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Introduction: Evobrutinib is a highly selective, covalent Bruton's tyrosine kinase inhibitor (BTKi) being investigated for the treatment of relapsing multiple sclerosis (RMS). Previous analysis showed that patients with systemic lupus erythematosus receiving evobrutinib could mount a humoral response to seasonal influenza vaccination. However, the effects of BTKi on vaccine response in patients with MS are presently unknown. Objective(s): To examine the humoral response to mRNA COVID-19 vaccination in patients with RMS (PwRMS) receiving evobrutinib during the open-label extension (OLE) of a Phase II trial (NCT02975349). Method(s): A post hoc analysis of PwRMS who received evobrutinib 75 mg twice-daily and two doses of mRNA COVID-19 vaccination during the OLE (n=24). Immunoglobulin G (IgG) anti-S1 and anti-S2 specific antibodies to COVID-19 were measured using an indirect chemiluminescence immunoassay (DiaSorin Molecular LLC, USA;lower limit of quantification, 3.8 AU/mL;seronegative <15.0 AU/mL [n=19], seropositive >=15 AU/mL [n=5]). Result(s): Baseline mean (+/-SD) age of patients in the analysis was 44.6 (+/-10.1), 79.2% were female and mean/minimum evobrutinib exposure pre-vaccination was 105.8/97.6 weeks. All but one of the evobrutinib-treated patients developed or increased S1/S2 IgG antibody levels after two doses of mRNA vaccine (geometric mean [SD] pre-/post-vaccination: 6.7 [2.6]/209.1 [3.6] AU/mL;median pre-/post-vaccination: 3.8/185.0 AU/mL). Patients who were either S1/S2 IgG seronegative or seropositive pre-vaccination demonstrated a strong antibody response following vaccination (seronegative pre-/post-vaccination median: 3.8/167.0 AU/ mL;seropositive pre-/post-vaccination median: 26.2/715.0 AU/ mL). The majority of patients (n=22), whether seronegative or positive, had at least a 10-60-fold induction of S1/S2 IgG antibody levels from pre-to post-vaccination (median fold change of S1/S2 IgG antibody levels for total/seronegative/seropositive patients: 32.6/34.2/18.3). Conclusion(s): PwRMS treated with evobrutinib were able to mount an antibody response to two doses of mRNA COVID-19 vaccination. The marked increase in antibody response in seronegative and seropositive patients demonstrates a preserved response to novel and recall antigens in PwRMS undergoing BTKi with evobrutinib. This demonstration of a strong humoral response to vaccination during evobrutinib treatment is the first such evidence for any BTKi under investigation for the treatment of MS.
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Introduction: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of adults with either relapsing forms of multiple sclerosis (RMS) or moderately to severely active ulcerative colitis. Objective(s): To report the safety and efficacy of extended exposure to ozanimod from an ongoing open-label extension (OLE) trial. Method(s): Patients with RMS who completed a phase 1, 2, or 3 ozanimod trial were eligible to enrol in DAYBREAK (NCT02576717), where they received ozanimod 0.92 mg/d. The primary objective was to evaluate safety in the overall population;treatment-emergent adverse events (TEAE) were monitored. Efficacy was evaluated with annualised relapse rate (ARR), calculated via negative binomial regression and pooled for all parent-trial treatment groups. Number of new/ enlarging T2 and gadolinium-enhancing (GdE) magnetic resonance imaging (MRI) brain lesions were reported for patients who entered the OLE from an active-controlled phase 3 trial. Result(s): In total, 2639 patients completed the parent trials;this interim analysis (datacut 1 February 2022) included 2494 patients with mean (range) ozanimod exposure of 56.4 (0.03- 74.7) months (11732.2 patient-years) in the OLE. In the OLE, 2199 patients (88.2%) had any TEAE, 352 (14.1%) had a serious TEAE (SAE), and 89 (3.6%) discontinued due to a TEAE. Similar rates of TEAEs and SAEs occurred when assessed by parent trial treatment group. The most common TEAEs (based on preferred terms) were nasopharyngitis (20.6%), headache (16.9%), upper respiratory tract infection (11.9%), COVID- 19 infection (11.5%), and lymphopenia (10.5%), which were generally similar to parent trial observations (excluding COVID-19 infection). Adjusted ARR in the OLE was 0.099 (95% CI, 0.083-0.119). After 60 months of treatment, 68% of patients were relapse free in the OLE. Three- and 6-month confirmed disability progression was observed in 15.9% and 14.0% of patients in the OLE, respectively. Mean number of new/enlarging T2 lesions per scan at 60 months was similar, regardless of parent trial treatment group (range, 0.77-0.98), as was mean number of GdE lesions at month 60 (range, 0.057-0.065). Conclusion(s): The safety and tolerability profile of ozanimod in DAYBREAK was consistent with prior reports. Ozanimod treatment demonstrated sustained efficacy on clinical and MRI measures of disease activity and on disability progression.
