Neurol Ther (2022) 11:741–758 https://doi.org/10.1007/s40120-022-00341-z ORIGINAL RESEARCH COVID-19 Outcomes and Vaccination in People with Relapsing Multiple Sclerosis Treated with Ofatumumab Anne H. Cross . Silvia Delgado . Mario Habek . Maria Davydovskaya . Brian J. Ward . Bruce A. C. Cree . Natalia Totolyan . Ratnakar Pingili . Linda Mancione . Xixi Hu . Roseanne Sullivan . Wendy Su . Ronald Zielman . Ayan Das Gupta . Xavier Montalban . Kevin Winthrop Received: January 26, 2022 / Accepted: February 28, 2022 / Published online: March 13, 2022 Ó The Author(s) 2022, corrected publication 2022 ABSTRACT status in ofatumumab-treated relapsing multi- ple sclerosis (RMS) patients. Introduction: The SARS-CoV-2 pandemic Methods: COVID-19 data analyzed were from necessitated better understanding of the impact the ongoing, open-label, long-term extension of disease-modifying therapies on COVID-19 phase 3b ALITHIOS study from December 2019 outcomes and vaccination. We report charac- (pandemic start) and post-marketing cases from teristics of COVID-19 cases and vaccination August 2020 (ofatumumab first approval) up to 25 September 2021. COVID-19 cases, severity, seriousness, outcomes, vaccination status, and Supplementary Information The online version breakthrough infection were evaluated. contains supplementary material available at https:// Results: As of 25 September 2021, 245 of 1703 doi.org/10.1007/s40120-022-00341-z. patients (14.4%) enrolled in ALITHIOS receiv- ing ofatumumab (median exposure: 2.45 years) A. H. Cross (&) Department of Neurology, Washington University, N. Totolyan St. Louis, MO, USA First Saint Petersburg State Medical University, St. e-mail: crossa@wustl.edu Petersburg, Russia S. Delgado R. Pingili  L. Mancione  X. Hu  R. Sullivan  W. Su University of Miami Miller School of Medicine, Novartis Pharmaceuticals Corporation, East Miami, FL, USA Hanover, NJ, USA M. Habek R. Zielman University Hospital Center Zagreb, University of Novartis Pharma B.V., Amsterdam, The Netherlands Zagreb, School of Medicine, Zagreb, Croatia A. D. Gupta M. Davydovskaya Novartis Healthcare Private Limited, Hyderabad, Moscow State Public Healthcare InsCity Clinical India Hospital 24, Moscow, Russia X. Montalban B. J. Ward Department of Neurology-Neuroimmunology, Infectious Diseases Division, Research Institute of Centre d’Esclerosi Múltiple de Catalunya (Cemcat), the McGill University Health Centre, Montreal, QC, Hospital Universitari Vall d’Hebron, Barcelona, Canada Spain B. A. C. Cree K. Winthrop UCSF Weill Institute for Neurosciences, Department School of Public Health at Oregon Health and of Neurology, University of California San Science University, Portland, OR, USA Francisco, San Francisco, CA, USA 742 Neurol Ther (2022) 11:741–758 reported COVID-19 (confirmed: 210; suspected: 35). Most COVID-19 was of mild (44.1%) or Key Summary Points moderate (46.5%) severity, but 9% had severe/ life-threatening COVID-19. There were 24 seri- Why carry out this study? ous cases (9.8%) with 23 patients hospitalized; 22 recovered and 2 died. At study cut-off, 241 With the growing knowledge about patients (98.4%) had recovered or were recov- COVID-19 and the launch of COVID-19 ering or had recovered with sequelae and 2 vaccinations, more evidence from clinical (0.8%) had not recovered. Ofatumumab was studies and real-world settings is needed temporarily interrupted in 39 (15.9%) patients. to understand the impact of COVID-19 Before COVID-19 onset, IgG levels were within and vaccination status in multiple the normal range in all COVID-19–affected sclerosis (MS) patients receiving disease- patients, while IgM was \ 0.4 g/l in 23 (9.4%) modifying therapies, especially patients. No patient had a reinfection. Overall, B-cell–depleting therapies. 559 patients were vaccinated (full, 476; partial, We analyzed the characteristics of COVID- 74; unspecified, 9). Breakthrough infection was 19 cases, outcomes, vaccination status, reported in 1.5% (7/476) patients, and 11 and breakthrough infections of relapsing reported COVID-19 after partial vaccination. As MS (RMS) patients receiving ofatumumab of 25 September 2021, the Novartis Safety in the open-label long-term phase 3b Database (* 4713 patient-treatment years) ALITHIOS study and Novartis post- recorded 90 confirmed COVID-19 cases receiv- marketing safety database as of September ing ofatumumab. Most cases were non-serious 25, 2021. (n = 80), and ten were serious (1 medically sig- nificant, 9 hospitalized, 0 deaths). Among 36 of What was learned from the study? 90 cases with outcomes reported, 30 recovered Most COVID-19 cases in MS patients and 6 did not recover. treated with ofatumumab were mild or Conclusion: COVID-19 in RMS patients on moderate in severity and characterized as ofatumumab was primarily of mild/moderate non-serious. severity and non-serious in these observational data. Most recovered from COVID-19 without A small proportion of patients had treatment interruption. Two people died with COVID-19 despite being fully or partially COVID-19. Breakthrough COVID-19 despite vaccinated, from which all recovered. being fully/partially vaccinated was These observational data provide relevant uncommon. information to help healthcare professionals better understand the Keywords: ALITHIOS; Anti-CD20 therapy; B- severity and outcomes of COVID-19 in cell therapy; COVID-19; Ofatumumab; Post- patients with RMS receiving ofatumumab, marketing; Relapsing multiple sclerosis; SARS- a B-cell–depleting therapy. CoV-2; Vaccination 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 Neurol Ther (2022) 11:741–758 743 infected with the severe acute respiratory syn- vaccination, and vaccine breakthrough infec- drome coronavirus 2 (SARS-CoV-2), resulting in tions. More evidence from clinical studies and more than 4.7 million deaths (2.1%) as of post-marketing settings regarding the impact of September 25, 2021, the data cut-off for the COVID-19 in people with MS treated with current study. As of January 17, 2022, 326 mil- B-cell–depleting therapies is needed [13]. lion cases and 5.5 million deaths worldwide Ofatumumab is a fully human anti-CD20 have been reported [2]. Vaccine breakthrough mAb that induces B-cell depletion and is COVID-19 constitutes a small percentage (up approved for the treatment of relapsing MS to 1.5%) of all fully vaccinated cases [3, 4] but is (RMS). Ofatumumab received marketing expected to rise as COVID-19 vaccine effective- authorization in the US on August 20, 2020, ness is waning over time and new SARS-CoV-2 which was in the midst of the COVID-19 pan- variants emerge. demic—declared by the World Health Organi- People with multiple sclerosis (MS) are at an zation (WHO) on March 11, 2020 [22]. The increased risk of serious infections due to con- present analyses aimed to describe the charac- comitant comorbidities or immunosuppressive teristics of COVID-19 cases, COVID-19 vacci- treatments [5–8]. A recently published pooled nation status, and breakthrough infections in analysis reported a 24% increased risk of death people with RMS receiving ofatumumab in the from COVID-19 in patients with MS after age ongoing open-label ALITHIOS study and from standardization as compared with the general post-marketing reports reported spontaneously population [9]. The hospitalization rate repor- to the Novartis Global Safety Database. ted due to COVID-19 in people with MS (gen- eral/with or without disease modifying