Abstract
Background and Objectives
Race and ethnicity may influence the efficacy of disease-modifying therapies in patients with multiple sclerosis (MS). Incidence of MS in ethnically diverse groups may be higher; however, these populations are under-represented in MS trials. This post hoc analysis compared the proportion of patients achieving 3-parameter no evidence of disease activity (NEDA-3) with ofatumumab vs teriflunomide in participants with relapsing MS (RMS) enrolled in the ASCLEPIOS I/II trials by race/ethnicity subgroup.
Methods
ASCLEPIOS I/II were identical, double-blind, double-dummy, active-controlled, multicenter, phase 3 trials. Participants were randomized (1:1) to receive ofatumumab 20 mg every 4 weeks or teriflunomide 14 mg once daily for up to 30 months. Pooled data were used to determine the efficacy/safety of ofatumumab vs teriflunomide in participants who self-identified as non-Hispanic Black, non-Hispanic Asian, Hispanic/Latino, or non-Hispanic White. Participants who did not self-identify into one of these groups were classified as other/unknown.
Results
Of the 1,882 participants, 64 (3.4%) self-identified as non-Hispanic Black, 71 (3.8%) as non-Hispanic Asian, 145 (7.7%) as Hispanic/Latino, and 1,538 (81.7%) as non-Hispanic White. Baseline participant demographics/characteristics were largely balanced across subgroups, aside from minor variations in sex, disease duration, and MRI lesions. From months 0 to 24, the proportion of ofatumumab vs teriflunomide-treated patients achieving NEDA-3 (odds ratio [95% CI]) was as follows: non-Hispanic Black, 33.3% vs 3.4% (15.9 [1.67–151.71; p = 0.0162]); non-Hispanic Asian, 42.9% vs 21.9% (3.18 [0.95–10.59; p = 0.06]); Hispanic/Latino, 36.6% vs 18.6% (3.21 [1.32–7.79; p = 0.01]); and non-Hispanic White, 37.4% vs 16.6% (3.57 [2.73–4.67; p < 0.0001]). Rates of AEs were generally similar between treatment groups and across race/ethnicity subgroups; no new or unexpected safety signals were identified.
Discussion
Ofatumumab was associated with greater proportions of NEDA-3 achievement than teriflunomide across race/ethnicity subgroups in the ASCLEPIOS trials. Within each treatment group, the proportion of patients achieving NEDA-3 from months 0 to 24 was similar across the subgroups and overall pooled population. Both ofatumumab and teriflunomide were well tolerated. Future MS trials should include ethnically diverse groups to better inform treatment decisions and improve real-world patient outcomes.
Trial Registration Information
ClinicalTrials.gov: NCT02792218 (clinicaltrials.gov/ct2/show/NCT02792218), NCT02792231 (clinicaltrials.gov/ct2/show/NCT02792231). Submission date: June 2, 2016. First enrollment: August 26, 2016.
Classification of Evidence
This study provides Class II evidence that among patients aged 18–55 years with RMS, the improvement in NEDA-3 with ofatumumab was comparably better than with teriflunomide among patients self-identified as non-Hispanic Black, non-Hispanic Asian, non-Hispanic White, Hispanic/Latino, and other/unknown.
Introduction
Multiple sclerosis (MS) is an inflammatory disorder of the CNS characterized by demyelination and axonal destruction, leading to neurologic dysfunction and progressively worsening disability.1 MS prevalence worldwide has been estimated at ∼2.8 million individuals, including more than 700,000 people in the United States.2,3
The risk of developing MS is multifactorial. Genetic factors include the presence of specific risk HLA alleles, which occur at a higher rate in individuals of European ancestry.4 Environmental factors, such as sun exposure/vitamin D levels, Epstein-Barr virus infection, and adolescent obesity, may trigger MS in genetically predisposed individuals.5 Social determinants of health (SDoH), such as living and work environment, may increase or decrease MS risk.6 The effect of genetic, environmental, and social differences related to race and ethnicity upon MS disease severity and progression is less clear, but may influence the efficacy and tolerability of disease-modifying therapies (DMTs).7-11
Clinical outcomes can differ between racial/ethnic subgroups.12-15 Differential B-cell responses have been observed between Black and African American and White populations.12-15 Reports of a higher immunoglobulin G (IgG) index in African American people with MS than in White populations may indicate a more active immune response.12 Similarly, people with MS who identified as Black, African American, or Latin American were found to have increased plasmablasts, possibly the result of heightened B-cell activity.14 Black and African American patients with neurologic diseases may have faster B-cell repletion after anti-CD20 infusion than White patients, indicating potential differences in B-cell dynamics between the 2 populations.13 Further research is needed to better understand potential implications of these differences. Clinical trials, which can provide equitable care across geographic locations, offer opportunities to improve our understanding of the relationship between SDoH, access to care, and clinical outcomes.
