Реальная эффективность, стойкость, терпимость и безопасность атумумаба в клинической практике.

Introduction

The therapeutic landscape for multiple sclerosis (MS) has expanded rapidly with > 20 disease-modifying therapies (DMTs) available for persons with MS (pwMS) [ 1 ]. Monoclonal antibodies (mAb) targeting CD20, a transmembrane antigen expressed on a variety of human B-cell lineage cells, are a class of DMTs with proven efficacy in relapsing MS [ 2 ]. Although the full extent of the underlying mechanism of action for this class remains the subject of ongoing research, anti-CD20 mAbs deplete B-cells with CD20 expression through complement dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis [ 3 ]. Currently, there are three available anti-CD20 mAbs approved for the treatment of MS: ocrelizumab, ublituximab, and ofatumumab (OMB).

OMB is a fully human mAb that can induce B-cell depletion primarily through CDC and to a lesser extent ADCC [ 4 ]. In comparison to other anti-CD20 mAbs used in MS, OMB is administered via subcutaneous injection. Its efficacy and safety in relapsing MS were demonstrated in two large randomized, double-blinded, double-dummy controlled trials (RCTs), ASCLEPIOS I and II [ 5 ]. In these trials, compared to teriflunomide, subcutaneous OMB in relapsing MS was associated with lower annualized relapse rates (ARR) and confirmed disability progression (CDP) and was well tolerated over the median follow-up duration of 1.6 years. Long-term efficacy and safety of OMB is being evaluated in a single-arm open-label extension study (ALITHIOS), and OMB was shown to be well tolerated without additional safety risks up to 4 years [ 6 , 7 ].

However, real-world effectiveness and safety data for OMB are lacking. Real-world data complement evidence from RCTs and may offer more realistic insights for treatment decision-making at the bedside. In this retrospective study, we aimed to evaluate the effectiveness, persistence, tolerability, and safety of OMB over 12 months in a real-world cohort of pwMS.

Patients & methods

Patient selection

Following institutional review board (IRB) approval (Cleveland Clinic IRB 21–1251), a retrospective review was conducted using the electronic medical record (EMR) of all pwMS prescribed OMB from October 2020 to August 2022 at two large tertiary MS referral centers: Cleveland Clinic Mellen Center and Cleveland Clinic Lou Ruvo Center for Brain Health. In light of the retrospective observational nature of the study, informed consent requirements were waived and approved by the IRB. Patients prescribed OMB who did not start treatment due to lack of insurance coverage or change in preference were excluded. Data were reviewed for up to 12 months or until documentation of OMB discontinuation. The authors used RedCap software to create an encrypted database on secure Cleveland Clinic servers.

Data collection

Multiple sclerosis performance test

Data were collected from the EMR and Multiple Sclerosis Performance Test (MSPT) assessments. MSPT is a previously validated, self-administered, tablet-based assessment tool for quantifying patient-reported outcomes and neuro-performance measures in pwMS [ 8 ] as part of the larger collaboration of MS Partners Advancing Technology and Health Solutions (MS PATHS) [ 9 ]. The MSPT provides comparable assessments to the MS Functional Composite (MSFC) [ 10 ]. Data are collected at routine follow-up visits and include sections on demographics, disease history, DMTs, PDDS (Patient Determined Disease Steps) [ 11 ], neuro-performance outcomes [ 7 ] and Neuro-QoL (Quality of Life in Neurological Disorders) [ 12 , 13 ]. Neuro-performance outcomes include four previously validated assessments, such as cognitive assessment through the processing speed test (PST) [ 14 ], upper extremity motor function through the manual dexterity test (MDT), lower extremity function through the walking speed test (WST), and vision assessment through the high and low contrast visual acuity test [ 15 ]. PST and visual acuity are scored based on the number of correct responses (with a higher score representing better performance), while MDT and WST are measured based on time to completion (with a lower score representing better performance).

Definition of time points

Data were collected at three time points: baseline, 6 months, and 12 months. The authors also calculated cumulative outcomes data between baseline and 12 months. The authors incorporated baseline data derived from information collected from the EMR in the 12 months prior to OMB exposure that was verified by an MS specialty provider prior to inclusion. A window of ±3 months was permitted for the 6-month and 12-month measurements. This allowed flexibility in data collection given the retrospective nature of the study with variable follow-up assessments. The time interval between baseline and 6-month (±3 months) assessments was defined as the “first 6-month window,” the time interval between 6-month and 12-month (±3 months) assessments was defined as the “second 6-month window,” and the time interval between baseline and 12-month (±3 months) assessments was referred to as the “cumulative interval.” The follow-up visits closest to the 6-month and 12-month time-points were used for analysis. For each time point, outcome measures of interest in patients who had the outcome measure available through EMR review were collected and reported.