therapy [DMT]) varied between 15.5% to 36.5% and the METHODS mortality rate from 1.97% to 10.3% [1, 9–13]. Several publications suggest that there is no Open-Label Extension Study increased risk of contracting COVID-19 in peo- ple with MS compared with the general popu- Data Collection lation [13]. However, several factors such as ALITHIOS (NCT03650114) is an ongoing, open- older age, presence of comorbidities, elevated label, single-arm, long-term extension phase 3b body mass index (BMI), MS-related disability, study designed to assess the safety, tolerability, progressive MS phenotype, type and duration of and effectiveness of ofatumumab 20 mg DMT, and recent corticosteroid treatment may administered subcutaneously every 4 weeks for affect the severity and outcome of COVID-19 in up to 5 years in people with RMS [23, 24]. The patients with MS [1, 9, 10, 14, 15]. study enrolled patients from the APLIOS [25] Anti-CD20 monoclonal antibodies (mAbs) (NCT03560739), APOLITOS [26] deplete B cells, an action that may compromise (NCT03249714), and ASCLEPIOS I/II [27] immune responses and lead to a higher risk of (NCT02792218/NCT02792231) phase 2 and 3 severe COVID-19 [16]. Opinions were published trials who were treated with ofatumumab in the during the COVID-19 pandemic recommending core studies and continued with the same delayed dosing for B-cell–depleting therapies treatment and patients who received terifluno- based on a perception of increased risk of mide in the core and switched to ofatumumab COVID-19 [14, 17, 18]. In addition, some stud- in the extension study. Data from ofatumumab- ies have observed that B-cell therapies impact treated ALITHIOS patients and their reported humoral responses to COVID-19 vaccination COVID-19 status from December 2019 to [19–21]. Although much was learned since the September 25, 2021 (data cut-off) were start of the pandemic, healthcare professionals analyzed. (HCPs) continue to face uncertainties in the management of patients with MS in routine COVID-19 Diagnosis clinical practice and are concerned with Cases were considered as confirmed COVID-19 potential reinfections, waning effect of if there was a positive laboratory test result 744 Neurol Ther (2022) 11:741–758 including real-time polymerase chain reaction, COVID-19 vaccine (excluding booster), and antigen detection, or serological evidence of partially vaccinated means either not received infection, as reported by the investigator. Cases all recommended doses or it was \ 14 days after were considered as suspected COVID-19 in the receiving all recommended doses of a COVID- absence of a positive SARS-CoV-2 laboratory test 19 vaccine [31]. result but with signs and symptoms consistent The last assessed serum immunoglobulin with COVID-19 (Fig. S1). (IgG and IgM) levels before COVID-19 onset and in relation to COVID-19 seriousness were Study Outcomes and Assessments evaluated. For serious COVID-19 cases, age, Demographics, key baseline disease character- BMI, Expanded Disability Status Scale (EDSS), istics and history were summarized for patients and other potential risk factors were collected. who entered the ALITHIOS study, for patients Additional risk factor modeling analysis was not with confirmed/suspected COVID-19, and for performed for these data, which will be in scope hospitalized COVID-19 patients. A Wilcoxon for future publications. rank sum test was also performed between hospitalized and non-hospitalized MS patients Ethics Statement for selected potential risk factors including age and BMI. Exposure to ofatumumab was expres- Ethics approval for the ALITHIOS study sed as the individual’s time at risk, which was (NCT03650114) was obtained from all ethics defined as time from the first dose of ofatu- committees or institutional review board at mumab until 100 days after the last dose of each site and the study is in accordance with the ofatumumab. ethical code of the ethics committee or institu- COVID-19 cases, seriousness and severity tional review board for each study site and the category, COVID-19 outcomes, reinfections, Declaration of Helsinki. After approval from the COVID-19 vaccination status, and vaccine ethics committee, written informed consent breakthrough infection with associated out- was obtained from all subjects before com- comes were assessed. COVID-19 seriousness mencing the trial-related procedures and category was based on the regulatory reporting allowed the results to be part of a publication. definition established by the International Council for Harmonisation of Technical Post-marketing Reports Requirements for Pharmaceuticals for Human Use (ICH) [28] guidelines E2A [29]. Severity Data Collection assessment was provided by the reporting The analysis included post-marketing COVID- investigator based on the National Cancer 19 cases in RMS patients from the Novartis Institute’s Common Terminology Criteria for Global Safety Database received from the time Adverse Events (CTCAE [v5.0]) grading system of ofatumumab’s first approval in August 2020 [30], as described in the protocol; adverse events up to September 25, 2021. The database cap- (AEs) were reported as mild (Grade 1), moderate tures AEs reported to Novartis by HCPs, (Grade 2), severe (Grade 3), or life-threatening patients, and other sources. (Grade 4). COVID-19 outcomes were reported by the investigator as recovered or recovering or recovered with sequelae, not recovered, or fatal COVID-19 Diagnosis (Fig. S1). Per the Centers for Disease Control COVID-19 cases were classified as confirmed if a and Prevention, reinfection was defined as a SARS-CoV-2–positive test result was available or second confirmed infection after 90 days from if the patient was reported to have been diag- the end date of the recovered first COVID-19. nosed with COVID-19. Cases without a positive Vaccine breakthrough COVID-19 was defined as test result or a definitive diagnosis were classi- confirmed COVID-19 after being fully vacci- fied as suspected (Fig. S1). nated. Fully vaccinated means at least 14 days after receiving all recommended doses of a Neurol Ther (2022) 11:741–758 745 Open-label ALITHIOS study Post-marketing reports Overall ALITHIOS patientsa Total patient years (N = 1703) (Years = 4,713) Patients with any COVID-19 Patients with any COVID-19 (N = 245) (N = 93) Confirmed Suspected Confirmed Suspected COVID-19 COVID-19 COVID-19 COVID-19 (N = 210) (N = 35) (N = 90) (N = 3) Serious cases Serious cases Serious cases (n = 23) (n = 1) (n = 10) Non-serious cases Non-serious cases Non-serious cases (n = 187) (n = 34) (n = 80) Fig. 1 Patient designation in the open-label ALITHIOS APOLITOS (n = 57), APLIOS (n = 279), and ASCLE- study and post-marketing setting. a Patients in the open- PIOS I/II (n = 1367) studies label ALITHIOS study (N = 1703) rolled-over from the Outcomes and Assessments ALITHIOS Long-Term Open-Label Patient demographics, COVID-19 cases, sever- Extension Study ity, seriousness (including hospitalization), outcomes, and COVID-19 vaccination status As of the cut-off, 1703 people with RMS had were summarized based on reported informa- received at least one dose of ofatumumab in the tion. Cases were considered ‘‘serious’’ based on ALITHIOS study who were rolled over from the ICH regulatory reporting definition. Sever- previously completed studies, namely, APOLI- ity assessment of COVID-19 cases was adjudi- TOS (n = 57), APLIOS (n = 279), and ASCLEPIOS cated