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Introduction: The long-term benefit-risk profile of ocrelizumab (OCR) in patients (pts) with multiple sclerosis (MS) can be evaluated by regular safety reporting of clinical trial (CT) and post-marketing (PM) data. Safety/efficacy of OCR have been characterised in Phase II (NCT00676715) and Phase III (NCT01247324;NCT01412333;NCT01194570) trials and related open-label extension (OLE) periods, in relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS). It is important to understand the long-term safety profile of OCR and consider the impact of COVID-19. Aim(s): To report the continuity in safety by reporting longer-term safety evaluations from OCR CT and OLE periods over a 9-year follow-up period (up to November 2021). Method(s): Safety outcomes, with and without COVID-19, are reported for the OCR all-exposure population from 11 ongoing CTs in MS. Rates per 100 patient years (PY) are presented. Result(s): Over more than 9 years of follow-up, 5,848 pts with MS received OCR treatment in 11 CTs (25,153 PY of exposure;November 2021). Reported rates per 100 PY (95% CI) were: Adverse events (AEs), 232.71 (230.83-234.60), [excluding COVID-19 (EX COV) 230.12 (228.25-232.01)];infections, 69.89 (68.86-70.93), [EX COV 67.37 (66.36-68.39)];serious AEs, 7.61 (7.27-7.96), [EX COV 6.90 (6.58-7.23)];serious infections (SI), 2.74 (2.54-2.96), [EX COV 2.04 (1.87-2.22)];malignancies, 0.41 (0.34-0.50);SI leading to withdrawal, 0.12 (0.08-0.18), [EX COV 0.08 (0.05-0.13)];and AEs leading to discontinuation, 0.97 (0.85-1.10), [EX COV 0.93 (0.81-1.06)]. As of March 2022, over 250,000 pts with MS initiated OCR globally in the PM setting. Data remain generally consistent with those observed in CTs factoring in the impact of the COVID-19 pandemic. Conclusion(s): AE rates in the OCR all-exposure population remain generally consistent with the controlled treatment period in RMS/PPMS populations. Serious infection and malignancy rates remain within the range reported for pts with MS in realworld registries. COVID-19 did not lead to increased treatment withdrawal. Over a 9-year follow-up period, no new or unexpected safety signal was seen in pts treated with OCR in ongoing CTs. OCR continues to exhibit a stable and favourable safety profile. Regular reporting of longer-term safety data will continue.
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Introduction: COVID-19 emerged in late 2019. It is unclear whether selective sphingosine 1-phosphate (S1P) receptor modulators affect clinical outcomes of COVID-19 in patients with relapsing multiple sclerosis (RMS), including those who received SARS-CoV-2 vaccination. Objective(s): To characterise COVID-19 outcomes and vaccine breakthrough infections during ozanimod use, an S1P1 and S1P5 modulator, for treatment of RMS in an ongoing open-label extension (OLE) study. Method(s): DAYBREAK (NCT02576717), an OLE study of ozanimod 0.92 mg/d, began 16Oct2015. Patients who completed a phase 1-3 ozanimod RMS trial were eligible;>90% are from Eastern Europe. In this post hoc analysis, COVID-19 events from 1Nov2019 to 28Jan2022 in DAYBREAK were identified by MedDRA 24.1 COVID-19 SMQ (narrow scope). Each patient's most recent infection and all postvaccination infections were characterised. Result(s): Of 2181 patients in DAYBREAK during the analysis period, 319 (14.6%) developed COVID-19 (274 confirmed, 45 suspected). COVID-19 was nonserious in 291 (91.2%). During COVID-19, ozanimod was continued in 220 (69.0%) patients, interrupted in 94 (29.5%), and permanently discontinued in 3 (0.9%);action was unknown in 2 (0.6%) patients. At data cutoff, 285 (89.3%) had recovered (including 195 who had continued ozanimod), 6 (1.9%) recovered with sequelae, 5 (1.6%) were recovering, 16 (5.0%) had not recovered, and 5 (1.6%) died;a sixth COVID-19-related death due to lung abscess occurred after recovery with sequelae from COVID-19 infection. Of 1984 patients in DAYBREAK on 11Dec2020, when COVID-19 vaccines emerged, 596 (30.0%) received >=1 vaccine dose (415 [69.6%] mRNA;99 [16.6%] replication-defective viral vector;65 [10.9%] inactivated SARS-CoV-2;26 [4.4%] other);504 (25.4%) were fully vaccinated. COVID-19 occurred in 39/596 (6.5%) vaccinated patients and 213/1388 (15.3%) unvaccinated patients;3 postvaccination cases (including 1 case after 2 mRNA doses) were serious. Of 39 patients with postvaccination infections, 28 (71.8%) recovered (including 2/3 serious cases), 1 (2.6%) recovered with sequelae, 3 (7.7%) were recovering, and 7 (17.9%, including the third serious case) had not recovered at data cutoff. There were no COVID-19-related deaths among vaccinated patients. Conclusion(s): COVID-19 cases were largely nonserious, and the majority of infected patients recovered while continuing ozanimod. Few vaccinated patients developed COVID-19;most who did recovered without sequelae.
