetes and hypertension in one patient and slightly overweight (BMI of 28.3 kg/m
2) in another patient, which are known risk factors for severe COVID-19 [
33]. The hospitalization rate due to COVID-19 observed in the ALITHIOS study (9.4%) was also lower than that previously reported for the general MS population (15.5–20.9%) [
1,
9,
12,
13,
34] as well as in patients with MS treated with DMTs (11.5–32.6%) [
1,
10‐
12] and without DMTs (16.2–42.9%) [
10,
12,
13,
34]. The findings of clinical severity and outcomes of COVID-19 cases in ofatumumab-treated patients are consistent with COVID-19 data presented previously with a data cut-off of January 29, 2021 [
35]. The present data analysis does not suggest any evidence of an increased risk of severe COVID-19 or fatal outcomes in MS patients treated with ofatumumab compared with the hospitalization and fatality rates as reported in published literature for the general and MS populations [
9,
13].
These comparisons should not be over-interpreted. Several factors may contribute to differences in the reported COVID-19 severity and outcomes in different MS populations. There may be relevant differences in the prevalence of known risk factors such as older age, type of MS, level of MS-related disability, and use of different types of DMTs. In addition, COVID-19 cases reported in MS registries are subject to ascertainment bias and may be skewed toward more severe cases being reported. It should be noted that the patients in ALITHIOS rolled over from earlier clinical trials that enrolled people up to 55 years of age and excluded those with certain comorbid conditions [
25‐
27]. Thus, they may not fully represent the real-world population of people with MS.
In the recently published retrospective report on the combined Italian and French registries of confirmed COVID-19 in patients with MS, worse COVID-19 outcomes in people with MS on two other B-cell–depleting agents (ocrelizumab and rituximab) were noted compared to other DMTs. Additionally, patients reported in the registries taking rituximab did worse than those treated with ocrelizumab, and the study did not report on COVID-19 cases in patients taking ofatumumab [
33]. Worse outcomes on rituximab versus ocrelizumab were also noted in the North American COViMS Registry data [
10]. Salter and colleagues reported three cases of COVID-19 in people taking ofatumumab, with one hospitalization and no deaths. Sormani and colleagues hypothesized that the worse outcomes in patients treated with rituximab compared with ocrelizumab were related to longer exposure to the drug [
33].
One concern with long-term B-cell depletion is the potential reduction in Ig production. Earlier studies found an increased risk of serious infections in patients with low IgG levels taking ocrelizumab [
36]. In previously reported findings on the ALITHIOS trial [
37] and the ASCLEPIOS I/II trials [
38], no association between infection and lower IgG/IgM levels was observed in the overall RMS population treated with ofatumumab for up to 3.5 years [
37,
38] and for up to 2 years [
38], respectively. Consistent with previous findings, the present analysis of data from the ALITHIOS trial showed no apparent association between IgG/IgM levels and COVID-19 occurrence or its severity or outcome. Among all 245 COVID-19 cases in the present analysis, all patients had IgG levels above the LLN, while 23 had IgM below the LLN. The mean IgG/IgM levels remained above the LLN for up to 168 weeks in people with COVID-19, although mean IgM levels declined during this time, consistent with the mean IgM/ IgG trend in the overall ofatumumab safety population (data not shown). Prior registry studies have not reported data on IgG or IgM levels [
10,
33,
39].
Data on the humoral and T-cell responses to COVID-19 in people taking ofatumumab are scarce. In an independent assessment of IgG antibodies during SARS-CoV-2 infection (funded by Novartis), four COVID-19 cases from the ALITHIOS study were examined, all of whom had mild COVID-19 and recovered. Three of the four patients had normal levels of IgM and IgG without measurable counts of CD19 cells prior to COVID-19. One patient had ofatumumab dosing temporarily interrupted because of low IgM. None of the three patients without circulating B cells developed detectable antibodies to SARS-CoV-2 [
40]. Conversely, all three patients tested for SARS-CoV-2 had T-cell responses detected by interferon-γ ELISpot assay. Further investigation of both humoral and T-cell responses in a larger cohort of ofatumumab-treated patients contracting COVID-19 is warranted.
The Novartis Safety Database might be more representative of real-world experience of people living with RMS. As of September 25, 2021, 90 confirmed COVID-19 post-marketing cases on ofatumumab had been reported in the Novartis Safety Database. This is a voluntary post-marketing database, and all but one case came from the US, making the data potentially subject to bias. Similar to the results from ALITHIOS, most of the confirmed COVID-19 cases were considered non-serious in nature except ten serious COVID-19 cases, including nine patients who were hospitalized. No fatal or life-threatening cases were reported. It has been suggested that in a general post-marketing setting, serious cases are reported more frequently than non-serious cases [
41].
Limitations
ALITHIOS is an open-label, single-arm, Phase 3b extension study. The inherent design of study lacks a control group. The relatively small number of patients in the hospitalized subgroup may hamper the risk factor and subgroup analyses.