independently by 2 experts (BJW and I/II (n = 1367). Demographics, baseline charac- BACC) using the US Food and Drug Adminis- teristics, and disease history of the patients who tration and WHO COVID-19 severity scales reported any COVID-19–related AE were com- where data were available. Cases were classified parable with those of the overall ALITHIOS as asymptomatic, mild, moderate, severe, or population (Table 1). critical (Fig. S1). If available, the outcome status of each COVID-19 Cases Clinical Severity, Seriousness, COVID-19–affected individual was reported as and Reinfection recovered/recovering/recovered with sequelae, Of the 1703 patients, 245 (14.4%) had reported condition unchanged, condition deteriorated, a COVID-19–related AE, including 210 (85.7%) or fatal. confirmed COVID-19 cases and 35 (14.3%) suspected COVID-19 cases (Fig. 1). Most RESULTS COVID-19 cases occurred in the timeframe of October 2020 to January 2021 (Fig. 2). Among As of September 25, 2021, COVID-19 was all reported cases, the majority (90.6%) had reported in 245 patients with RMS receiving infection of mild (108 [44.1%]) or moderate ofatumumab in the long-term open-label (114 [46.5%]) severity, while 19 had severe extension ALITHIOS study and 90 patients with (7.8%) and 3 had life-threatening (1.2%) RMS in the post-marketing setting (Fig. 1). COVID-19; CTCAE grading was missing for 1 (0.4%) case. A total of 24 serious COVID-19 cases were reported; all but 1 patient were hos- pitalized, 2 patients required (non-invasive) 746 Neurol Ther (2022) 11:741–758 Table 1 Patient demographics and disease characteristics in the open-label ALITHIOS study Characteristics OMB overall Any COVID–19 related AE 20 mg Overall Confirmed Suspected Hospitalized overall N = 1703a COVID-19 COVID-19 COVID-19 COVID-19 n = 245 n = 210 n = 35 n = 23 Age (years), mean ± SD 38.6 ± 9.06 37.9 ± 8.75 38 ± 8.79 37.5 ± 8.58 41.7 ± 7.5 Age [ 41 years, n (%) 725 (42.6) 98 (40.0) 85 (40.5) 13 (37.1) 16 (69.6) Female, n (%) 1186 (69.6) 171 (69.8) 147 (70.0) 24 (68.6) 13 (56.5) Race, n (%) White 1525 (89.5) 224 (91.4) 191 (91.0) 33 (94.3) 22 (95.7) Asian 75 (4.4) 7 (2.9) 7 (3.3) 0 1 (4.3) Black or African American 39 (2.3) 6 (2.4) 5 (2.4) 1 (2.9) 0 b Country , n (%) Russian Federation 386 (22.7) 71 (29.0) 60 (28.6) 11 (31.4) 7 (30.4) US 275 (16.1) 36 (14.7) 29 (13.8) 7 (20.0) 3 (13.0) Poland 213 (12.5) 35 (14.3) 30 (14.3) 5 (14.3) 5 (21.7) Spain 117 (6.9) 18 (7.3) 15 (7.1) 3 (8.6) 3 (13.0) Czech Republic 108 (6.3) 19 (7.8) 19 (9.0) 0 0 BMI categories, n (%) Overweight: BMI 25 427 (25.1) 62 (25.3) 52 (24.8) 10 (28.6) 9 (39.1) to \ 30 kg/m2 Obese: BMI C 30 kg/m2 307 (18.0) 45 (18.4) 40 (19.0) 5 (14.3) 7 (30.4) BMI (kg/m2), mean ± SD 25.42 ± 5.92 25.42 ± 5.941 25.49 ± 6.022 25 ± 5.489 27.32 ± 5.316 EDSS [ 3.5, n (%) 430 (25.2) 44 (18.0) 40 (19.0) 4 (11.4) 3 (13.0) EDSS, mean ± SD 2.84 ± 1.381 2.63 ± 1.205 2.65 ± 1.226 2.49 ± 1.074 2.67 ± 1.104 Type of MS, n (%) RRMS 1621 (95.2) 239 (97.6) 204 (97.1) 35 (100) 22 (95.7) SPMS 82 (4.8) 6 (2.4) 6 (2.9) 0 1 (4.3) Selected AEs prior to 60 (3.5) 60 (24.5) 52 (24.8) 8 (22.9) 3 (13.0) COVID-19 onsetc, n (%) Cardiac disorders 9 (0.5) 9 (3.7) 8 (3.8) 1 (2.9) 0 Metabolism and nutrition 14 (0.8) 14 (5.7) 13 (6.2) 1 (2.9) 1 (4.3) disorders Respiratory, thoracic and 28 (1.6) 28 (11.4) 25 (11.9) 3 (8.6) 1 (4.3) mediastinal disorders Neurol Ther (2022) 11:741–758 747 Table 1 continued Characteristics OMB overall Any COVID–19 related AE 20 mg Overall Confirmed Suspected Hospitalized overall N = 1703a COVID-19 COVID-19 COVID-19 COVID-19 n = 245 n = 210 n = 35 n = 23 Vascular disorders 18 (1.1) 18 (7.3) 15 (7.1) 3 (8.6) 2 (8.7) For age, BMI, and EDSS, baseline was the value at or the last non-missing assessment prior to the first dose of ofatumumab. Type of MS was assessed at the screening of core studies. Cardiac disorders include tachycardia, angina pectoris, atrial fibrillation, bradycardia, nodal arrhythmia supraventricular extrasystoles, Wolff-Parkinson-White syndrome, and car- diomyopathy. Metabolism and nutrition disorders include hypertriglyceridemia, vitamin D deficiency, hyperglycemia, hypercholesterolemia, iron deficiency, decreased appetite, diabetes mellitus, hypovitaminosis, and vitamin B complex defi- ciency. Respiratory, thoracic, and mediastinal disorders include cough, oropharyngeal pain, rhinitis allergic, nasal congestion, asthma, bronchial hyperreactivity, catarrh, chronic obstructive pulmonary disease, dyspnea, nasal discomfort, pharyngeal inflammation, respiratory disorder, rhinorrhea, and throat irritation. Vascular disorders include hypertension, hematoma, extremity necrosis, orthostatic hypertension, peripheral venous disease, superficial vein thrombosis, thrombophlebitis, and hypertensive crisis AE, adverse event; BMI, body mass index; COVID-19, coronavirus disease; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; OMB, ofatumumab; RRMS, relapsing–remitting multiple sclerosis; SD, standard deviation; SPMS, secondary progressive multiple sclerosis a N = 1703 represents the enrolled population in the ALITHIOS study b Overall COVID-19 rate of [ 5% c The selection of prior AEs was based on the following MedDRA System Organ Classes (SOCs) Cardiac disorders,’ ‘Metabolism and nutrition disorders,’ ‘Respiratory, thoracic and mediastinal disorders,’ and ‘Vascular disorders’ mechanical ventilation, and 2 patients died. No p = 0.038). The mean EDSS at first dose of ofa- patient had reinfection. tumumab was comparable between COVID- 19–affected patients (2.63 ± 1.2) and those Demographics and Disease Characteristics hospitalized (2.67 ± 1.1). Overall, 24.5% of of Overall and Hospitalized COVID-19 Cases patients with COVID-19 had relevant previ- Patient demographics and disease characteris- ously reported AEs prior to COVID-19 onset tics of COVID-19 patients are summarized in compared to 13% of hospitalized patients. Table 1. COVID-19–affected patients had a The median (range) ofatumumab exposure mean ± standard deviation (SD) age of duration (expressed as ‘‘time at risk’’) of the 245 37.9 ± 8.75 years at first initiation of ofatu- patients with COVID-19 was 2.45 [0.1–4.98] mumab, while hospitalized (n = 23) patients years. The median onset time of COVID-19 were older (41.7 ± 7.5 years; Wilcoxon rank- since the first dose of ofatumumab was sum text of hospitalized vs non-hospitalized 2.08 years. Among COVID-19–affected patients, p = 0.026). Moreover, 69.8% of all COVID-19 ofatumumab treatment interruption was repor- patients were female, while 56.5% of hospital- ted in 39 (15.9%) patients, none of whom per- ized patients were female. The percentage of manently discontinued treatment, except for patients who were overweight or obese two people who had a fatal COVID-19 outcome (BMI: C 25 kg/m2) was 43.7% among overall (Table 2). COVID-19–affected patients and higher among those hospitalized (69.6%; Wilcoxon rank-sum text on BMI of hospitalized vs. non-hospitalized 748 Neurol Ther (2022) 11:741–758 COVID-19 cases worldwide from WHO dashboard Number of confirmed cases 1st SARS-CoV-2 vaccines available Dec-2020 6,000,000 5,000,000 1st case of Delta variant per week (n) 4,000,000 Oct-2020a WHO reports 3,000,000 cluster of cases of pneumonia in WHO declared 2,000,000 Wuhan, China global pandemic Dec-31-2019 Mar-11-2020 1,000,000 0 Dec-1-19 Mar-1-20 Jun-1-20 Sep-1-20 Dec-1-20 Mar-1-21 Jun-1-21 Sep-1-21 COVID-19 cases in the ALITHIOS study (N=245) Data cutoff date