Baseline and outcome measures

Demographics (age, sex, ethnicity, and race) and disease characteristics (disease duration, disease course, prior DMTs, prior relapses and MRI data, PDDS, and comorbidities) were collected based on available EMR data at the time of OMB initiation. DMT history was extracted from the clinical notes. High efficacy DMTs were defined as mAbs, whereas all other DMTs were categorized as low/medium efficacy DMTs. Treatment switch was defined as transitioning to OMB within 3 months of the last DMT scheduled dose.

Clinical relapses, defined as new or worsening symptoms attributable to MS that lasted for at least 24 h outside of an infection or fever, were documented in the chart by the treating neurologist. Treating neurologists at our institution are board certified in neurology and have undergone fellowship advanced training in multiple sclerosis and related disorders. Patient reported outcomes (PRO) extracted from the EMR included the Neuro-QoL and PDDS. Such domains included motor function, cognition, fatigue, sleep, anxiety, depression, and stigma. Neuro-performance measures including the PST, low- and high-contrast visual acuity, dominant and non-dominant MDT, and WST were extracted from the MSPT. MRI studies were acquired as part of routine clinical practice.

Radiology reports obtained at Cleveland Clinic facilities for MS monitoring have a standardized format. Radiological disease activity (e.g., gadolinium-enhancing (GdE) and/or new T2 lesions) was confirmed by review of the reading radiologist’s and treating neurologist’s assessments. Assessment for GdE was only performed if contrast was administered for the MRI. If multiple MRI scans were completed during a time-period, the MRI with contrast was specifically evaluated for the assessment of GdE lesions. New T2 lesions were assessed by comparing the MRI with a comparator scan completed immediately prior when available. If multiple MRI scans were completed during a time period, all were considered, and results were combined.

Adverse events (AE) were defined as any adverse clinical event or symptoms documented in the EMR with a temporal association of starting DMT. AEs were further subclassified as side effects or intolerance: side effects- AEs that could be explained by drug pharmacology; intolerance- symptom reporting by the patient that may not have been related to drug but correlated temporally with DMT use. Incidence of infections is collected and reported separately as documented in the EMR by the provider or reported by the patient. Lower limit of normal (LLN) for immunoglobulin values was defined using the local laboratory reference ranges.

When available, disability progression measures were calculated for patients. No evidence of disease activity (NEDA-2) status was defined and measured as the absence of clinical relapses and new/enlarging T2 and GdE lesions. NEDA-3 status was defined as components of NEDA-2 and the absence of PDDS score worsening. NEDA-2 and NEDA-3 were only evaluated in patients who had all relevant parameters available for review.

Statistical analysis

Our analysis included all pwMS who started OMB from October 2020 to August 2022. All percentages were reported as a proportion of patients at risk. Mean and standard deviation (SD) for normally distributed variables and median and interquartile range (IQR) for non-normally distributed variables and variables with very small sample sizes were reported. Approximate normality of distribution was assessed visually. Descriptive statistics were used to describe persistence and AEs. Event numbers (e.g., relapses, number of new T2 and GdE lesions) between treatment periods were compared using negative binomial generalized linear mixed effects models (GLMM), which included a random intercept to adjust for clustering within subjects. Binary outcomes for these variables (presence or absence of each event) were compared using logistic GLMM. Immunoglobulin levels were compared using linear mixed effects models (LMM). Immunoglobulin G (IgG) and immunoglobulin M (IgM) values for the subset of patients who switched to OMB from other anti-CD20 mAbs were assessed using the Kruskal–Wallis rank-sum test. The distribution of categorical outcomes for these variables (below vs within vs above the normal range) was compared using proportional odds multinomial logistic GLMM. Cox proportional hazard models were used to evaluate whether discontinuation of OMB over time was associated with age, sex, race, ethnicity, disease duration, or prior DMT category (high/low efficacy). The Friedman test was used to compare disability score measures across the three time points. Paired t-test or 1-way Wilcoxon signed-rank test was conducted to assess changes between time points, adjusted for multiple comparisons using the Holm – Bonferroni method. One-proportion Z-tests were conducted to assess whether the proportion during each time interval differed from zero. Statistical significance for all outcomes was defined as p  < 0.05.