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Introduction: The approval of ocrelizumab (OCR) for the treatment of primary progressive MS (PPMS) showed that the course of progressive MS (PMS) can be altered with effective treatment;however, direct evidence across the spectrum of PMS, including secondary progressive MS (SPMS), is still lacking. Objective(s): CONSONANCE (NCT03523858) is a single-arm, phase 3b, 4-year study designed to evaluate for the first time the effectiveness and safety of OCR in patients with SPMS or PPMS. Year 2 results are reported. Method(s): Patients with active or non-active PMS but showing disability progression in the past 2 years were enrolled. Primary outcomes are (1) proportion of patients with no evidence of progression (NEP) defined as no progression confirmed for >=24 weeks on Expanded Disability Status Scale (EDSS), no >=20% increase in timed 25-foot walk test (T25FWT), no >=20% increase in nine-hole peg test (9HPT) time, and no MS-related death or treatment discontinuation due to efficacy failure;(2) proportion of patients with no evidence of progression and no active disease (NEPAD) defined as NEP plus no protocol-defined relapse, no new/enlarging T2 lesions (N/E-T2, re-baselined at week 24), and no T1 gadolinium-enhanced lesions. Result(s): Patients (n=629;SPMS n=324, PPMS n=305) had mean (SD) age of 48.5 (9.2) years and 52.3% were female. At baseline (BL), median (IQR)/mean (SD) EDSS scores were 6.0 (4.5- 6.0)/5.3 (1.3) for patients with SPMS and 5.0 (4.0-6.0)/4.8 (1.3) for PPMS. Overall median times for 9HPT and T25FWT were 27.9 and 9.4 seconds, respectively. Over 2 years, 311/586 (53.1%) patients had NEP (SPMS 55.8%;PPMS 50.2%;progression was mostly driven by increases in T25FWT) and 283/588 (48.1%) had NEPAD (SPMS 49.5%;PPMS 46.7%;acute activity predominantly driven by N/E-T2 lesions). Overall EDSS remained stable from BL to year 2 (mean [SD] change of +0.07 (0.79) points). In patients with EDSS >=2.0 at BL (n=526), 24-week confirmed disability improvement in any of the components (EDSS, T25FWT, 9HPT) was observed in 29.8% of cases. Rates of serious AEs and serious infections were 7.6/100PY and 3.2/100PY, respectively. Eight deaths were reported (COVID=6, pulmonary embolism=1, non-small cell lung cancer=1). Conclusion(s): Over a 2-year period, treatment with OCR was associated with comparable rates of NEP and NEPAD in patients with SPMS and PPMS, and with functional improvement in about one-third of patients. Safety outcomes were consistent with known safety profile.
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Background: Vaccination during immunosuppression can result in impaired vaccine responses. In highly active patients requiring a rapid treatment initiation, vaccination can delay treatment onset. Natalizumab (NTZ) is a high-efficacy agent with potential low interference in vaccination responses, and could be a bridge therapy to achieve an adequate immunisation before starting another treatment. Objective(s): To assess the safety and immunogenicity of inactivated vaccines administered during NTZ treatment. Method(s): Self-controlled study based on an ongoing prospective cohort that included adult MS patients with complete immunisation schedules for hepatitis B vaccine (HBV), hepatitis A vaccine (HAV) and/or COVID-19 vaccine during NTZ treatment, between September 2016 and February 2022. Seroprotection rates were calculated for each vaccine. Demographic, clinical and radiological characteristics were collected the year before (pre-exposure period) and after vaccination (post-exposure period). Differences in annual relapse rate (ARR), contrast-enhancing lesions (CELs), new T2 lesions (NewT2) and changes in Expanded Disability Status Scale (EDSS) during pre and post exposure period were evaluated. Patients were also categorised according to time on NTZ exposure before vaccination (long-term exposure >1 year and short-exposure <=1 year) and according to JCV status. Result(s): From 248 patients treated with NTZ, 60 were vaccinated during NTZ exposure: 44 (73%) women, mean age 45 years, mean disease duration 17 (SD 8.7) years. Thirty (50%) patients bridged to anti-CD20 after immunisation, because of high titers of JC virus. Between the pre and post-exposure period, we observed a decrease in both the AAR (0.28 vs 0.01;p=0.004) and newT2 (0.8 vs 0.02;p=0.1) and no changes in disability accumulation (EDSS 3.5 vs 3.5 p=0.6). The global seroprotection rate was 93% (91.6% (IC95% 73-99) for HAV (n=24), 92.6% (IC95% 76- 99) for HBV (n=27), 100% (IC95% 84-100) for Covid-19 (n=23)). No differences were seen between short and long term NTZ exposure or between JCV positive or negative patients, in terms of safety and immunogenicity. Conclusion(s): Immunisation with inactivated vaccines during NTZ treatment is safe and effective, both for short and long term NTZ exposure. In highly active PwMS who need immunisation, NTZ could be a valuable strategy to avoid delays in the onset of high-efficacy DMD, even in JC virus positive in which it could be used as a bridge therapy strategy.