Sep-25-2021 Life-threatening Severe Severity grade Moderate Mild Missingb Dec-1-19 Mar-1-20 Jun-1-20 Sep-1-20 Dec-1-20 Mar-1-21 Jun-1-21 Sep-1-21 Partially Vaccinated Fully Vaccinated Unvaccinated/Unspecified Fig. 2 COVID-19 cases over time in the open-label ongoing study, and the data are subject to change. ALITHIOS study by severity and vaccine status. aFirst case COVID-19, coronavirus disease; SARS-CoV-2, severe of Omicron variant reported after data cut-off: November acute respiratory syndrome coronavirus-2; WHO, World 24, 2021. bSeverity grade for one patient was not yet Health Organization reported at the time of data cut-off, as ALITHIOS is an COVID-19 Outcomes and Duration 4 days. Her latest reported EDSS was 3.5. The At the time of data cut-off (Table 2), the patient was hospitalized with COVID-19 pneu- majority (241, 98.4%) of COVID-19 cases had monia and required prolonged mechanical either recovered or recovered with sequelae, or ventilation; 33 days after the start of COVID-19, were recovering, while two (0.8%) had not yet the patient died because of COVID-19 pneu- recovered, and two cases (0.8%) had a fatal monia. The second fatal COVID-19 case was a outcome (Fig. S2). male patient in his 4th decade of life from Asia Of the 24 serious cases, 22 recovered and 2 who was on ofatumumab treatment for were fatal. The first fatal COVID-19 case was a 1.5 years. Reported comorbidities for this case female patient in her 5th decade of life from were diabetes and hypertension. This patient Europe who was on ofatumumab for 3.7 years. was diagnosed with COVID-19 but was not The patient was slightly overweight and had hospitalized. Ten days after the start of COVID- experienced a MS relapse 2.5 months before the 19, the patient died because of COVID-19. onset of COVID-19, which was treated with Neither of the fatal cases were vaccinated methylprednisolone 1 g intravenously daily for against COVID-19; their serum IgG and IgM Neurol Ther (2022) 11:741–758 749 Table 2 Summary of COVID-19 cases in the open-label ALITHIOS study Characteristics Any COVID–19 related AE Overall Confirmed Suspected Hospitalized COVID-19 COVID-19 COVID-19 overall N = 245 n = 210 n = 35 COVID-19 n = 23 COVID-19 seriousness, n (%) Non-serious 221 (90.2) 187 (89.0) 34 (97.1) 0 Serious 24 (9.8) 23 (11.0) 1 (2.9) 23 (100) Hospitalized 23 (9.4) 22 (10.5) 1 (2.9) 23 (100) COVID-19 maximum severity, n (%) Mild 108 (44.1) 90 (42.9) 18 (51.4) 1 (4.3) Moderate 114 (46.5) 99 (47.1) 15 (42.9) 5 (21.7) Severe 19 (7.8) 17 (8.1) 2 (5.7) 14 (60.9) Life-threatening 3 (1.2) 3 (1.4) 0 3 (13.0) Missing CTCAE grading 1 (0.4) 1 (0.5) 0 0 COVID-19 outcome, n (%) Recovered/recovered with sequalae/recovering 241 (98.4) 206 (98.1) 35 (100) 22 (95.7) Not recovered 2 (0.8) 2 (1.0) 0 0 Fatal 2 (0.8) 2 (1.0) 0 1a (4.3) COVID-19 duration in days, median (range) 15 (1–216) 15 (1–216) 14 (3–47) 14 (4–57) COVID-19 onset time since the first dose of 2.32 ± 0.999 2.38 ± 1 1.91 ± 0.903 2.52 ± 0.86 ofatumumab, years, mean ± SD AE led to ofatumumab interruption, n (%) 39 (15.9) 34 (16.2) 5 (14.3) 9 (39.1) AE led to ofatumumab discontinuation, n (%) 2 (0.8) 2 (1.0) 0 1 (4.3) COVID-19 duration could not be calculated for 2 patients because of missing AE end date. Please refer to supplementary material (Fig. S1) for severity and seriousness definitions AE adverse event; COVID-19 coronavirus disease; CTCAE Common Terminology Criteria for Adverse Events; SD standard deviation a One patient with a fatal outcome was not admitted to the hospital owing to personal circumstances and financial reasons levels were within the normal range throughout Immunoglobulin Levels and Their Association the study. with COVID-19 Occurrence and Seriousness The overall median (range) COVID-19 dis- Of the 245 COVID-19 cases, no COVID-19–af- ease duration was 15 (1 to 216) days in 243 fected participant had IgG levels below the patients with non-missing end date (Table 2). lower limit of normal (LLN; 5.65 g/l) before COVID-19 onset. Twenty-three participants (9.4%) (confirmed: n = 19; suspected: n = 4) had 750 Neurol Ther (2022) 11:741–758 IgM levels below the LLN (0.4 g/l) before COVID-19 Post-marketing Patient COVID-19 onset, 22 of whom had non-serious Characteristics COVID-19, and one 56-year-old male patient For the 90 confirmed cases, information on age who was hospitalized with pneumonia and had was available for 62 patients, and the mean an IgM level of 0.34 g/l 3 months before his (range) age was 45 (19–66) years; 60 patients diagnosis of COVID-19. The 22 non-serious were female, 22 were male, and gender was not cases were of mild-to-moderate severity, and all reported for the remainder. Many of the post- patients recovered with or without sequelae. marketing cases had limited information Low IgG/IgM levels were not associated with regarding prior MS DMTs, comorbidities, MS any serious SARS-CoV-2 infections. duration, time of exposure to ofatumumab, EDSS/disability status, COVID-19 symptoms, Vaccination Status, Vaccine Breakthrough and outcome, and some patients were lost to Infections, and Their Severity and Outcomes follow-up. All of the patients reported COVID- In total, 559 ALITHIOS patients were vaccinated 19 from the US, with the exception of one from of whom 476 were fully vaccinated (of these 27 France (diagnosed with neuromyelitis optica - patients received a booster vaccination), 74 spectrum disorder and aquaporine?) [32]. were partially vaccinated, and 9 received an unspecified COVID-19 vaccination (Table S1). COVID-19 Cases, Seriousness, Severity, Among 550 fully or partially vaccinated and Outcomes patients, messenger ribonucleic acid (mRNA)- Of the 90 confirmed cases (Table 3), 10 were based vaccine (78.9%) was the most commonly serious in nature, including 1 medically signif- received, followed by viral-vector-based (non- icant case and 9 hospitalizations. No fatalities or replicating) vaccine (16.9%; Fig. S3). Among life-threatening COVID-19 cases were reported 476 fully vaccinated patients, 7 (1.5%) had in the post-marketing setting. breakthrough COVID-19, of which 5 were Of the 90 confirmed COVID-19 cases, sever- mild/moderate or non-serious, 1 was severe, ity of COVID-19 was assessed as mild in 32 and 1 was life-threatening, and all 7 patients patients, moderate in 7 patients, severe in 3 recovered. Among vaccinated patients, 11 patients, and critical in 1 patient by indepen- (1.97%) had confirmed COVID-19 after partial dent adjudication. In the remaining 47 cases, vaccination, of which 9 were mild/moderate or severity could not be assessed because of the non-serious and 2 were severe, and all 11 insufficient information provided. Limited patients recovered. No cases of COVID-19 were information was provided for the 9 hospitalized reported after COVID-19 booster vaccination as patients. Age was included in four of the nine per the data cut-off. cases (29, 42, 60, and 64 years of age). There was no information regarding comorbidities or MS Post-marketing Setting severity. Outcome was provided in one of the nine cases, and the patient’s condition was improving; outcome was not provided in the As of September 25, 2021, 90 confirmed and 3 remaining eight cases. suspected COVID-19 cases were reported to the Thirty of the post-marketing patients on Novartis Safety Database from the post-market- ofatumumab with COVID-19 recovered or were ing setting for patients with RMS on ofatu- recovering, 6 patients