Results on SARS-CoV-2 mRNA Vaccine Booster from an Open-Label Multicenter Study in Ofatumumab-Treated Participants with Relapsing Multiple Sclerosis.

BACKGROUND: Few data exist on how ofatumumab treatment impacts SARS-CoV-2 booster vaccination response. METHODS: KYRIOS is an ongoing prospective open-label multicenter study on the response to initial and booster SARS-CoV-2 mRNA vaccination before or during ofatumumab treatment in relapsing MS patients. The results on the initial vaccination cohort have been published previously. Here, we describe 23 patients who received their initial vaccination outside of the study but booster vaccination during the study. Additionally, we report the booster results of two patients in the initial vaccination cohort. The primary endpoint was SARS-CoV-2-specific T-cell response at month 1. Furthermore, serum total and neutralizing antibodies were measured. RESULTS: The primary endpoint was reached by 87.5% of patients with booster before (booster cohort 1, N = 8) and 46.7% of patients with booster during ofatumumab treatment (booster cohort 2, N = 15). Seroconversion rates for neutralizing antibodies increased from 87.5% at baseline to 100.0% at month 1 in booster cohort 1 and from 71.4% to 93.3% in booster cohort 2. Of note, 3 of 4 initially seronegative patients in booster cohort 2 and one seronegative patient in the initial vaccination cohort seroconverted after the booster during ofatumumab treatment. CONCLUSIONS: Booster vaccinations increase neutralizing antibody titers in ofatumumab-treated patients. A booster is recommended in ofatumumab-treated patients.

Tixagevimab and Cilgavimab (Evusheld) Boosts Antibody Levels to SARS-Cov-2 in Patients with Multiple Sclerosis on B-Cell Depleters

Introduction: B-cell-depleting therapies may affect the development of a protective immune response following vaccination against SARS-CoV-2. It is important to have a different strategy for creating immunity. Evusheld (tixagevimab co-packaged with cilgavimab) is currently approved by the FDA under an emergency use authorization (EUA) for use in patients who are not able to mount an immune response to the COVID-19 vaccines. No study has been undertaken to evaluate its efficacy in people with MS. The objective of this study was to evaluate whether Evusheld (tixagevimab co-packaged with cilgavimab) affects the antibody response to SARS-CoV-2 following an existing attenuated response to the vaccines against SARS-CoV-2. Material(s) and Method(s): This was a single-center cohort study performed at Methodist Hospitals in Merrillville, IN, USA. It included patients with multiple sclerosis treated with ocrelizumab and ofatumumab. Patients had already received the mRNA vaccinations against SARS-CoV-2 and had demonstrated an attenuated response on antibody testing. All participants received 150mg of Evusheld (tixagevimab co-packaged with cilgavimab). Antibody levels were measured at least two weeks following Evusheld injections. Result(s): All patients (100%) developed the highest level of antibodies possible at least two weeks following Evusheld injections. Conclusion(s): In this study, patients with MS who had an attenuated antibody response to the COVID-19 vaccines due to exposure to b-cell depleters now had the highest antibody response possible after receiving Evusheld. This is important as it provides a different strategy for protection against COVID-19.Copyright © 2022

Current and Future Trends in MS Management: Near East Perspective

Objective(s): The objectives were to provide an overview of the current practices of Near East (NE) healthcare practitioners (HCPs) by probing their prescribing decisions, to report the COVID-19 impacts on neurologists' prescribing habits, and to explore the future relevance of current medication used in MS management among other newcomers Material(s) and Method(s): A cross-sectional study was carried out using an online survey from April 27, 2022, to July 5, 2022. The questionnaire was designed with the input of five neurologists representing five NE countries (Iran, Iraq, Lebanon, Jordan & Palestine). They identified several factors that play a crucial role in the optimal care of MS patients. The link was shared among neurologists using snowball sampling Result(s): The survey included 98 neurologists from the included NE countries, the majority of whom had more than 15 years of experience in the field, and 39% were seeing more than 40 MS patients a month. Effectiveness and safety balance was the most important factor considered when selecting the MS treatment. In the treatment of mild to moderate RRMS in men, Interferon beta 1a SC, Fingolimod, and Glatiramer acetate were the most commonly recommended treatments. Dimethyl fumarate substituted fingolimod in female patients. According to 80.7% of participants, interferon beta 1a SC was the safest treatment for mild to moderate RRMS. Interferon beta 1a SC was preferred over other treatments for patients with mild to moderate MS and planning for pregnancy (56.6%) or breastfeeding (60.2%). Fingolimod was not a choice for these patients. Neurologists seemed to discuss the top three treatments of Natalizumab, Ocrelizumab, and Cladribine with patients with highly active MS. Conclusion(s): Most neurologists in the NE region followed MENACTRIMS recommendations for prescribing treatment. The treatment choice also depended on the availability of DMTs in the region. Regarding the use of upcoming DMTs such as Ofatumumab, Siponimod, Ozanimod, and BTK inhibitors, there is a clear need for real-world data, long-term extension studies, and comparative studies to support their efficacy and safety profiles in treating patients with MSCopyright © 2022