Results

Baseline demographics

A total of 175 patients who started OMB were included in the analysis ( Figure 1 ). Baseline demographics and clinical characteristics of these patients within 12 months of starting OMB are summarized in Table 1 . The mean age of patients starting OMB was 44.9 years, the majority were female (73.7%) and White (81.1%) with a relapsing-remitting disease course (79.4%). Most patients had previously been exposed to prior DMTs (86.3%), with median two agents, which were most commonly moderate/low efficacy DMTs (56.3% of those previously on DMT). Amongst those who switched from a high efficacy DMT ( n  = 67), the most common agent was ocrelizumab (80.6%). Of the 56 patients who had most recently been treated with an anti-CD20 mAb (either ocrelizumab or rituximab), 38 were considered a switch therapy (started OMB within 9 months of last infusion) who were all on ocrelizumab previously. The primary reasons for anti-CD20 therapy switch were the following: 18 (47.4%) due to convenience factors, 7 (18.4%) due to wearing-off phenomenon, 6 (15.8%) due to intolerance, 5 (13.2%) due to symptom/disability progression, and 2 (5.3%) due to infusion-related reactions. In the prior 12 months, patients experienced mean 0.24 (SD 0.467) relapses. Discontinuation reasons for prior DMTs are shown in Figure 2 . Amongst those who discontinued prior DMT ( n  = 151), the most common reason was side effects (23.2%).

Study flowchart of inclusion/exclusion criteria.

Table 1. Baseline characteristics and demographics of patients prior to starting ofatumumab ( N  = 175). SD: standard deviation. IQR: interquartile range. RRMS: relapsing-remitting MS. CIS: clinically isolated syndrome. SPMS: secondary progressive MS. PPMS: primary progressive MS. PDDS: patient determined disease steps. Variable Statistical summary Age, years: mean (SD), range 44.9 (10.4), 21–72 Sex: female (%) 129 (73.7) Race: (%) White Black Multiracial/Multicultural Asian Unknown 142 (81.1) 22 (12.6) 4 (2.3) 1 (0.6) 6 (3.4) Ethnicity: (%) Hispanic Not Hispanic Unknown 8 (4.6) 161 (92.0) 6 (3.4) Disease duration, years: mean (SD), range 13.6 (9.6), 0–48 Most recent disease course: (%) RRMS/CIS SPMS PPMS 140 (80.0) 27 (15.4) 8 (4.6) PDDS: (%) 1 0 Normal 1 Mild disability 2 Moderate disability 3 Gait disability 4 Early cane 5 Late cane 6 Bilateral support 7 Wheelchair bound 23 (31.1) 11 (14.9) 8 (10.8) 13 (17.6) 5 (6.8) 2 (2.7) 9 (12.2) 3 (4.1) Comorbidities: (%) Hypertension Hyperlipidemia Type 2 diabetes mellitus 34 (19.4) 25 (14.3) 12 (6.9) DMT experience Naïve to DMT: (%) Number of prior DMTs: median [IQR] DMT switch to OMB: (%) Interval between prior DMT and OMB, months: median [IQR] Most recent prior DMT: (%)  High efficacy   ocrelizumab   natalizumab   rituximab   alemtuzumab  Medium/low efficacy   dimethyl fumarate   fingolimod   teriflunomide   glatiramer acetate   interferon beta   siponimod   ozanimod   monomethyl fumarate   diroximel fumarate   cladribine   cyclophosphamide 24 (13.7) 2 [1,4] 103 (58.9) 5.3 [1.0,12.5] 67 (38.3) 54 (30.9) 10 (5.7) 2 (1.1) 1 (0.6) 84 (48.0) 30 (17.1) 17 (9.7) 11 (6.3) 8 (4.6) 7 (4.0) 4 (2.3) 3 (1.7) 1 (0.6) 1 (0.6) 1 (0.6) 1 (0.6) a PDDS data at baseline were only available for 74 patients, which served as the denominator when calculating percentages.

Baseline characteristics and demographics of patients prior to starting ofatumumab ( N  = 175). SD: standard deviation. IQR: interquartile range. RRMS: relapsing-remitting MS. CIS: clinically isolated syndrome. SPMS: secondary progressive MS. PPMS: primary progressive MS. PDDS: patient determined disease steps.

a PDDS data at baseline were only available for 74 patients, which served as the denominator when calculating percentages.