had no change in condi- mumab subcutaneous 20 mg dose (Fig. 1). The tion at the time of the report, and outcomes cumulative post-marketing patient exposure were not available for the remaining 54 patients since the first launch of ofatumumab up to data (Fig. S4). cut-off is estimated to be approximately 4713 patient-treatment years. The patient exposure data are derived from sales data and are there- fore estimates. Neurol Ther (2022) 11:741–758 751 Table 3 Summary of confirmed COVID-19 cases in the Vaccine Breakthrough Infections and Their post-marketing setting Severity and Outcomes Limited information regarding vaccination sta- Confirmed tus was available. There were four post-market- COVID-19 N = 90 ing cases in which patients developed COVID- 19 post-vaccination; however, with limited Reporter type, n (%) information on vaccination dates, only one of HCP 12 (13.3) these cases can be determined as breakthrough COVID-19 (recovered) while the other 3 (2 cases Non-HCP 78 (86.7) with outcome unknown and 1 case with con- a COVID-19 seriousness , n (%) dition unchanged) are considered as COVID-19 post full/partial unspecified vaccination. Non-serious 80 (88.9) b Serious 10 (11.1) DISCUSSION Fatal 0 Hospitalization 9 (0.1) The data presented herein are reassuring in the sense that most MS patients with COVID-19 Life-threatening 0 reported in the open-label ALITHIOS study and Medically significant 1 (1.11) the post-marketing setting had non-serious COVID-19 disease and the majority recovered COVID-19 maximum severityc, n despite being treated with ofatumumab, which Mild 32 depletes circulating B cells. Of 245 patients recorded as COVID-19 cases Moderate 7 in ALITHIOS, fewer than 10% were serious or Severe 3 resulted in hospitalization with only two Critical 1 deaths. Fatal outcomes (2/245 or 0.8%) due to COVID-19 in ofatumumab-treated patients COVID-19 worst outcome, n were lower than those reported in the general Recovered/recovered with sequalae/ 30 population (2.1%) [2], overall MS general pop- recovering ulation (1.97%) [9], and MS patients with DMTs (1.4–5.9%) [1, 11, 12] and without DMTs Condition unchanged 6 (10.3%) [12]. The two ALITHIOS patients with a Fatal 0 fatal outcome were unvaccinated and had underlying comorbidities of diabetes and Not reported 54 hypertension in one patient and slightly over- Severity was assessed using the WHO and FDA guidelines weight (BMI of 28.3 kg/m2) in another patient, COVID-19 coronavirus disease; HCP healthcare profes- which are known risk factors for severe COVID- sional; US FDA United States Food and Drug Adminis- 19 [33]. The hospitalization rate due to COVID- tration; WHO World Health Organization 19 observed in the ALITHIOS study (9.4%) was a Percentages are calculated based on available information also lower than that previously reported for the for seriousness (N = 90) general MS population (15.5–20.9%) b No information regarding comorbidities was provided; in [1, 9, 12, 13, 34] as well as in patients with MS the post-marketing setting serious cases are likely to be treated with DMTs (11.5–32.6%) [1, 10–12] and reported more frequently than non-serious cases without DMTs (16.2–42.9%) [10, 12, 13, 34]. c Percentages are calculated based on available information The findings of clinical severity and outcomes for severity (N = 90) of COVID-19 cases in ofatumumab-treated patients are consistent with COVID-19 data presented previously with a data cut-off of Jan- uary 29, 2021 [35]. The present data analysis 752 Neurol Ther (2022) 11:741–758 does not suggest any evidence of an increased ASCLEPIOS I/II trials [38], no association risk of severe COVID-19 or fatal outcomes in MS between infection and lower IgG/IgM levels was patients treated with ofatumumab compared observed in the overall RMS population treated with the hospitalization and fatality rates as with ofatumumab for up to 3.5 years [37, 38] reported in published literature for the general and for up to 2 years [38], respectively. Consis- and MS populations [9, 13]. tent with previous findings, the present analysis These comparisons should not be over-in- of data from the ALITHIOS trial showed no terpreted. Several factors may contribute to apparent association between IgG/IgM levels differences in the reported COVID-19 severity and COVID-19 occurrence or its severity or and outcomes in different MS populations. outcome. Among all 245 COVID-19 cases in the There may be relevant differences in the present analysis, all patients had IgG levels prevalence of known risk factors such as older above the LLN, while 23 had IgM below the age, type of MS, level of MS-related disability, LLN. The mean IgG/IgM levels remained above and use of different types of DMTs. In addition, the LLN for up to 168 weeks in people with COVID-19 cases reported in MS registries are COVID-19, although mean IgM levels declined subject to ascertainment bias and may be during this time, consistent with the mean IgM/ skewed toward more severe cases being repor- IgG trend in the overall ofatumumab safety ted. It should be noted that the patients in population (data not shown). Prior registry ALITHIOS rolled over from earlier clinical trials studies have not reported data on IgG or IgM that enrolled people up to 55 years of age and levels [10, 33, 39]. excluded those with certain comorbid condi- Data on the humoral and T-cell responses to tions [25–27]. Thus, they may not fully repre- COVID-19 in people taking ofatumumab are sent the real-world population of people with scarce. In an independent assessment of IgG MS. antibodies during SARS-CoV-2 infection (fun- In the recently published retrospective report ded by Novartis), four COVID-19 cases from the on the combined Italian and French registries of ALITHIOS study were examined, all of whom confirmed COVID-19 in patients with MS, had mild COVID-19 and recovered. Three of the worse COVID-19 outcomes in people with MS four patients had normal levels of IgM and IgG on two other B-cell–depleting agents (ocre- without measurable counts of CD19 cells prior lizumab and rituximab) were noted compared to COVID-19. One patient had ofatumumab to other DMTs. Additionally, patients reported dosing temporarily interrupted because of low in the registries taking rituximab did worse than IgM. None of the three patients without circu- those treated with ocrelizumab, and the study lating B cells developed detectable antibodies to did not report on COVID-19 cases in patients SARS-CoV-2 [40]. Conversely, all three patients taking ofatumumab [33]. Worse outcomes on tested for SARS-CoV-2 had T-cell responses rituximab versus ocrelizumab were also noted detected by interferon-c ELISpot assay. Further in the North American COViMS Registry data investigation of both humoral and T-cell [10]. Salter and colleagues reported three cases responses in a larger cohort of ofatumumab- of COVID-19 in people taking ofatumumab, treated patients contracting COVID-19 is with one hospitalization and no deaths. Sor- warranted. mani and colleagues hypothesized that the The Novartis Safety Database might be more worse outcomes in patients treated with ritux- representative of real-world experience of peo- imab compared with ocrelizumab were related ple living with RMS. As of September 25, 2021, to longer exposure to the drug [33]. 