Assessment of the treating physicians' first-hand experience with handling and satisfaction of ofatumumab therapy: findings from the PERITIA survey conducted in Europe.

BACKGROUND: Real-world evidence on experience and satisfaction of ofatumumab as a treatment option for relapsing multiple sclerosis (RMS) is limited. OBJECTIVE: To present cumulative responses from a questionnaire related to first-hand experience of treating physicians on handling and convenience of ofatumumab therapy along with concerns related to COVID-19. METHODS: PERITIA was a multicentre survey conducted to collect responses from the ASCLEPIOS I/II trial investigators from Europe via an online questionnaire. RESULTS: Forty-six physicians (Germany, n = 14; Spain, n = 12; Portugal, n = 10; Italy, n = 10) completed the survey. Overall, 43% of the physicians considered the benefit-risk ratio of ofatumumab as very good. Over 93% were in favour of ofatumumab self-administration at home and the majority (83%) believed it to be completely true that self-administration of ofatumumab eases the burden for patients in terms of time. All investigators would like to potentially use anti-CD20 therapy as a long-term strategy. Even during the COVID-19 pandemic, physicians were in favour of a self-administration of MS therapy at home over other anti-CD20 therapy infusions. CONCLUSION: European neurologists who were part of this survey considered the benefit-risk-ratio of ofatumumab as favourable and the monthly self-administered subcutaneous injections offering convenience for patients in the clinical practice.

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.

Immune Response to SARS-CoV-2 mRNA Vaccines in an Open-Label Multicenter Study in Participants with Relapsing Multiple Sclerosis Treated with Ofatumumab.

BACKGROUND: It is unclear whether multiple sclerosis (MS) patients receiving ofatumumab mount an immune response after SARS-CoV-2 mRNA vaccination. METHODS: KYRIOS is an ongoing, multicenter, open-label, prospective clinical study on immune responses in MS patients after initial or booster SARS-CoV-2 mRNA vaccination prior to (cohort 1) or during (cohort 2) ofatumumab treatment. We report one-week and one-month results of the initial vaccination. A comparison with patients vaccinated while receiving beta-interferon, glatiramer acetate, dimethyl fumarate, teriflunomide or no treatment was included (cohort 3). RESULTS: In total, 11 patients received their initial vaccination during the study. The primary endpoint of SARS-CoV-2-specific T-cells at month 1 was reached by 80.0% of patients in cohort 1 (N = 6) and 100.0% in cohort 2 (N = 5). T-cell reactivity peaked at week 1. All cohort 1 patients reached seroconversion for SARS-CoV-2 neutralizing antibodies at week 1 and month 1. In cohort 2, neutralizing antibodies increased in all patients and exceeded the cut-off for seropositivity in 40.0% of patients at week 1 and 25.0% at month 1. Immune responses in cohort 3 were comparable to cohort 1. CONCLUSION: Presence of T-cell response and increase in levels of neutralizing antibodies, although less pronounced compared to controls, suggest that MS patients receiving ofatumumab are able to mount an immune response to SARS-CoV-2 mRNA vaccination.

Group counselling consultations: the way forward?