Number of patients discontinuing disease-modifying therapy prior to ofatumumab stratified by the reason (plot scale representing absolute counts). Radiological activity was defined as interval new lesions on MRI compared to prior scan. Disability progression was defined as documentation by the treating neurologist. Wearing-off phenomenon was defined as recurrence of symptoms attributed to MS near the end of the dose interval. Side effects were based on adverse events that could be explained by drug pharmacology while intolerance was determined based on other complaints that may not have been related to drug but correlated temporally with ofatumumab use.

JCV, John Cunningham Virus antibody.

OMB persistence, tolerability, and safety

Over 12 months, the majority of patients (90.6%) remained on OMB. For those who discontinued treatment, the majority [ n  = 15 (88.2%)] discontinued OMB in the first 6-month window and 2 (11.8%) discontinued OMB in the second 6-month window. OMB discontinuation reasons for each 6-month period are summarized in Figure 3 .

Number of patients discontinuing ofatumumab stratified by reason during each time window (plot demonstrating overall cumulative incidence; plot scale representing absolute counts). Radiological activity was defined as interval new lesions on MRI compared to prior scan. Disability progression was defined as documentation by the treating neurologist. Side effects were based on adverse events that could be explained by drug pharmacology while intolerance was determined based on other complaints that may not have been related to drug but correlated temporally with ofatumumab use.

During the first 6 months, the most common reason for OMB discontinuation was drug-related tolerability issues [ n  = 8 (47.1%)], and both patients who discontinued OMB in the latter 6 months did so for financial reasons.

Systemic injection-related reactions were reported in less than half of patients during either time period: 62 (35.4%) patients in the first 6-month window, 10 (5.7%) patients in the second 6-month window, and cumulatively in 63 (36.0%) patients ( Table 2 ). Injection site reactions only occurred in 4 (2.3%) patients cumulatively over 12 months. A total of 17 (9.7%) patients reported missing any doses during the study period. The most commonly experienced systemic injection-related reactions in either time window were headache [ n  = 24 (38.7%) in the first 6-month window and n  = 5 (50.0%) in the second 6-month window] and fatigue [ n  = 15 (24.2%) in the first 6-month window and n  = 4 (40.0%) in the second 6-month window]. The incidence of these reactions decreased consistently with subsequent injections (supplementary Figure S1). No unexpected side effects were observed in our analysis with reference to previously reported safety data.

Table 2. Systemic injection-related reactions by patients during each time window. Numbers in each row are not mutually exclusive, and there may be overlap between categories in a single patient.   First 6 months ( N  = 175) Second 6 months ( N  = 175) Cumulative Interval ( N  = 175) Flu-Like Symptoms 51 (29.1%) 9 (5.1%) 52 (29.7%) Headache 24 (13.7%) 5 (2.9%) 25 (14.3%) Fatigue 15 (8.6%) 4 (2.3%) 17 (9.7%) Chills 12 (6.9%) 0 (0%) 12 (6.9%) Myalgias 10 (5.7%) 0 (0%) 10 (5.7%) Unspecified Flu-like 8 (4.6%) 2 (1.1%) 8 (4.6%) Fever 3 (1.7%) 0 (0%) 3 (1.7%) Rhinorrhea 1 (0.6%) 0 (0%) 1 (0.6%) GI Symptoms 6 (3.4%) 1 (0.6%) 7 (4.0%) Nausea 5 (2.9%) 0 (0%) 5 (2.9%) Abdominal Pain 1 (0.6%) 0 (0%) 1 (0.6%) Unspecified GI 0 (0%) 1 (0.6%) 1 (0.6%) Dermatological Symptoms 3 (1.7%) 0 (0%) 3 (1.7%) Flushed 2 (1.1%) 0 (0%) 2 (1.1%) Angioedema 1 (0.6%) 0 (0%) 1 (0.6%) Pruritus 1 (0.6%) 0 (0%) 1 (0.6%) Other Symptoms 7 (4.0%) 0 (0%) 7 (4.0%) Palpitations 2 (1.1%) 0 (0%) 2 (1.1%) Bladder Retention 1 (0.6%) 0 (0%) 1 (0.6%) Shakiness 1 (0.6%) 0 (0%) 1 (0.6%) Mood Changes 1 (0.6%) 0 (0%) 1 (0.6%) Leg Cramps 1 (0.6%) 0 (0%) 1 (0.6%) Light Headedness 1 (0.6%) 0 (0%) 1 (0.6%)

Systemic injection-related reactions by patients during each time window. Numbers in each row are not mutually exclusive, and there may be overlap between categories in a single patient.