90 confirmed COVID-19 post-marketing cases One concern with long-term B-cell depletion on ofatumumab had been reported in the is the potential reduction in Ig production. Novartis Safety Database. This is a voluntary Earlier studies found an increased risk of serious post-marketing database, and all but one case infections in patients with low IgG levels taking came from the US, making the data potentially ocrelizumab [36]. In previously reported find- subject to bias. Similar to the results from ALI- ings on the ALITHIOS trial [37] and the THIOS, most of the confirmed COVID-19 cases Neurol Ther (2022) 11:741–758 753 were considered non-serious in nature except immunity [42], both of which could be ten serious COVID-19 cases, including nine impaired because of B-cell depletion [19–21] patients who were hospitalized. No fatal or life- Studies that further evaluate immunization threatening cases were reported. It has been responses to COVID-19 vaccination in patients suggested that in a general post-marketing set- on ofatumumab therapy are in progress. ting, serious cases are reported more frequently A COVID-19 vaccination sub-study embedded than non-serious cases [41]. in the ALITHIOS open-label extension is underway to investigate the effect of ofatu- Limitations mumab on humoral and T-cell responses fol- lowing selected COVID-19 vaccines. In ALITHIOS is an open-label, single-arm, Phase 3b addition, three phase 4 studies are underway to extension study. The inherent design of study evaluate the immune response to the COVID-19 lacks a control group. The relatively small mRNA vaccine, two being conducted in the US number of patients in the hospitalized subgroup (clinicaltrials.gov NCT04878211 and may hamper the risk factor and subgroup NCT04847596) and one in Germany (clinical- analyses. trials.gov NCT04869358). The post-marketing surveillance includes the Evidence-based guidelines for treatment relatively small number of reported COVID-19 decisions for MS in the current COVID-19 pan- cases, which likely reflects the limited overall demic are starting to emerge. However, much of post-marketing exposure to ofatumumab, as it the current guidelines continue to derive from received marketing authorization in August expert opinions. At this point, treatment should 2020. Moreover, reporting of post-marketing be tailored in consideration of the individual cases is voluntary or spontaneous in nature, and patient’s history, existing comorbid conditions, a large proportion of cases had incomplete data and severity of MS [1, 14]. Initiation or contin- or incomplete follow-up. The post-marketing uation of ofatumumab treatment should be setting also includes literature reports of AEs, decided based on the benefit-risk assessment of but cases gleaned from the scientific literature each individual. are typically delayed in acquisition. Therefore, interpretation of these post-marketing reports CONCLUSIONS should be made with caution. Although both the ALITHIOS clinical trial and post-marketing The current study included comprehensive data surveillance did not capture information on the from the ongoing open-label extension study SARS-CoV-2 variants causing COVID-19 in the (ALITHIOS) and post-marketing reports of ofa- ofatumumab-treated patients, most cases were tumumab-treated RMS patients with confirmed likely caused by either the alpha or delta variant or suspected COVID-19. These observational as these variants were the most dominant vari- data were reassuring in that most COVID-19 ants up to the data cut-off of September 25, cases were mild or moderate in severity and 2021. most patients recovered from COVID-19 despite To date (December 2021), this is one of the being on ofatumumab, a B-cell-depleting ther- largest studies in patients with RMS treated with apy. Two fatal cases of COVID-19 were reported a B-cell depleting therapy to report on COVID- in ALITHIOS. There were no cases of reinfec- 19 cases post-vaccination. A small number of tion, and a small proportion of patients had vaccinated patients in the ALITHIOS study and COVID-19 despite being fully or partially vac- post-marketing setting reported breakthrough cinated, from which all patients recovered. 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 ACKNOWLEDGEMENTS an interplay of both cellular and humoral We thank the participants of the study. 754 Neurol Ther (2022) 11:741–758 Funding. The study sponsor (Novartis Disclosures. Anne H. Cross has received Pharma AG, Basel, Switzerland) participated in consulting fees, research support, and honoraria the design and conduct of the study, data col- from Biogen, Celgene, Bristol Myers Squibb, lection, data management, data analysis and EMD Serono, Merck, Genentech, Roche, data interpretation; preparation, review, and Greenwich Biosciences, Horizon, Janssen (sub- approval of the manuscript, as well as writing of sidiary of Johnson & Johnson), Novartis, TG the report and decision to submit the paper for Therapeutics, Academic CME, Projects in publication. All authors had full access to all Knowledge, CME Outfitters, WebMD, Conrad study data and took final responsibility for the N. Hilton Foundation, The Potomac Center for decision to submit the manuscript for publica- Medical Education, Consortium of Multiple tion. The journal rapid service fee for this pub- Sclerosis Centers, and ACTRIMS; serves on the lication was funded by Novartis Pharma AG, scientific advisory board for ASCLEPIOS I/II for Basel, Switzerland. Novartis; has received grants from the National Institutes of Health, the Department of Defense, Medical Writing and Other Assistance. We USA; has held an elected office (secretary) on thank Swetha Sirimalla, Anuja Shah and Vaish- the Board of Governors of the Consortium of navi Khandal (Novartis Healthcare Ltd, Hyder- Multiple Sclerosis Centers; was a member of the abad, India) for providing medical writing scientific advisory board of Race to Erase MS, support, which encompassed a literature search, program committee (chair) of ACTRIMS, mem- writing of the manuscript, formatting, refer- ber of the COVID-19 advisory committee of the encing, preparation of tables and figures per the National Multiple Sclerosis Society USA and journal guidelines, and incorporating the National Multiple Sclerosis Society representa- authors’ revisions and finalizing the draft for tive on the Progressive MS Alliance; and has submission, all under the direction of the received a patent for ‘‘Yablonskiy DA, Sukstan- authors. The assistance of manuscript develop- sky AL, Wen J, Cross AH. Methods for simulta- ment and submission was funded by Novartis neous multi-angular relaxometry of tissue using Pharma AG. Basel, Switzerland. magnetic resonance imaging. Patent 15060-630 (015875).’’Silvia Delgado has received fees as a Authorship. All named authors meet the consultant on scientific advisory boards for International Committee of Medical Journal Novartis and research grants through the Editors (ICMJE) criteria for authorship for this University of Miami from EMD Serono, MAPI manuscript, take responsibility for the integrity Pharma, NIH/NINDS, NMSS, and Novar- of the work, and have given final approval to tis.Mario Habek participated as a clinical inves- the version to be published. All authors are tigator and/or received consultation and/or responsible for intellectual content and data speaker fees from Biogen, Sanofi Genzyme, accuracy. Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, Author Contributions. Anne H. Cross and and TG Pharmaceuticals.Maria Davydovskaya Brian J. Ward contributed to writing and critical received grants for consulting or speaking fees revisions of the manuscript. Silvia Delgado, from Biogen Idec, Celgene/Receptos, Janssen/ Mario Habek, Maria Davydovskaya, Natalia Actelion, Merck/EMD Serono, Novartis, Roche Totolyan and Xavier Montalban contributed to Sanofi Genzyme, and TG Pharmaceuticals; par- critical revisions of the manuscript.Bruce A.C. ticipated on the advisory board of Biogen Idec, Cree and Kevin Winthrop contributed to data Merck/EMD Serono and served as a president of analysis and critical revisions of the manuscript. Medicine Association of Professional and MS Ratnakar Pingili, Linda Mancione, Xixi Hu, centers.Brian J. Ward serves on a scientific Roseanne Sullivan, Wendy Su, Ronald Zielman, advisory board for Novartis and reports personal Ayan Das Gupta, contributed to critical revi- fees from Novartis for this activity. He is also sions of the manuscript. medical officer for Medicago Inc and holds parts of patents for vaccines targeting influenza, Neurol Ther (2022) 11:741–758 755 Clostridioides difficile and Schistosoma man- Data Availability. The datasets generated soni. In the last 5 years, he has held academic during and/or analyzed during the current industry awards with Medicago, MIT Canada, study are available from the corresponding and Aviex Technologies.Bruce A.C. Cree has author on reasonable request. received personal compensation for consulting from Alexion, Atara Biotherapeutics, Autobahn, Open Access. This article is licensed under a Avotres, Biogen, EMD Serono, Novartis, Sanofi, Creative Commons Attribution-Non- TG Therapeutics, and Therini and received Commercial 4.0 International License, which research support from Genentech.Natalia permits any non-commercial use, sharing, Totolyan has received fees for advisory boards adaptation, distribution and reproduction in or speaking for Merck and Novartis and insti- any medium or format, as long as you give tutional grants for conducting clinical trials for appropriate credit to the original author(s) and Alexion, BIOCAD, Janssen, MAPI Pharma, Mer- the source, provide a link to the Creative ck, Novartis, Receptos, Roche, Sanofi, and TG Commons licence, and indicate if changes were Therapeutics.Ratnakar Pingili, Linda Mancione, made. The images or other third party material Xixi Hu, Roseanne Sullivan, Wendy Su, Ronald in this article are included in the article’s Zielman, and Ayan Das Gupta are employees of Creative Commons licence, unless indicated Novartis.Roseanne Sullivan is employee of otherwise in a credit line to the material. If Novartis and has Novartis stock owner- material is not included in the article’s Creative ship.Xavier Montalban has received speaking Commons licence and your intended use is not honoraria and travel expenses for participation permitted by statutory regulation or exceeds the in scientific meetings, has been a steering permitted use, you will need to obtain permis- committee member of clinical trials or partici- sion directly from the copyright holder. To view pated in advisory boards of clinical trials in the a copy of this licence, visit http:// past years with Actelion, Alexion, Bayer, Bio- creativecommons.org/licenses/by-nc/4.0/. gen, Celgene, EMD Serono, Genzyme, Hoff- mann-La Roche, Immunic, Medday, Merck, Mylan, NervGen, Novartis, Roche, Sanofi-Gen- zyme, Teva Pharmaceutical, TG Therapeutics, REFERENCES EXCEMED, MSIF, and NMSS.Kevin Winthrop has received consulting fees from Novartis, 1. Reder AT, Centonze D, Naylor ML, Nagpal A, Rajbhandari R, Altincatal A, et al. COVID-19 in Roche, and Genentech. patients with multiple sclerosis: associations with disease-modifying therapies. CNS Drugs. Prior Presentation. Some results from this 2021;35(3):317–30. study were summarized in one research abstract and conference posters, presented at the 2. World Health Organization. WHO Coronavirus (COVID-19) dashboard. 2021. https://covid19.who. ECTRIMS 2021 Virtual Congress (October int/. Accessed 17 Jan 2022. 13–15, 2021). 3. Gazit. Comparing SARS-CoV-2 Natural immunity to Compliance with Ethics Guidelines. The vaccine-induced immunity: reinfections versus ALITHIOS (NCT03650114) study was conducted breakthrough infections. 2021. https://ncrc.jhsph. edu/research/comparing-sars-cov-2-natural- in accordance with the International Confer- immunity-to-vaccine-induced-immunity- ence on Harmonisation guidelines for Good reinfections-versus-breakthrough-infections/. Clinical Practice [43], local regulatory require- Accessed 13 Jan 2022. ments, and the principles of the Declaration of 4. Naleway AL, Groom HC, Crawford PM, Salas SB, Helsinki [44]. The study was approved by ethics Henninger ML, Donald JL, et al. Incidence of SARS- committees or institutional review board for CoV-2 infection, emergency department visits, and each study site, and all patients provided writ- hospitalizations because of COVID-19 among per- ten informed consent before commencing trial- sons aged C12 Years, by COVID-19 vaccination status - Oregon and Washington, July 4-September related procedures. 756 Neurol Ther (2022) 11:741–758 25, 2021. MMWR Morb Mortal Wkly Rep. 16. Louapre C, Ibrahim M, Maillart E, Abdi B, Papeix C, 2021;70(46):1608–12. Stankoff B, et al. Anti-CD20 therapies decrease humoral immune response to SARS-CoV-2 in 5. Wijnands JM, Kingwell E, Zhu F, Zhao Y, Fisk JD, patients with multiple sclerosis or neuromyelitis Evans C, et al. Infection-related health care utiliza- optica spectrum disorders. J Neurol Neurosurg Psy- tion among people with and without multiple chiatry. 2021. https://doi.org/10.1136/jnnp-2021- sclerosis. Mult Scler. 2017;23(11):1506–16. 326904. 6. Winkelmann A, Loebermann M, Reisinger EC, 17. Brownlee W, Bourdette D, Broadley S, Killestein J, Hartung HP, Zettl UK. Disease-modifying therapies Ciccarelli O. Treating multiple sclerosis and neu- and infectious risks in multiple sclerosis. Nat Rev romyelitis optica spectrum disorder during the Neurol. 2016;12(4):217–33. COVID-19 pandemic. Neurology. 2020;94(22): 949–52. 7. Druyan A, Lidar M, Brodavka M, Levy I, Barzilai A, Pavlotsky F. The risk for severe COVID 19 in 18. Rolfes L, Pawlitzki M, Pfeuffer S, Nelke C, Lux A, Pul patients with autoimmune and/or inflammatory R, et al. Ocrelizumab Extended interval dosing in diseases: first wave lessons. Dermatol Ther. multiple sclerosis in times of COVID-19. Neurol 2021;34(1):e14627. Neuroimmunol Neuroinflamm. 2021;8(5):e1035. 8. Chaudhry F, Jageka C, Levy PD, Cerghet M, Lisak 19. Gadani SP, Reyes-Mantilla M, Jank L, Harris S, RP. Review of the COVID-19 risk in multiple scle- Douglas M, Smith MD, et al. Discordant humoral rosis. J Cell Immunol. 2021;3(2):68–77. and T cell immune responses to SARS-CoV-2 vac- cination in people with multiple sclerosis on anti- 9. Prosperini L, Tortorella C, Haggiag S, Ruggieri S, CD20 therapy. EBioMedicine. 2021;73:103636. Galgani S, Gasperini C. Increased risk of death from COVID-19 in multiple sclerosis: a pooled analysis of 20. Novak F, Nilsson AC, Nielsen C, Holm DK, Øster- observational studies. J Neurol. 2021. https://doi. gaard K, Bystrup A, et al. Humoral immune org/10.1016/j.jns.2021.117776. response following SARS-CoV-2 mRNA vaccination concomitant to anti-CD20 therapy in multiple 10. Salter A, Fox RJ, Newsome SD, Halper J, Li DKB, sclerosis. Mult Scler Relat Disord. 