Introduction: Virtual patient consultations have become increasingly common following the COVID-19 pandemic. In our region, we have utilised virtual group meetings of up to 30 patients to deliver education sessions regarding drug therapy for multiple sclerosis. Counselling sessions using Microsoft Teams provided information for either Siponimod, Fampridine, or Ocrelizumab and Ofatumumab, with opportunity following the presentation for questions. Patients were subsequently offered an individual Consultant review for a personalised discussion. Objective(s): All individuals who attend a virtual session during February 2021 - March 2022 will be sent an online questionnaire to complete. Aim(s): To determine the effectiveness of online group counselling consultations in providing information on medication. Method(s): Patients attending a virtual session during February 2021 - March 2022 were contacted to complete an online questionnaire. Result(s): More than half (42/80) of patients who responded had no previous experience of using MS Teams. Sessions were considered easy to access (average rating 8.8/10) and technical issues with sound or connection were only reported by 9/80. Average knowledge of the drug prior to the session was 3.8/10 and following the session this improved to 7.9/10. A virtual group session allowed the opportunity to hear the questions of other patients and this was felt to be beneficial (average rating 8.9/10). The vast majority (78/80) had no concerns regarding their confidentiality. Preference for this session to be delivered virtually rather than in person, favoured virtual delivery (7.6/10). Final comments highlighted the time and travel savings, with no significant concerns raised. Conclusion(s): Virtual group counselling sessions provide clear advantages to both patients and clinicians, saving time for the clinicians, but also giving patients group support around medication decisions. This review confirms that the majority of patients report group sessions are an effective, convenient and safe method of discussing medication. As treatment options for patients with MS expand and demand on services increases, this group counselling platform will allow greater flexibility to deliver information to patients.

Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination.

Objective: The pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood. Methods: We here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls. Results: We show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1). Interpretation: In summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity.

B-CELL MALIGNANCIES TREATED WITH TARGETED DRUGS AND SARS-COV-2 INFECTION. A EUROPEAN HEMATOLOGY ASSOCIATION SURVEY (EPICOVIDEHA)

Background: Patients with lymphoproliferatie diseases (LPD) appear particularly ulnerable to SARS-CoV-2 infection, partly because of the effects of the anti-neoplastic regimens (chemotherapy, signaling pathway inhibitors, and monoclonal antibodies) on the immune system. The real impact of COVID-19 on the life expectancy of patients with different subtypes of lymphoma and targeted treatment is still unknown. Aims: The aim of this study is to describe and analyse the outcome of COVID-19 patients with underlying LPD treated with targeted drugs such as monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, niolumab or pembrolizumab), BTK inhibitors (ibrutinib, acalabrutinib), PI3K inhibitors (idelalisib), BCL2 inhibitors (enetoclax) and IMIDs, (lenalidomide). Methods: The surey was supported by EPICOVIDEHA registry. Adult patients with baseline CLL or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between January 2020 and January 2022 were selected. Results: The study included 368 patients (CLL n=205, 55.7%;NHL n=163, 44.3%) treated with targeted drugs (Table 1). Median follow-up was 70.5 days (range 19-159). Most used targeted drugs were ITKs (51.1%), anti-CD20 other than rituximab (16%), BCL2 inhibitors (7.3%) and lenalidomide (7.9%). Of note, only 16.0% of the patients were accinated with 2 or more doses of accine at the onset of COVID-19. Pulmonary symptoms were present at diagnosis in 244 patients (66.2%). Seere COVID-19 was obsered in 47.8 % patients while 21.7% were admitted to to intensie care unit (ICU), being 55 (26.8%) CLL patients and 25 (15.3%) NHL patients. More comorbidities were reported in patients with seere-critical COVID-19 compared to those with mild- asymptomatic infection (p=0.002). This difference was releant in patients with chronic heart diseases (p=0.005). Oerall, 134 patients (36.4%) died. Primary cause of death was COVID-19 in 92 patients (68.7%), LPD in 14 patients (10.4%), and a combination of both in 28 patients (20.9%).Mortality was 24.2% (89/368) at day 30 and 34.5%(127/368) at day 200. After a Cox multiariable regression age >75 years (p<0.001, HR 1.030), actie malignancy (p=0.011, HR 1.574) and admission to ICU (p<0.00, HR 4.624) were obsered as risk factors. Surial in patients admitted to ICU was 33.7% (LLC 38.1%, NHL 24%). Mortality rate decreased depending on accination status, being 34.2% in not accinated patients, 15.9-18% with one or two doses, decreasing to 9.7% in patients with booster dose (p<0.001). There was no difference in OS in NLH s CLL patients (p=0.344), nor in ITKs s no ITKs treated patients (p=0.987). Additionally, mortality rate dropped from the first semester 2020 (41.3%) to last semester 2021 (25%). Summary/Conclusion: - Our results confirm that patients with B--mallignancies treatted with targeted drugs hae a high risk off seere infection (47.8%) and mortality (36.4%) from COVID-19. - Pressence of comorbidities,, especially heart disease,, is a risk factor for seere COVIID--19 infection in ourr series. - Age >75 years,, actie mallignancy att COVIID--19 onset and ICU admission were mortality risk factors. - COVIID--19 acination was a protectie factor for mortality,, een iin this popullation wiitth humorall immunity impairment. - The learning cure in the management of the infection throughout the pandemiic and the deelopmentt off COVIID--19 treatments showed benefit in this partticullarlly ullnerablle popullation? (Table Presented).