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Background: Multiple sclerosis (MS) is a chronic disabling disease associated with negative effects on quality of life (QoL), including physical and mental health. The objective of this investigation was to evaluate the change in QoL for patients with highly active relapsing MS at 1 year after initiating treatment with cladribine tablets (CladT), by assessing changes in the physical and mental health composite scores of Multiple Sclerosis Quality of Life-54 (MSQoL-54). Material(s) and Method(s): In CLARIFY-MS (NCT03369665), patients with highly active relapsing MS were assigned to receive CladT 3.5 mg/kg cumulative dose over 2 years. Patients were recruited as per the EU label. Results in this interim analysis, conducted prior to the second year of treatment, were assessed using a mixed-effects linear model. Analyses were also conducted for cohorts separated by treatment naïve/prior disease-modifying therapy (DMT), and MSQoL reporting performed before/after the start of the COVID-19 pandemic, as defined as the first reported fatality within each country. Result(s): Of the 482 patients treated with CladT, 70.1% were female and the mean age was 37.4 years. Of the 426 patients who provided MSQoL-54 data, statistically significant (p<0.0001) improvements from Baseline to Month 12 were observed for physical and mental health composite scores with estimated changes of 4.51 (95% confidence interval [CI] 3.24–5.77) and 4.53 (95% CI 3.00–6.05), respectively. Similar trends were apparent for treatment naïve (n=121) and prior DMT (n=305) cohorts. There was no indication that the start of the COVID-19 pandemic had an impact on MSQoL-54 reporting. Regarding safety, 322 patients (66.8%) experienced at least one treatment-emergent adverse event, most commonly headache (16%), nasopharyngitis (9%), and lymphopenia (9%). The majority of observed post-baseline lymphopenia events were grade 1–2;fewer patients reported grade 3 lymphopenia, no grade 4 lymphopenia was observed. Conclusion(s): With only half a therapeutic dose of CladT, this interim analysis demonstrates a statistically significant improvement in the physical and mental health composite scores of MSQoL-54 at 1 year. No new safety concerns were found in this 1-year interim analysis, with no new severe or opportunistic infections that could have an impact on the established benefit:risk profile of CladT in MS.
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Background and aims: Evobrutinib, a Bruton's tyrosine kinase inhibitor, was well tolerated and effective in a double-blind, randomised Phase II trial in patients with relapsing multiple sclerosis (pwRMS;NCT02975349). Objective: report evobrutinib safety and efficacy data 2.5 years into an open-label extension (OLE). Methods: In the 48-week (W) double-blind period (DBP), pwRMS (n=267) received placebo (switched to evobrutinib 25mg once-daily, W24), evobrutinib 25mg once-daily, 75mg once-daily, or 75mg twice-daily, or open-label dimethyl fumarate (DMF;240mg twice-daily). At W48 patients could enter the OLE (DMF: 4-8W washout);evobrutinib 75mg once-daily (median ∼48W) then 75mg twice-daily. We report the latest available OLE data. Results: Of 267 DBP patients, 213 (80%) entered the OLE;164 (61%) completed ≥132W OLE treatment. Treatmentemergent adverse events (TEAEs) were reported by 165/213 patients (77.5%);59 (27.7%) had a treatment-related TEAE (six were serious;Table). Severe/opportunistic infections (≥Grade 3) were reported by 9/213 patients (4.2%);three (not treatment related;Covid pneumonia [n=2]) were fatal. Most patients had normal IgG (91%), IgA (88%) and IgM (82%) levels (OLE W120). Mean CD19+ B cells levels were 0.218x106cells/mL (OLE baseline) and 0.122x106cells/ mL (OLE W96). ALT/AST elevations only occurred in patients previously receiving DMF/evobrutinib 25mg, and within 12W of OLE initiation. Amylase/lipase increases occurred in 6 (2.8%)/24 (11.3%) patients, without clinical signs and symptoms. ARR, for patients receiving 75mg twice-daily in the DBP, was 0.12 (95%CI 0.07-0.20 [all available OLE data]). Conclusion: Evobrutinib safety and efficacy data over 2.5 years shows acceptable tolerability, no new safety signals and maintained efficacy in pwRMS.