Survival analysis for time to OMB discontinuation did not reveal any patient characteristics with a significant impact on the hazard of discontinuing treatment in both the univariate and multivariate analyses (supplementary Table S1).

Available results for measured IgG and IgM levels at baseline, the first 6-month window, and the second 6-month window are summarized in Table 3 . There were no statistically detectable differences across IgG at baseline and either the first or second 6-month windows. Although there were 15 (8.6%) patients at baseline, 7 (4.0%) patients at 6 months, and 7 (4.0%) patients at 12 months whose IgG levels were below the LLN, there were no significant differences in the proportion of patients with IgG values less than the LLN between time periods. Out of 15 patients with low IgG at baseline, 6 had a follow-up IgG available at either 6 or 12 months. Out of these six patients, four had normal IgG levels at follow-up and two continued to have low IgG. Although mean IgM values were lower across the follow-up periods versus baseline ( p  < 0.001), there were no significant differences in the proportions of patients with IgM values less than the LLN at baseline compared to the first or second 6-month windows. There were no significant differences in the prevalence of infections across patients with IgM or IgG values below the LLN compared to those with IgM or IgG values above the LLN respectively (supplementary Table S3). In the subset of patients who switched to OMB from other anti-CD20 mAbs, rituximab and ocrelizumab ( n  = 38), there were no significant differences across IgM or IgG values at baseline and either the first or second 6-month windows.

Table 3. Immunoglobulin values across different time periods for all patients on OMB and subset of patients who had switched from other anti-CD20 therapies. For each variable, the number of subjects with available information is listed. SD: standard deviation. LLN: lower limit of normal. All percentages were calculated out of patients with available data.   Baseline 6 months 12 months p-value (Overall)*   All patients IgG, mg/dL N = 134 N = 57 N = 62    Mean (SD) 945 (221) 907 (210) 924 (227) 0.871  Range {547, 1750} {500, 1440} {586, 1780} Abnormal IgG (%) N = 134 N = 57 N = 62    IgG below LLN 15 (11.1) 7 (12.3) 7 (11.3) 0.892 IgM, mg/dL N = 117 N = 54 N = 61    Mean (SD) 94.2 (54.4) 85.0 (57.9) 78.3 (62.9) <0.001  Range {13.0, 283} {16.0, 318} {9.00, 463} Abnormal IgM (%) N = 117 N = 54 N = 61    IgM below LLN 15 (12.8) 10 (18.5) 12 (19.7) 0.411   Subset who switched from other anti-CD20 therapies IgG, mg/dL N = 29 N = 12 N = 10    Mean (SD) 890 (199) 895 (109) 887 (147) 0.930  Range {567, 1390} {751, 1080} {694, 1090} IgM, mg/dL N = 24 N = 12 N = 10    Mean (SD) 58.5 (29.7) 60.6 (32.4) 53.3 (22.4) 0.860  Range {18.0, 141} {16.0, 131} {16.0, 90.0} *Overall p-value represents change across the measured time points.

Immunoglobulin values across different time periods for all patients on OMB and subset of patients who had switched from other anti-CD20 therapies. For each variable, the number of subjects with available information is listed. SD: standard deviation. LLN: lower limit of normal. All percentages were calculated out of patients with available data.

*Overall p-value represents change across the measured time points.

Clinical and radiological disease activity and patient reported outcomes

Clinical and radiological disease activity outcomes for the patients with available information are summarized in Table 4 . There was a significant reduction in the number of patients experiencing clinical relapses over the study period [baseline: n  = 39 (22.3%); first 6-month window: n  = 1 (0.6%); second 6-month window: n  = 0; cumulative: n  = 1 (0.6%); p  < 0.001]. There was also a significant reduction in the number of patients with new intracranial T2 lesions [baseline: n  = 54 (34.2%); cumulative: n  = 22 (17.5%), p  < 0.001] and GdE lesions [baseline: n  = 27 (15.4%); cumulative: n  = 2 (1.1%), p  < 0.001]. The single patient who experienced a clinical relapse during the 12-month study period was a 49-year-old woman with relapsing-remitting MS who had previously been exposed to four other DMTs, most recently ozanimod approximately 2 months prior to starting OMB. She reported symptoms consistent with a clinical relapse approximately 4 months after starting OMB and was treated with high-dose steroids. Follow-up MRI after approximately 2 months did not reveal any evidence of radiological disease activity, and she continued OMB.