Humoral Immune Response to SARS-CoV-2 Vaccination in MS Patients

Objective(s): The aim of this study was to study the humoral immune response to SARS-CoV-2 following vaccination in MS patients. Material(s) and Method(s): We performed a prospective study including all MS patients receiving one of the approved COVID-19 vaccines since January to September 2021. Demographic characteristics, MS treatments and adverse events reports after COVID-19 vaccination of vaccinated MS patients were collected. We analyzed the antibody response to SARS-CoV-2 vaccines with a chemiluminescent microparticle immunoassay (CMIA) from Abbot in MS patients with different DMTs at week 3, week 6 and month 3 after the first dose. The positivity cutoff is ≥50 AU/ml (manufacturer defined). 200 Healthy healthcare professionals were the control group. Result(s): We analyzed 165 vaccinated MS patients: 106 with Pfizer, 14 with Moderna, 42 with both doses of Astra zeneca and 3 with Jannsen. The mean age of patients was 45 (range: 21-71) and 46 for the controls. The most frequent adverse events were pain at injection site, headache and fatigue for 24-48 hours. No differences between MS patients and controls. No increased risk of relapse was noted in the first six months. 120 patients have received both doses of mRNA vaccine. Overall, mean antibody titers response to SARS-CoV-2 SARS-CoV-2 at three weeks was 7910,3 AU/mL (range 0-74947), at 6 weeks 16347,9 UA/mL (range:0-52380,5) and at 3 months 8182,10 UA/ml (range:0-33752,4) in mRNA vaccinated patients. By the mRNA vaccinated control group mean antibody titers response to SARS-CoV-2 SARS-CoV-2 at three weeks was 9397 AU/mL and at 6 weeks 18120 UA/mL Performing a subanalysis of the different DMTs: Only 3 out of 20 patients treated with ocrelizumab developed antibodies. Six vaccinated patients treated with rituximab had no antibody response. Four from 16 patients treated with fingolimod failed to develop a post-vaccination humoral response (< 50 AU/ml). 4 of 5 patients treated with ofatumumab developed have an adequate humoral response. Patients treated with interferon Beta, glatiramer acetate, teriflunomide, dimethyl fumarate, vaccinated with mRNA vaccines developed a similar post vaccination humoral response than healthy controls. Conclusion(s): Most of MS treated patients developed enough antibodies to SARS-CoV-2. The adverse events on MS patients were similar to the general population. No increase of relapse activity was observed. Some patients treated with ocrelizumab, rituximab and fingolimod have no developed a humoral response to SARS-CoV-2 vaccination. Hence we conclude that all approved COVID-19 vaccines are safe in MS patients and effective in most patients. However vaccine strategy in patients treated with anti-CD20 and fingolimod need further studies.

Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years.

BACKGROUND: Ofatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit-risk profile. OBJECTIVE: Report the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years. METHODS: Patients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide. RESULTS: The safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections. CONCLUSION: In patients with up to 3.5 years' exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit-risk profile of ofatumumab in RMS.

Immunocompetence after SARS-CoV-2 Infection in a Patient with Multiple Sclerosis Treated with Ofatumumab: A Case Report.

Ofatumumab is the first fully human anti-CD20 monoclonal antibody that, on March 26, 2021, was approved by the EMA to treat patients with relapsing multiple sclerosis. This paper aimed to present a case confirming the ability to produce and maintain anti-SARS-CoV-2 antibodies in a patient treated with ofatumumab for over 4 years. The course of the infection was moderate, and the patient did not require hospitalization. Antibody measurements were performed five times post-COVID-19 infection. The first test was performed in the fourth month (131 days), and the last, over 1 year after the infection. To date, only 2 cases have been published describing the ability of a patient treated with the same drug to produce antibodies against SARS-CoV-2, although the observation was conducted over a shorter period. In our case study, we have 15-month follow-up data. The patient was not vaccinated and additionally received suppressive steroid therapy due to the relapse. We observed an increase in antibodies up to 10 months from the infection. The case under analysis suggests that patients treated with ofatumumab, despite complete peripheral B-cell depletion, can produce and maintain a long-lasting immune response.