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Objective: Report the safety and efficacy of evobrutinib over 2.5 years in an open-label extension (OLE). Background: Evobrutinib, a covalent, blood-brain barrier-penetrating Bruton's tyrosine kinase inhibitor, was well tolerated and effective at reducing gadolinium-enhancing lesions in a double-blind, randomized phase II trial in patients with relapsing multiple sclerosis (pwRMS;NCT02975349). Design/Methods: In the 48-week (W) double-blind period (DBP), pwRMS (n=267) received placebo (switched to evobrutinib 25mg once-daily at W24), evobrutinib 25mg once-daily, 75mg once-daily, or 75mg twice-daily, or open-label dimethyl fumarate (DMF;240mg twice-daily). At W48 patients could enter the OLE (DMF: 4-8W washout);evobrutinib 75mg once-daily (median ~48W) then 75mg twice-daily. The latest available OLE data are now reported. Results: Of 267 DBP patients, 213 (80%) entered the OLE;164 (61%) completed ≥132W of OLE treatment. Treatment-emergent adverse events (TEAEs) were reported by 165/213 patients (77.5%);59 (27.7%) had a treatment-related TEAE. Six serious TEAEs were deemed treatment-related. Severe/opportunistic infections (≥Grade 3) were reported by 9/213 patients (4.2%);3 were fatal (Covid-19 pneumonia [n=2] and E. coli sepsis [n=1];not considered treatment-related). At OLE W120, most patients had IgG (91%), IgA (88%) and IgM (82%) within normal ranges. Overall mean CD19+ B cells levels were 0.218×10 cells/mL (OLE baseline) and 0.122×10 cells/mL (OLE W96). ALT/AST elevations were observed only in patients previously receiving DMF/evobrutinib 25mg and occurred within 12W of OLE initiation. Amylase/lipase increases occurred in 6 (2.8%)/24 (11.3%) patients, but without clinical signs and symptoms. Based on all available OLE data, ARR was 0.12 (95%CI 0.07-0.20) for patients receiving 75mg twice-daily in the DBP. 6 6 Conclusions: Evobrutinib safety and efficacy data over 2.5 years in pwRMS continue to show acceptable tolerability, with no new safety signals, and maintained efficacy.
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Background: Since the Covid-19 pandemic started, it has been necessary to adapt our clinical practice to limit physical contact. We have established a virtual/presential rehabilitation program (VPR) in patients with EDSS ≤6.5. Methods: Our aim was to compare the effectiveness of the VPR with the previous face-to-face rehabilitation program (PR). Retrospective data were obtained from all patients with an EDSS≤6.5 who were admitted between September and December of 2019 and 2020. All patients were attended 3 times per week for 4 months. In the 2019 group the sessions were PR based, whereas in the 2020 group patients received a VPR, with one face-to-face session plus 2 virtual sessions. Outcomes (obtained pre and post rehabilitation programs) compared between VPR and PR groups were: 10MWT, Tinnetti Test (TT) and Berg Balance Scale (BBS). A minimally clinical significant difference was established for each test: 20% for 10MWT, 3 points for BBS and 1 point for TT. Results: One hundred and forty people were included in the groups VPR (n=80) / PR (N=60). For VPR and PR groups, mean age was 51.45y (SD10.71) / 54.65y (SD11.19) and mean EDSS 4.62 (SD1.45) / 4.64 (SD1.46). All clinical outcomes demonstrated statistically significant improvements pre-post intervention in both groups. Comparing VPR vs PR scores, test didn't show differences using a U of Mann-Whitney for independent samples: BBS 54.2%/44.1% (p =0.27);10MWT 36.7%/22.0% (p =0.13) and TT 40.7%/37.3% (p =0.72). Conclusions: No differences were observed in the effectiveness of VPR versus PR in any of the tests. The VPR program could be a useful tool for patients with an EDSS≤6.5, as the VPR provides a series of subjective benefits (ease of occupational and family life, reduction of fatigue caused by long journeys) while maintaining effectiveness. Further studies with improved designs are warranted to confirm these findings.
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Objectives: To analyse the degree of adherence to the Cemcat choir, the reasons for interrupting participation and the degree of satisfaction of the participating patients. Methodology: Fifty-seven patients have participated in the faceto- face Cemcat choir from September 2015 until March 2020 (SARS-Cov-2 pre-pandemic period). The choir runs once a week for 90 minutes. It is led by a professional music therapist with a speech and language therapist, and a social worker is also involved. Analysis will include: amount of long-lasting participants (with or without some intermittence), reasons why participants gave up the activity and patients' degree of satisfaction by year measured through a Visual Analogical Scale (VAS) being 0 the lowest and 10 the highest satisfaction. Results: Twenty-six patients (45,6%) have continued their participation, twenty-four patients uninterruptedly (92.3%) and two patients (7.6%) with some interruption.Thirty-one patients (54%) gave up the choir and the reasons for stopping the participation were difficulties to manage attendance (n=8, 26%), lack of interest (n=15, 48%), health-related reasons (n=4, 13%), exitus (n=1, 3%) and unknown or other reasons (n=3, 10%). The mean VAS of satisfaction for having sung in the choir is 9.2 and the mode is 10. Conclusions: Adherence to the Cemcat choir is high. A significant number of patients have maintained their participation for a long time. Fifteen patients of the whole sample (26.3%) gave up because of lack of interest. The degree of satisfaction of the participants is very high and it is consistent with the reported high adherence to this activity.