Table 4. Clinical and radiological disease activity at baseline, each 6-month period, and cumulative over 12 months when available. For each variable, the number of subjects with available information is listed. GdE: gadolinium enhancing. DNC: unable to calculate due to presence of 0 in a category. All percentages were calculated out of patients with available data.   Baseline During first 6 months During second 6 months Cumulative interval p-value (Overall)* p-value (Baseline vs Cumulative)* Clinical disease activity Number of Relapses (%) N = 175 N = 161 N = 125 N = 161    0 136 (77.7) 160 (99.4) 125 (100) 160 (99.4) <0.001 <0.001  1 36 (20.6) 1 (0.6) 0 (0) 1 (0.6)  2 3 (1.7) 0 (0) 0 (0) 0 (0)  Any 39 (22.3) 1 (0.6) 0 (0) 1 (0.6) <0.001 <0.001 Radiological disease activity Number of New Brain T2 Lesions (%) N = 158 N = 87 N = 68 N = 126    0 104 (65.8) 74 (85.1) 59 (86.8) 104 (82.5) <0.001 <0.001  1 16 (10.1) 10 (11.5) 5 (7.4) 15 (11.9)  2 14 (8.9) 2 (2.3) 1 (1.5) 3 (2.4)  3 2 (1.3) 0 (0) 0 (0) 0 (0)  >3 22 (13.9) 1 (1.1) 3 (4.4) 4 (3.2)  Any 54 (34.2) 13 (14.9) 9 (13.2) 22 (17.5) <0.001 <0.001 Number of New Brain GdE Lesions N = 160 N = 86 N = 66 N = 124    0 133 (83.1) 84 (97.7) 66 (100) 122 (98.4) <0.001 <0.001  1 12 (7.5) 2 (2.3) 0 (0) 2 (1.6)  2 6 (3.8) 0 (0) 0 (0) 0 (0)  3 4 (2.5) 0 (0) 0 (0) 0 (0)  >3 5 (3.1) 0 (0) 0 (0) 0 (0)  Any 27 (16.9) 2 (2.3) 0 (0) 2 (1.6) DNC <0.001 Disability status PDDS N = 74 N = 60 N = 54    0 Normal 23 (31.1) 14 (23.3) 18 (33.3)   0.104    1 Mild disability 11 (14.9) 14 (23.3) 12 (22.2)  2 Moderate disability 8 (10.8) 6 (10.0) 2 (3.7)  3 Gait disability 13 (17.6) 6 (10.0) 7 (13.0)  4 Early cane 5 (6.8) 8 (13.3) 4 (7.4)  5 Late cane 2 (2.7) 2 (3.3) 1 (1.9)  6 Bilateral support 9 (12.2) 6 (10.0) 3 (5.6)  7 Wheelchair bound 3 (4.1) 4 (6.7) 7 (13.0) *Overall p-value represents change across the measured time points while baseline vs. cumulative p-value provides pairwise comparison.

Clinical and radiological disease activity at baseline, each 6-month period, and cumulative over 12 months when available. For each variable, the number of subjects with available information is listed. GdE: gadolinium enhancing. DNC: unable to calculate due to presence of 0 in a category. All percentages were calculated out of patients with available data.

*Overall p-value represents change across the measured time points while baseline vs. cumulative p-value provides pairwise comparison.

Of the subset of patients who had available data for review for each time period, 73 (83.9%; n  = 87, p  < 0.001) patients during the first 6-month window, 52 (85.2%; n  = 61, p  < 0.001) patients during the second 6-month window, and 52 (85.2%; n  = 61, p  < 0.001) patients cumulatively from baseline to 12 months met NEDA-2 (supplementary Table S2). Data for the NEDA-3 definition were more limited at all three time points (summarized in supplementary Table S2). We did not detect a statistically significant change across the mean values for any of the Neuro-QoL measures (supplementary Table S2).

Disease progression

Only a limited number of patients had available PDDS measurements (baseline, n  = 74; first 6 months, n  = 60; second 6 months, n  = 54) ( Table 2 and supplementary Table S2). The most frequently reported PDDS scores were normal (31.1% at baseline, 23.3% at 6 months, and 33.3% at 12 months), mild disability (14.9% at baseline, 23.3% at 6 months, and 22.2% at 12 months), and gait disability (17.6% at baseline, 10.0% at 6 months, and 13.0% at 12 months). There were no significant differences in PDDS change across the study time points for patients who had all three time-period PDDS scores available ( p  = 0.104). Although only a limited number of patients had available results ( n  = 10–50), there were no significant differences across quantitative values of neuro-performance testing from baseline to 12 months (supplementary table S2). Analysis for categorical data classified based on ≥ 20% worsening in each outcome for MDT and WST is also presented in supplementary table S2, although limited by small sample sizes.