Tracking the immune response to SARSCoV- 2 mRNA vaccines in ofatumumab treated RMS patients in a multicenter study

Background and aims: Initial and booster vaccination with the newly developed SARS-CoV-2 mRNA vaccines efficiently protect healthy individuals against COVID-19. As only limited data is available for Multiple Sclerosis (MS) patients with immunosuppressive treatment, this study aims to comprehend the impact of ofatumumab treatment on mounting cellular and humoral immune responses to SARS-CoV-2 mRNA vaccines. Methods: KYRIOS is an open-label, two-cohort study including 40 MS patients at 8 sites in Germany. Patients receive initial or booster SARS-CoV-2 mRNA vaccination either before (cohort 1) or at least 4 weeks after starting ofatumumab treatment (cohort 2). The impact of ofatumumab treatment on development of SARS-CoV-2 reactive T-cells (primary endpoint) and neutralizing antibodies (secondary endpoint) will be evaluated. Furthermore, immune responses will be monitored and phenotypically described for up to 18 months. Results: Results of an interim analysis show that SARSCoV- 2 mRNA vaccines can induce cellular and humoral immune responses in ofatumumab-treated patients. Immune responses could be detected as soon as 1 week after the initial vaccination cycle for all patients receiving their initial SARS-CoV-2 vaccines during stable ofatumumab treatment (n=4) or before ofatumumab initiation (n=5). The interim analysis further shows the effect of ofatumumab treatment on development of immune responses after booster vaccines (n=23). Conclusion: The KYRIOS study demonstrates for the first time that ofatumumab treated patients can mount specific immune responses towards SARS-CoV-2 mRNA vaccines. The results further suggest that both, humoral and cellular immune response, need to be considered for interpretation of vaccine efficacy and are in line with other recently published studies.

Ofatumumab subcutaneous injection for the treatment of relapsing forms of multiple sclerosis.

INTRODUCTION: In recent years, different studies have highlighted the importance of B cells in the pathophysiology of multiple sclerosis (MS): they secrete cytokines to modulate the inflammatory environment, present antigens for the activation of T lymphocytes, and they secrete antibodies contributing to the destruction of the myelin sheath. Combined, these findings have lead to new possible means for treating MS. AREAS COVERED: In this review, we provide an up-to-date overview of the characteristics of ofatumumab (aka Kesimpta), and the differences between this drug and the other anti-CD20 monoclonal antibodies used to treat MS. EXPERT OPINION: The evolution of disease-modifying treatment algorithms in MS underlines the importance of starting treatment as soon as the diagnosis is defined, and with adequate 'treatment intensity.' Monoclonal antibodies and other aggressive treatments are now considered as an option at the clinical presentation of the disease, based to the prognostic profile emerging through clinical and paraclinical investigations. The recent adoption of new diagnostic criteria allows for the early diagnosis of MS. This, together with the availability of disease-modifying therapies (DMTs), such as ofatumumab, with a good efficacy/safety profile and which are easy to administer, could contribute to significant improvements in the long-term prognosis of MS.

The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura.

Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13.

Tracking the immune response to SARS-CoV-2 mRNA vaccines in an open-label multicenter study in participants with relapsing multiple sclerosis treated with ofatumumab s.c. (KYRIOS clinical trial)

Objective: This study aims at understanding the impact of ofatumumab treatment on the development of cellular and humoral immune responses to initial and booster SARS-CoV-2 mRNA vaccines. Background: Recently developed SARS-CoV-2 mRNA vaccines have been shown to efficiently protect healthy individuals against COVID-19 and contribute greatly towards fighting the COVID-19 pandemic. However, only limited data is available about vaccine-induced immune responses in immunosuppressed patients. Design/Methods: KYRIOS is an open-label, prospective, two-cohort study at eight sites in Germany including 40 MS patients who receive SARS-CoV-2 mRNA vaccination either before starting ofatumumab treatment (cohort 1) or during stable ofatumumab treatment for at least 4 weeks (cohort 2). The impact of ofatumumab treatment on the proportion of patients having established SARS-CoV-2 reactive T-cells (primary endpoint) and developing SARS-CoV-2 neutralizing antibodies (secondary endpoint) after initial and booster vaccination will be assessed. Additionally, cellular and humoral immune responses will be monitored for up to 18 months and cellular response will be further described by immunophenotyping. Results: Results of this second interim analysis show the efficacy of SARS-CoV-2 mRNA vaccines to induce cellular and humoral immune responses in MS patients depending on the timing of ofatumumab treatment initiation. First data indicate that in patients vaccinated during stable ofatumumab treatment, specific immune response is detectable as soon as 1 week after the initial vaccination cycle and further increases afterwards. Conclusions: KYRIOS data show for the first time that patients vaccinated during stable ofatumumab treatment can mount immune responses to SARS-CoV-2 mRNA vaccines. The presented data further emphasize the importance of considering both, humoral and cellular immune response, for interpretation of vaccine efficacy.