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Introduction: Information about how SARS-CoV-2 specific humoral and cellular response is modified by disease-modifying therapies (DMTs) is scarce. Objective: To investigate humoral and cellular responses to SARS-CoV-2 and factors for presenting them in a Barcelona cohort of pwMS. Methods: Retrospective cohort study of adult unvaccinated PwMS with confirmed COVID-19 with at least one SARS-CoV-2 antibody (Ab) determination included from February 2020 to May 2021 and followed until May 2021. Demographic, clinical and laboratory data were obtained. Humoral SARS-CoV-2 response was measured with commercial chemiluminescence immunoassays targeting specific Ab against spike (IgG-S) and nucleocapsid proteins (Ig-N), as per clinical practice. SARS-CoV-2 specific T-cell response was studied in 42 selected pwMS according to DMT by a whole blood Interferon-Gamma (IFN-y) Release Immunoassay. Humoral and cellular response was assesed using a logistic regression model corrected for age, sex, comorbidities, MS form, expanded disability status scale, DMT, COVID-19 severity and PCR result. Results: 145 pwMS were enrolled (mean age 46.8 years;64.1% female;18.6% progressive forms, 20.7% untreated, 22.8% on anti-CD20s therapies and 56.6% on other DMTs). Humoral and cellular tests were performed from 0.3 to 13.1 months after COVID-19. 121(83.5%) presented positive Ab (57.6% anti-CD20 therapy, 90.2% other DMTs, 93.3% untreated). Untreated patients presented higher Ig-N titres (34.3[128.8]) compared to those with anti-CD20s (0.08[0.13], p<0.01), and other DMTs (19.55[42.92], p<0.01). Humoral response persisted over 6 months in 12/12 untreated, 9/22 with anti-CD20s and 22/28 with other DMTs (p=0.068). 31/42(73.8%) presented cellular response (81.0% anti- CD20, 62.5% other DMTs, 80.0% untreated), with similar levels of IFN-y levels among DMTs. 5/12(41.7%) anti-CD20-treated PwMS with negative Ab presented cellular response. In the multivariate analysis, humoral response decreased in anti-CD20 therapy (OR 0.08[95% CI,0.01-0.55]) and was associated with male sex (OR 3.59[1.02-12.68]). Cellular response was associated with seropositivity (OR13.0[1.29-130.4]), but can be present even in the absence of Ab. Conclusions: Humoral response is altered by DMTs, specially in anti-CD20-treated PwMS. Cellular response is associated with seropositivity but can be present in anti-CD20-treated PwMS even in the absence of Ab. Both can be detected up to 13.1 months after COVID-19.
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Background: Information about humoral and cellular responses to SARS-CoV-2 vaccination in patients with Multiple Sclerosis (PwMS) and other autoimmune diseases (AID) is scarce. Objective: To determine humoral and cellular responses after SARS-CoV-2 vaccination in PwMS and anti-CD20-treated patients with other AID. Methods: Ongoing prospective study performed in two Catalan MS centres from February 2021. Unvaccinated adult pwMS and other anti-CD20-treated AID were recruited. Demographic, clinical and laboratory data were obtained. Whole blood samples were obtained before and 30-90 days after vaccination. The humoral response to SARS-CoV-2 was qualitatively and quantitatively measured before and after vaccination with commercial chemiluminescence immunoassays targeting SARS-CoV-2 antibodies against spike (TrimericS, IgG anti-S) and nucleocasid proteins (Elecsys, Ig anti-N). In 150 selected patients according to diseasemodifying therapy (DMT), the SARS-CoV-2 specific T-cell response was assessed after vaccination by a whole blood Interferon-Gamma Release immuno Assay (IGRA) that uses two Qiagen proprietary mixes of SARS-CoV-2 S protein (Ag.1 and Ag.2) selected to activate both CD4 and CD8 T cells. Results: 457 patients have been enrolled in the study (anti-CD20 therapy n=164, S1P DMTs n=37, natalizumab n=32, cladribine n=29, alemtuzumab n=31, other DMTs n=129, no DMT n=35). Participants characteristics are: mean age 48.1 years (SD 12.0), 69% female, 422 pwMS (29.4% progressive forms) and 35 with other AID, disease duration 13.9 years (IQR 14.1), median EDSS 3.0 (IQR 3.0). 450 have been fully vaccinated (94.2% mRNA vaccine). Pre-vaccination samples were collected 0.33 days (SD 0.5) before the first vaccine dose of which 12 (3.35%) had positive anti S/N immunoglobulin (Ig). As of June 30th, 42 post-vaccination samples have been obtained (1.3 months [SD 0.42] after the 2nd vaccination dose). Positive IgG rates were 44.8% (n=13/29) for CD20s, 100% (8/8) for other DMTs and 100% (4/4) for no DMT. No anti-N Ig were detected. Media titres of anti-S IgG were lower in anti-CD20-treated patients (7.8 [IQR 50.1]) compared to untreated patients (800 [0], p<0.01) or other DMTs (755 [228], p<0.01). Conclusions: Initial results of the study suggest blunted anti-S/N Ig response under anti-CD20 therapy. Knowledge of the cellular response in these patients will be crucial. Data from the cellular study and the completed humoral study will be presented at the meeting.