The post-marketing surveillance includes the relatively small number of reported COVID-19 cases, which likely reflects the limited overall post-marketing exposure to ofatumumab, as it received marketing authorization in August 2020. Moreover, reporting of post-marketing cases is voluntary or spontaneous in nature, and a large proportion of cases had incomplete data or incomplete follow-up. The post-marketing setting also includes literature reports of AEs, but cases gleaned from the scientific literature are typically delayed in acquisition. Therefore, interpretation of these post-marketing reports should be made with caution. Although both the ALITHIOS clinical trial and post-marketing surveillance did not capture information on the SARS-CoV-2 variants causing COVID-19 in the ofatumumab-treated patients, most cases were likely caused by either the alpha or delta variant as these variants were the most dominant variants up to the data cut-off of September 25, 2021.
To date (December 2021), this is one of the largest studies in patients with RMS treated with a B-cell depleting therapy to report on COVID-19 cases post-vaccination. A small number of vaccinated patients in the ALITHIOS study and post-marketing setting reported breakthrough infections of which most cases were of mild-to-moderate severity and had a non-serious nature; all recovered. The immunization response to COVID-19 vaccinations is complex involving an interplay of both cellular and humoral immunity [
42], both of which could be impaired because of B-cell depletion [
19‐
21] Studies that further evaluate immunization responses to COVID-19 vaccination in patients on ofatumumab therapy are in progress. A COVID-19 vaccination sub-study embedded in the ALITHIOS open-label extension is underway to investigate the effect of ofatumumab on humoral and T-cell responses following selected COVID-19 vaccines. In addition, three phase 4 studies are underway to evaluate the immune response to the COVID-19 mRNA vaccine, two being conducted in the US (clinicaltrials.gov NCT04878211 and NCT04847596) and one in Germany (clinicaltrials.gov NCT04869358).
Evidence-based guidelines for treatment decisions for MS in the current COVID-19 pandemic are starting to emerge. However, much of the current guidelines continue to derive from expert opinions. At this point, treatment should be tailored in consideration of the individual patient’s history, existing comorbid conditions, and severity of MS [
1,
14]. Initiation or continuation of ofatumumab treatment should be decided based on the benefit-risk assessment of each individual.
Acknowledgements
We thank the participants of the study.
Disclosures
Anne H. Cross has received consulting fees, research support, and honoraria from Biogen, Celgene, Bristol Myers Squibb, EMD Serono, Merck, Genentech, Roche, Greenwich Biosciences, Horizon, Janssen (subsidiary of Johnson & Johnson), Novartis, TG Therapeutics, Academic CME, Projects in Knowledge, CME Outfitters, WebMD, Conrad N. Hilton Foundation, The Potomac Center for Medical Education, Consortium of Multiple Sclerosis Centers, and ACTRIMS; serves on the scientific advisory board for ASCLEPIOS I/II for Novartis; has received grants from the National Institutes of Health, the Department of Defense, USA; has held an elected office (secretary) on the Board of Governors of the Consortium of Multiple Sclerosis Centers; was a member of the scientific advisory board of Race to Erase MS, program committee (chair) of ACTRIMS, member of the COVID-19 advisory committee of the National Multiple Sclerosis Society USA and National Multiple Sclerosis Society representative on the Progressive MS Alliance; and has received a patent for “Yablonskiy DA, Sukstansky AL, Wen J, Cross AH. Methods for simultaneous multi-angular relaxometry of tissue using magnetic resonance imaging. Patent 15060-630 (015875).”
Silvia Delgado has received fees as a consultant on scientific advisory boards for Novartis and research grants through the University of Miami from EMD Serono, MAPI Pharma, NIH/NINDS, NMSS, and Novartis.
Mario Habek participated as a clinical investigator and/or received consultation and/or speaker fees from Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, and TG Pharmaceuticals.
Maria Davydovskaya received grants for consulting or speaking fees from Biogen Idec, Celgene/Receptos, Janssen/Actelion, Merck/EMD Serono, Novartis, Roche Sanofi Genzyme, and TG Pharmaceuticals; participated on the advisory board of Biogen Idec, Merck/EMD Serono and served as a president of Medicine Association of Professional and MS centers.
Brian J. Ward serves on a scientific advisory board for Novartis and reports personal fees from Novartis for this activity. He is also medical officer for Medicago Inc and holds parts of patents for vaccines targeting influenza, Clostridioides difficile and Schistosoma mansoni. In the last 5 years, he has held academic industry awards with Medicago, MIT Canada, and Aviex Technologies.
Bruce A.C. Cree has received personal compensation for consulting from Alexion, Atara Biotherapeutics, Autobahn, Avotres, Biogen, EMD Serono, Novartis, Sanofi, TG Therapeutics, and Therini and received research support from Genentech.
Natalia Totolyan has received fees for advisory boards or speaking for Merck and Novartis and institutional grants for conducting clinical trials for Alexion, BIOCAD, Janssen, MAPI Pharma, Merck, Novartis, Receptos, Roche, Sanofi, and TG Therapeutics.
Ratnakar Pingili, Linda Mancione, Xixi Hu, Roseanne Sullivan, Wendy Su, Ronald Zielman, and Ayan Das Gupta are employees of Novartis.
Roseanne Sullivan is employee of Novartis and has Novartis stock ownership.
Xavier Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Medday, Merck, Mylan, NervGen, Novartis, Roche, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, EXCEMED, MSIF, and NMSS.
Kevin Winthrop has received consulting fees from Novartis, Roche, and Genentech.