Lowered COVID-19 mRNA vaccine antibody response in MS patientstreated with B-cell depleting and S1P-receptor-targeting therapies compared to controls: interim analysis

Objective: Assess the SARS-CoV2 Spike antibody response in multiple sclerosis (MS) patients on high efficacy immunotherapies. Background: There is limited knowledge about SARS-CoV2 mRNA vaccine response in MS patients on immunotherapy. Design/Methods: Patients with MS, aged 18-65, on fingolimod, siponimod, ofatumumab, or ocrelizumab for at least 3 months prior to first mRNA SARS-CoV2 vaccine (Pfizer or Moderna) were offered enrollment. A cohort of healthy controls who received the mRNA vaccines were also enrolled. Blood samples for the SARS-CoV2 Spike antibody (Anti-SARS-CoV2 S, RocheElecsys) were collected 2-3 months after the second mRNA vaccine. The proportion who seroconverted (antibody>0.4 U/ml), and SARS-CoV2 Spike antibody levels were assessed. Results: A total of 39 MS patients (6 fingolimod, 33 ocrelizumab) and 31 controls were included in this interim analysis. 33%(13/39) of MS patients seroconverted, compared to 100%(31/31) in the control group, with an estimated risk difference of -0.67,(95% confidence interval: -0.81, -0.52;Fisher's exact test, p=9.0∗10-10 ). There was no difference in seroconversion rates between MS patients who received the Pfizer (34%, 10/29) versus the Moderna vaccine (30%, 3/10) (95% confidence interval -0.38, 0.29;Fisher's exact test=1). Seroconversion was found in 100% (31/31) of controls, 66.7% (4/6) of fingolimod-treated patients, and 27.3% (9/33) of ocrelizumab-treated patients (three group comparison, Fisher's exact test p-value =2.7∗10 -10). The median Spike antibody level was <0.4 U/ml in MS patients, and 1,663 U/ml in controls (Wilcoxon rank sum test, p-value= 1.0∗10-12 ). The median Spike antibody level in the ocrelizumab group was <0.4 U/ml, 3.45 U/ml in the fingolimod group, and 1,663 U/ml in the control group (Kruskal Wallis test, p-value=5.9∗10-12 ). Total IgG correlated with Spike antibody levels in the ocrelizumab-treated group only (Spearman correlation, p=0.025). Conclusions: MS patients on ocrelizumab and fingolimod have significantly lower rates of seroconversion, and lower median Spike antibody levels in response to the mRNA SARS-CoV2 vaccines compared to controls.

Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study.

BACKGROUND: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS). OBJECTIVE: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion. METHODS: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUCτ) and maximum plasma concentration (Cmax) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed. RESULTS: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUCτ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); Cmax, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated. CONCLUSION: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.

Tixagevimab and Cilgavimab (Evusheld) boosts antibody levels to SARS-CoV-2 in patients with multiple sclerosis on b-cell depleters.

BACKGROUND AND OBJECTIVES: B-cell-depleting therapies may affect the development of a protective immune response following vaccination against SARS-CoV-2. It is important to have a different strategy for creating immunity in this patient population. The objective of this study was to evaluate whether Evusheld (tixagevimab co-packaged with cilgavimab) affects the antibody response to SARS-CoV-2 following an attenuated response to the vaccines against SARS-CoV-2 in patients on b-cell depleters who have multiple sclerosis. METHODS: This was a single-center cohort study performed at Methodist Hospitals in Merrillville, IN, USA. It included patients with multiple sclerosis treated with ocrelizumab and ofatumumab. Patients had already received the mRNA vaccinations against SARS-CoV-2 and had demonstrated an attenuated response on baseline antibody testing. All participants received 150 mg of Evusheld. Follow-up antibody levels were measured at least two weeks following Evusheld injections. RESULTS: All patients (100%) developed the highest level of antibodies possible at least two weeks following Evusheld injections. DISCUSSION: In this study, patients with MS who had an attenuated antibody response to the COVID-19 vaccines due to exposure to b-cell depleters now had the highest antibody response possible after receiving Evusheld. This is important as it provides a different strategy for protection against COVID-19.