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Introduction: Per WHO, >190 million people worldwide have been affected by COVID-19 as of 20-Jul-2021. Although people with MS are not at a higher risk of SARS-CoV-2 infection, factors such as age, comorbidity, MS severity and treatment with DMTs may affect COVID-19 severity and outcomes. Understanding the risks, severity and outcomes of COVID-19 in people with MS receiving DMTs, including anti-CD20 DMTs, is important to healthcare practitioners (HCPs) managing MS. Objectives: To report the characteristics and outcomes of COVID- 19 adverse events (AEs) in relapsing MS (RMS) patients taking ofatumumab enrolled in the ongoing, open-label, long-term extension Phase 3b ALITHIOS study and from post-marketing surveillance of people receiving ofatumumab 20 mg subcutaneously. Methods: Patient demographics, baseline characteristics, incidence of COVID-19 AEs, seriousness category (including hospitalization), severity, outcomes, ofatumumab exposure before the start of infection, and action taken with ofatumumab were assessed. Results: As of 29-Jan-2021, 139/1703 (8.2%) patients enrolled in ALITHIOS (mean±SD age at baseline: 37.7±8.7 years;female, 64%) treated with ofatumumab reported COVID-19 AEs (confirmed: 115 [82.7%];suspected: 24 [17.3%]). Of these, 10 (7.2%) experienced COVID-19 serious AEs and all 10 (7.2%) were hospitalized. Most AEs reported were mild (Grade [G] 1;69 [49.6%]) or moderate (G2;62 [44.6%]) in severity. Severe (G3) and life threatening (G4) AEs were reported in 6 (4.3%) and 2 (1.4%) patients, respectively. One (0.7%) patient (48-year-old at COVID- 19 onset;BMI 28.3 kg/m2;recent MS relapse) with confirmed COVID-19 and pneumonia had a fatal outcome. At data cut-off, most patients (128 [92.1%]) had recovered from COVID-19 AEs;2 (1.4%) were recovering, 4 (2.9%) had recovered with sequelae and 4 (2.9%) had not recovered. COVID-19 AEs led to temporary interruption of ofatumumab in 22 (15.8%) patients. As of 31-Jan- 2021, an additional 28 RMS patients with COVID-19 AEs were identified in the Novartis safety database. Further details to be presented. Conclusions: In ALITHIOS, 139 RMS patients on ofatumumab reported COVID-19 AEs (as of 31-Jan-2021). Most (94%) COVID-19 cases were mild or moderate in severity. There were few hospitalizations but one fatal outcome. At data cut-off, most (92%) patients had recovered/resolved from COVID-19. ALITHIOS data extends the understanding of the long-term safety profile of ofatumumab in people living with MS.
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Introduction: Ongoing consistent safety reporting is crucial to understand the long-term benefit-risk profile of ocrelizumab (OCR) in patients with multiple sclerosis (MS), in both clinical trials and globally, in the post-marketing (PM) setting. Safety/efficacy of OCR have been characterised in Phase II (NCT00676715) and Phase III (NCT01247324;NCT01412333;NCT01194570) trials and related open-label extension (OLE) periods, in patients with relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS). It is important to understand the longterm safety profile of OCR independent of any impact of COVID- 19 infections. Aims: To maintain continuity in the safety update by reporting longer-term safety evaluations from OCR clinical trials and OLE periods up to November 2020 and selected PM data, excluding COVID-19 cases;the latter will be communicated in a separate late-breaking abstract. Methods: Safety outcomes, excluding COVID-19, are reported for the OCR all-exposure population in Phase II/III trials and associated OLEs plus ongoing Phase IIIb trials in MS (VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, LIBERTO and CONSONANCE). To account for different exposure lengths, rates per 100 patient years (PY) are presented. The number of postmarketing OCR-treated patients is based on estimated number of vials sold and US claims data. Results: In clinical trials, 5,688 patients with MS received OCR (21,675 PY of exposure;Nov 2020). Reported rates per 100 PY (95% confidence interval) were: Adverse events (AEs), 238 (236- 240);infections, 71.8 (70.7-73.0);serious AEs, 7.05 (6.71-7.42);serious infections, 2.0 (1.82-2.20);malignancies, 0.42 (0.34- 0.52);and AEs leading to discontinuation, 0.96 (0.83-1.10). As of December 2020, over 200,000 patients with MS initiated OCR globally in the PM setting. Data remain generally consistent with those observed in clinical trials. Conclusions: AE rates in the OCR all-exposure population and PM settings, excluding COVID-19 infections, remain generally consistent with the controlled treatment period in RMS/PPMS populations. Serious infection and malignancy rates remain within the range reported for patients with MS in real-world registries. In patients with RMS and PPMS, OCR demonstrates a consistent and favourable safety profile;these longer-term data are in accordance with the safety outcomes initially observed during the controlled treatment periods. Regular reporting of longer-term safety data will continue.