Discussion

To date, there is limited real-world evidence reporting on OMB effectiveness, persistence, tolerability, and safety in clinical practice in the United States. Reviewing a recently published observational study of 127 patients in Germany treated with OMB who were followed for a mean duration of 9.8 months, our patient population had superior OMB tolerability (77% with AEs in the German study during initial application vs. 36% with AE cumulatively in our study) [ 16 ]. Although MRI data were not collected in the German study, similar to our investigation, only one patient, who had previously been treated with four prior DMTs [glatiramer acetate, fingolimod (discontinued due to breakthrough disease), teriflunomide, ozanimod (discontinued due to AEs)], experienced a clinical relapse during the observed period. Additionally, there were some differences in patient characteristics between the two studies. The cohort in our study was slightly older (mean age 44.9 vs. 42.2 years old) and with longer disease duration (mean duration 13.6 vs. 9.1 years).

Observational real-world data complement evidence generation from RCTs, allowing evaluation in a more representative patient population [ 17 , 18 ]. In our study, OMB demonstrated good clinical and radiographic effectiveness and was well tolerated with excellent patient compliance and persistence. AEs were reported in fewer than half of patients with the most common being flu-like injection-related reactions. AEs subsided over time with continued treatment. There were no significant reductions in IgG and IgM levels across the evaluated time points in our study, and there was no clear association between immunoglobulin levels below the LLN and infections. Although a significant reduction in immunoglobulin levels would not be expected within the first 12 months of treatment with OMB, early 12-month safety data are useful to report for facilitating DMT decision-making at the bedside, especially when observing those who switched from one anti-CD20 mAb to another treatment in the same class. No significant predictors were identified for DMT discontinuation.

There was a notable reduction in the proportion of patients experiencing clinical relapses and radiological disease activity during the first 12 months of OMB, with only one patient discontinuing OMB due to new MRI lesions. No patients discontinued OMB due to clinical relapses. We provided MRI data at 6 months in addition to 12 months, in part for the purpose of providing a re-baseline scan while on a higher efficacy therapy to better report on short-term radiographic stability. Patient reported Neuro-QoL assessing several domains including physical symptoms, sleep and fatigue quality, mental symptoms, cognitive health, and social health remained unchanged throughout the observed period. Although limited by small sample sizes, disability levels (measured via PDDS) did not change significantly throughout the study.

The ARR of OMB in the phase 3 ASCLEPIOS I and II trials was low (0.10–0.11) [ 5 ]. Although we were unable to formally compare across investigations, our 12-month study similarly demonstrated a low ARR. In the RCTs, 82.2% − 85.0% of patients receiving OMB demonstrated AEs, while this cumulative number was about 36% in our study over the 12-month period [ 5 ]. Similarly, in the extension study of 1,969 patients on OMB enrolled in ASCELEPIOS I, ASCELEPIOS II, APLIOS, and APOLITOS, approximately 83.8% had at least one adverse reaction, and IgG levels remained stable [ 6 ]. Similar to our results, mean IgM levels decreased but mostly remained above the LLN. AEs leading to treatment discontinuation were reported as 5.6%–5.8% of patients in the phase 3 trials. Similarly, 11 (6.2%) patients in our study discontinued OMB due to AEs and DMT tolerability issues [ 5 ]. It is important to note that there are differences in AE reporting and monitoring due to study design distinctions between RCTs and observational studies.

Although our effectiveness, persistence, tolerability, and safety results were generally similar to phase 3 trial and extension data, there are several unique features in our patient population that lend complementary data to a more generalized population. Such characteristics include an older patient population (mean age 44.9 years in our study vs. 38.9/38.0 years in the pivotal RCTs) and longer disease duration (mean 13.6 years in our study vs. 8.4/8.2 years in the pivotal RCTs) [ 5 ]. Our study also included a higher proportion of patients who had previously been exposed to DMTs compared to the trial populations (86.3% in our study vs. 58.9%/59.5% in the RCTs). In our study, there was a lower number of baseline relapses within 12 months of starting OMB (0.24) vs. 1.2–1.3 relapses in the 12 months prior to OMB in the RCTs [ 5 ]. These results highlight that OMB can be used effectively and safely in a broader patient population, specifically those who are older with a longer disease course at baseline and previously exposed to a higher number of DMTs pre-OMB.