2021;56:103251. Kanellis P, et al. Outcomes and risk factors associ- ated with SARS-CoV-2 infection in a North Ameri- 21. Sormani MP, Inglese M, Schiavetti I, Carmisciano L, can Registry of patients with multiple sclerosis. Laroni A, Lapucci C, et al. Effect of SARS-CoV-2 JAMA Neurol. 2021;78(6):699–708. mRNA vaccination in MS patients treated with disease modifying therapies. EBioMedicine. 11. Hughes R, Whitley L, Fitovski K, Schneble HM, 2021;72:103581. Muros E, Sauter A, et al. COVID-19 in ocrelizumab- treated people with multiple sclerosis. Mult Scler 22. World Health Organization. Archived: WHO time- Relat Disord. 2021;49:102725. line-COVID-19. 2022. https://www.who.int/news/ item/27-04-2020-who-timeline—covid-19. Acces- 12. Simpson-Yap S, De Brouwer E, Kalincik T, Rijke N, sed 13 Jan 2022. Hillert JA, Walton C, et al. Associations of disease- modifying therapies with COVID-19 severity in 23. Fox E, Mayer L, Aungst A, Mancione L, Rennie N, multiple sclerosis. Neurology. 2021. https://doi.org/ Roustan A, Stoneman D, Su W, Gupta A, Zalesak M, 10.1212/WNL.0000000000012753. Ziehn M, Robertson D, Cohen J. Long-term safety, compliance, and effectiveness of ofatumumab in 13. Barzegar M, Mirmosayyeb O, Gajarzadeh M, patients with relapsing multiple sclerosis: The ALI- Afshari-Safavi A, Nehzat N, Vaheb S, et al. COVID- THIOS Phase 3b study. Jt ACTRIMS-ECTRIMS Meet 19 among patients with multiple sclerosis: a sys- (Virtual). 2020;0218:223–659. tematic review. Neurol Neuroimmunol Neuroin- flamm. 2021;8(4):e1001. 24. Medicine USNLO. Long-term safety, tolerability and effectiveness study of ofatumumab in patients 14. Thakolwiboon S, Zhao-Fleming H, Pan J, Scott JK, with relapsing MS (ALITHIOS). 2022. https:// Shoji E, Sohn G, et al. Disease-modifying therapies clinicaltrials.gov/ct2/show/NCT03650114. Acces- during the COVID-19 outbreak: a narrative review sed 17 Dec 2021. of international and national recommendations. Int J MS Care. 2020;22(4):151–7. 25. Bar-Or A, Wiendl H, Montalban X, Alvarez E, Davydovskaya M, Delgado SR, et al. Rapid and 15. Garjani A, Evangelou N, Das Nair R, Hunter R, sustained B-cell depletion with subcutaneous ofa- Tuite-Dalton K, Coles A, et al. COVID-19 in people tumumab in relapsing multiple sclerosis: APLIOS, a with MS: a large community-based study of the UK randomized phase-2 study. Mult Scler. 2021. MS register. Mult Scler J. 2020;26(3_Suppl):46–7. https://doi.org/10.1177/13524585211044479. Neurol Ther (2022) 11:741–758 757 26. Kira JI, Nakahara J, Sazonov DV, Kurosawa T, Tsu- Mancione L, Sullivan R, Su W, Zielman R, Das miyama I, Willi R, et al. Effect of ofatumumab Gupta A, Montalban X, Winthrop K. Outcomes of versus placebo in relapsing multiple sclerosis COVID-19 in patients with relapsing multiple scle- patients from Japan and Russia: Phase 2 APOLITOS rosis receiving ofatumumab: data from the ALI- study. Mult Scler. 2021. https://doi.org/10.1177/ THIOS study and post marketing surveillance. In: 13524585211055934. European Committee for Treatment and Research in Multiple Sclerosis-37th Congress; 2021. 27. Hauser SL, Bar-Or A, Cohen JA, Comi G, Correale J, Coyle PK, Cross AH, de Seze J, Leppert D, Montal- 36. Hauser SL, Kappos L, Montalban X, et al. Safety of ban X, Selmaj K, Wiendl H, Kerloeguen C, Willi R, ocrelizumab in patients with relapsing and primary Li B, Kakarieka A, Tomic D, Goodyear A, Pingili R, progressive multiple sclerosis. Neurology. Häring DA, Ramanathan K, Merschhemke M, Kap- 2021;97(16):e1546–59. https://doi.org/10.1212/ pos L, ASCLEPIOS I and ASCLEPIOS II Trial Groups. WNL.0000000000012700. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020;383(6):546–57. 37. Jasińska E, Habek M, Wynn D, Dunphy S, Mancione L, Rennie N, Su W, Zielman R, Delgado S. Impact of 28. European Medicines Agency (EMA). ICH guideline ofatumumab on immune responses post-vaccina- E2B (R3) on electronic transmission of individual tion in RMS patients: ALITHIOS vaccination sub- case safety reports (ICSRs)-data elements and mes- study design. In: Presented at 7th Congress of the sage specification-implementation guide. 2022. European Academy of Neurology, (Virtual); June https://www.ema.europa.eu/en/documents/ 19–22, 2021, OPR-207. scientific-guideline/international-conference- harmonisation-technical-requirements- 38. Wiendl H, Seze J, Bar-Or A, Correale J, Cross A, registration-pharmaceuticals-human-use_en-4.pdf. Kappos L, Selmaj K, Gupta A, Häring D, Jehl V, Accessed 17 Dec 2021. Kerloeguen C, Pingili R, Su W, Sullivan R, Zalesak M, Hauser S. Serum immunoglobulin levels and 29. E2A I. ICH harmonised tripartite guideline clinical infection risk in the Phase 3 trials of ofatumumab in safety data management: definitions and standards relapsing multiple sclerosis. Jt ACTRIMS-ECTRIMS for expedited reporting E2A. 2022. https://database. Meet (Virtual). 2020;P0236:233–659. ich.org/sites/default/files/E2A_Guideline.pdf. Accessed 17 Dec 2021. 39. Alshamrani F, Alnajashi H, AlJumah M, Almuaigel M, Almalik Y, Makkawi S, et al. Registry of patients 30. Common Terminology Criteria for Adverse Events with multiple sclerosis and COVID-19 infection in (CTCAE) v5.0. 2022. https://ctep.cancer.gov/ Saudi Arabia. Mult Scler Relat Disord. 2021;52: protocoldevelopment/electronic_applications/ 103004. docs/ctcae_v5_quick_reference_5x7.pdf. Accessed 17 Dec 2021. 40. Adamec I, Rogić D, Penz MG, Braun C, Habek M. Humoral and cellular immunity in convalescent 31. COVID-19 CVf. Vaccines for COVID-19. 2022. COVID-19 people with multiple sclerosis treated https://www.cdc.gov/coronavirus/2019-ncov/ with ofatumumab. J Neuroimmunol. 2022;362: vaccines/effectiveness/why-measure-effectiveness/ 577788. breakthrough-cases.html. Accessed 17 Dec 2021. 41. Alomar M, Tawfiq AM, Hassan N, Palaian S. Post 32. Maillart E, Papeix C, Lubetzki C, Roux T, Pourcher marketing surveillance of suspected adverse drug V, Louapre C. Beyond COVID-19: DO MS/NMO-SD reactions through spontaneous reporting: current patients treated with anti-CD20 therapies develop status, challenges and the future. Ther Adv Drug SARS-CoV2 antibodies? Mult Scler Relat Disord. Saf. 2020;11:2042098620938595. 2020;46:102482. 42. Apostolidis SA, Kakara M, Painter MM, et al. Cel- 33. Sormani MP, Salvetti M, Labauge P, Schiavetti I, lular and humoral immune responses following Zephir H, Carmisciano L, et al. DMTs and Covid-19 SARS-CoV-2 mRNA vaccination in patients with severity in MS: a pooled analysis from Italy and multiple sclerosis on anti-CD20 therapy. Nat Med. France. Ann Clin Transl Neurol. 2021;8(8):1738–44. 2021;27(11):1990–2001. https://doi.org/10.1038/ s41591-021-01507-2. 34. Mohn N, Konen FF, Pul R, Kleinschnitz C, Pruss H, Witte T, et al. Experience in multiple sclerosis 43. European Medicines Agency. International Confer- patients with covid-19 and disease-modifying ence on Harmonisation: Guideline for good clinical therapies: a review of 873 published cases. J Clin practice E6(R2). 2016. https://www.ema.europa.eu/ Med. 2020;9(12):4067. en/documents/scientific-guideline/ich-e-6-r2- guideline-good-clinical-practice-step-5_en.pdf. 35. Cross AH, Delgado S, Habek M, Davydovskaya M, Accessed 13 Jan 2022. Ward BJ, Cree BAC, Totolyan N, Pingili R, 758 Neurol Ther (2022) 11:741–758 44. World Medical Association. WMA Declaration of wma.net/policies-post/wma-declaration-of- Helsinki—ethical principles for medical research helsinki-ethical-principles-for-medical-research- involving human subjects. 2018. https://www. involving-human-subjects/. Accessed 13 Jan 2022.