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Background: Data on the effects of multiple sclerosis (MS) disease modifying therapies (DMTs) on SARS-CoV-2 vaccine response are needed. Initial studies suggest CD20 cell depleting therapies and fingolimod attenuate IgG response to SARS-CoV-2 vaccination in MS patients (pts), consistent with previous studies of vaccine responses in pts treated with those DMTs. Methods: Participants with MS enrolled in the MS PATHS network in the US, Germany, and Spain were asked to provide blood serum samples up to 30 days pre-SARS-CoV-2 vaccination and 28-90 days post final vaccine dose. The goal is to obtain & ge;45 post-vaccination samples per approved DMT and among pts not currently treated with a DMT. Semi-quantitative measures of SARS-CoV-2 IgG response to spike protein (Siemens SARSCoV- 2 IgG assay) and nucleocapsid protein (Abbott SARS-CoV-2 IgG assay) will be used to distinguish humoral responses to vaccination vs prior infection. The impact of demographic factors, MS disease subtype and duration, disability level, DMT type, vaccine type, and time since last DMT dose, and vaccine dose on IgG response will be evaluated. Results: As of May 17, 2021, 379 unique pts provided a serum sample: CD20 DMTs (n=139), S1P DMTs (n=31), natalizumab (n=39), other DMTs (n=117), and no DMT (n=53);183 pts have a pre-vaccination sample awaiting a post-vaccination sample, 186 have only a post-vaccination sample, and 10 have both. Prevaccination samples were collected at a mean (SD) of 4.5 (7.5) days prior to the first vaccine dose, and post-vaccination samples were collected 46.6 (15.2) days after the last dose, 91.8% following an mRNA vaccine. Pt (n=379) characteristics were: age 50.3 (12.5) yrs, 67% female, disease duration 16.6 (9.6) yrs, 27.7% progressive MS, and Patient Determined Disease Steps 2.0 (2.3). Reactive IgG rates (IgG index & gt;1) from initial post-vaccination testing were CD20 DMTs 21/41 (51%), S1P DMTs 4/8 (50%), and 100% for all other groups, including natalizumab (n=9), fumarates (n=8), interferons (n=8), glatiramer acetate (n=8), teriflunomide (n=2), alemtuzumab (n=1) and no DMT (n=17). Conclusions: Preliminary results, based on a limited sample size, suggest CD20 and S1P DMTs may reduce IgG response to SARS-CoV-2 vaccination. Quantifying post-vaccination IgG response across DMTs is crucial to optimize MS management. Data from ongoing sample collection will be presented at the meeting.
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Objective: Report characteristics of COVID-19 infections in people with multiple sclerosis (pwMS) receiving subcutaneous 20mg of atumumab, a human anti-CD20 monoclonal antibody, every 4 weeks. Background: A global pandemic of COVID-19 has resulted in over 40 million cases as of 19 October 2020. Risks of COVID-19 in pwMS receiving disease-modifying therapies are of increased interest, but still under investigation. Design/Methods: Demographics, COVID-19 seriousness category, of atumumab treatment duration and action taken with of atumumab, interventions and COVID-19 outcomes were recorded for pwMS in the open-label extension study ALITHIOS or in the post-marketing setting. Results: As of 28 September 2020, 12/1623 pwMS (5/12 females;9/12 white) in the ALITHIOS study were reported to have laboratory-confirmed SARS-CoV-2 infection. Mean age was 37.8 years (median 44 years, range 25-51 years), disease duration 3 to 23 years, and EDSS score 0-5.5. Ofatumumab exposure range was 8.5-13.8 months (n=6 who received of atumumab only in ALITHIOS) and 17.4-44.2 months (n=6 who continued of atumumab from prior trials). One of 12 had COVID-19 seriousness grade 3-A 39 year old white male with bilateral pneumonia requiring hospitalization who recovered with normal follow-up chest X-ray. The remaining 11 cases were non-serious grades 1 or 2: Seven reported as completely recovered, one recovering, two as ongoing and one asymptomatic with SARS-CoV-2 IgM and IgG positive. Six patients were treated with anti-infectives (three received both antivirals and antibacterials and three received antibacterials). Ofatumumab treatment was unchanged in seven and interrupted in four (resumed in three;information not available for one) patients;action unknown in one. To date, no post-marketing COVID-19 cases have been reported. Conclusions: We report 12 cases (11 non-serious;one serious hospitalized for bilateral pneumonia) of laboratory-confirmed SARS-CoV-2 infection in pwMS treated with of atumumab. More surveillance data are needed to determine the risks associated with COVID19 in pwMS treated with of atumumab.