Some limitations of our study deserve mention. Owing to the inherent nature of retrospective observational studies, there were missing data, especially for patient-reported and disability measures, due to incomplete patient follow-up and data acquisition. In this context, interpretation of these results should be made with caution. We attempted to mitigate some of these limitations by allowing a time-window of ±3 months around each time-point and performing intention-to-treat analyses. Further, all statistical tests were appropriately designed for variable sample sizes to allow appropriate inference. Another limitation of the study was inconsistency in follow-up that can result in several biases (e.g., recall and reporting), potentially leading to over- or under-estimation of relapses, patient reported outcomes, and AEs. Our study is also limited by a relatively short follow-up period and relatively small sample size, limiting our ability to evaluate outcomes such as disability and quantitative MRI measures, which are better evaluated over the long term. Longitudinal MRI data will be useful to verify the durability of radiographic stability with OMB that was observed in our study. In this context, continued data collection and analysis is planned by the investigators, which will allow for evaluation of longer-term effectiveness and safety of OMB in a larger cohort. Nevertheless, we believe early 12-month data are relevant for clinicians and patients to inform DMT decision-making at the bedside. Reporting on early effectiveness, tolerability, and safety, especially when switching DMTs, is important to guide clinical practice.

Conclusions

The results of this real-world study demonstrated that OMB has good effectiveness, tolerability, and safety and excellent persistence in clinical practice by 12-month follow-up. Although we are unable to base any formal conclusions on comparative effectiveness with the pivotal RCTs and extension studies, our findings in an older and more DMT-experienced population were reassuringly similar.

Supplementary Material

Supplemental Material

Funding Statement

The work was supported by the Novartis Pharmaceuticals Corporation.

Article highlights

This ofatumumab treated cohort was older and more DMT experienced than in RCTs.

Ofatumumab demonstrated excellent persistence and good tolerability over 12 months.

Over 90% of patients treated with OMB remained on it over 12 months.

The most common reason for stopping OMB was medication intolerance.

Systemic injection-related reactions were observed in <50% of patients.

The incidence of systemic injection-related reactions decreased with subsequent injections.

Patients treated with ofatumumab had low disease activity over 12 months.

Ig mostly remained within normal range, and low values were not associated with infections.

Author contribution

Moein Amin, Dan Michael Pineda, Brandon Moss, Devon S. Conway, and Carrie M. Hersh were responsible for study conception, design, data collection, drafting, and revision of the manuscript.

Tucker Harvey was responsible for study design, statistical analysis, drafting, and revision of the manuscript.

Ming-Hui, Tai, Qiujun Shao, Brandon Brown, Abhijit Gadkari were responsible for study conception and revision of the manuscript.

Disclosure statement

Data collection and statistical analysis were performed by the study team at the Cleveland Clinic.

Moein Amin has received Novartis fellowship award NGC44741.

Tucker Harvey and Dan Michael Pineda have no disclosures.

Brandon Moss has received research support paid to his institution from Novartis and Genentech. He has received consulting fees from Biogen. He has an ownership interest in Pfizer.

Devon Conway has received research support paid to his institution from Novartis Pharmaceuticals, EMD Serono, Biogen, and Horizon Therapeutics. He has received speaking fees from Biogen and consulting fees from Novartis.

Carrie M. Hersh has received speaking, consulting, and advisory board fees from Genentech, Genzyme, Biogen, Novartis, EMD-Serono, Bristol Myers Squibb, TG Therapeutics, Horizon Therapeutics, and Alexion. She has received research support paid to her institution by Biogen, Novartis, Bristol Myers Squibb, Patient-Centered Outcomes Research Institute (PCORI) and NIH – NINDS 1U01NS111678-01A1 sub-award.

Ming-Hui, Tai, Qiujun Shao, Brandon Brown, Abhijit Gadkari are employees of Novartis Pharmaceuticals Corporation.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval (Cleveland Clinic institutional review board (IRB). Study approval number: IRB 21–1251) and/or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Financial disclosure

This study was funded by Novartis Pharmaceuticals Corporation. All data collection and statistical analyses were conducted by Cleveland Clinic affiliated authors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17582024.2025.2452150

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

• Clinical trial evaluating the safety of ofatumumab.

Associated Data

Supplementary Materials

Supplemental Material