Ofatumumab is a fully human anti-CD20 monoclonal antibody that depletes CD20+ B cells and CD20+ T cells in the blood and lymphoid tissues through complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.16 Ofatumumab has regulatory approval for the treatment of adults with relapsing MS (RMS) in multiple countries.17,18 In the randomized, double-blind, phase 3 ASCLEPIOS I and II trials, monthly subcutaneous ofatumumab had greater efficacy vs oral once-daily teriflunomide in participants with RMS.19 In addition, 3-parameter no evidence of disease activity (NEDA-3) was previously assessed in recently diagnosed, treatment-naïve participants from the ASCLEPIOS I and II trials; the proportions of ofatumumab-treated participants achieving NEDA-3 were 47.0%, 92.1%, and 44.6% in year 1, year 2, and from baseline through year 2, respectively.20 NEDA-3 is an important end point in MS because it provides a comprehensive composite assessment of disease activity and progression.21
Ethnically diverse groups, including Black and African American, Hispanic and Latino, and Asian individuals, are consistently under-represented in clinical trials,22,23 limiting the data available to inform clinical decision making for patients in these groups. To better understand the efficacy and safety of ofatumumab in diverse populations, this post hoc analysis of the phase 3 ASCLEPIOS I and II trials compared ofatumumab vs teriflunomide in race and ethnicity subgroups of participants with RMS. The primary research questions being addressed here are (1) can the overall efficacy and safety outcomes reported from the ASCLEPIOS I and II trials be generalized to its race and ethnicity subpopulations, and (2) are ofatumumab and teriflunomide similarly efficacious and well tolerated across different race and ethnicity groups?
Methods
Trial Design: ASCLEPIOS I and II
The ASCLEPIOS I and II trials were identical, randomized, double-blind, double-dummy, active-controlled, multicenter, phase 3 trials conducted concurrently that investigated the efficacy and safety of ofatumumab and teriflunomide in adult participants aged 18–55 years with RMS.19 Detailed methodology and primary results have been previously published.19 In short, participants were randomized (1:1) to receive ofatumumab 20 mg subcutaneously every 4 weeks (after 20-mg loading doses at days 1, 7, and 14) or teriflunomide 14 mg orally once daily for up to 30 months.19 The ASCLEPIOS trials were not designed to reach a target diversity representative of the background population.
Race and Ethnicity
Participants self-identified their race as Black or African American, Asian, and White. Participants also reported their ethnicity as Hispanic or Latino or not Hispanic or Latino. Participants who did not self-identify as any of the aforementioned subgroups were categorized as other/unknown. The Hispanic/Latino subgroup included those who identified as Black Hispanic/Latino or White Hispanic/Latino. To ensure that race and ethnicity subgroups were mutually exclusive, participants who identified as Hispanic/Latino were not included in the racial subgroups. Thus, subgroups included in this analysis were non-Hispanic Black, non-Hispanic Asian, Hispanic/Latino, non-Hispanic White, and other/unknown.
Outcomes
These post hoc analyses used pooled data from the ASCLEPIOS I and II trials to determine potential differences in efficacy and tolerability associated with ofatumumab and teriflunomide treatment across racial and ethnic subgroups. Clinical end points included treatment efficacy as measured by NEDA-3 (achievement of NEDA-3 and individual NEDA-3 components) and annualized relapse rate (ARR), adverse events (AEs), serious AEs (SAEs), and AEs leading to drug discontinuation. Serum Ig levels were also obtained. NEDA-3 was defined as no confirmed MS relapse, no gadolinium-enhancing (Gd+) T1 lesions or new or enlarging T2 lesions, and no 6-month confirmed disease worsening (CDW; based on the Expanded Disability Status Scale [EDSS]).24 NEDA-3 was assessed over months 0–12, 12–24, and 0–24 (the 2-year study period). Efficacy subanalyses for study participants enrolled in the United States were conducted to determine whether there were any differences in therapeutic benefit for individuals within the US health care delivery system (further details are presented in eAppendix 1).
Statistical Analyses
All analyses were conducted using SAS 9.4 or higher (Cary, NC). The proportion of participants achieving NEDA-3 was summarized with odds ratios (ORs) and associated 95% CIs comparing ofatumumab vs teriflunomide and was analyzed by a logistic regression model including study (ASCLEPIOS I or II), treatment, region, and race/ethnicity as factors and age, baseline EDSS, and number of Gd+ T1 lesions at baseline as covariates. The models also tested for an interaction between treatment and race/ethnicity. The models were run for the modified full analysis set, defined as all participants in the full analysis set according to the intent-to-treat principle, but participants who discontinued treatment prematurely for reasons other than “lack of efficacy” or “death” and who had NEDA-3 before early discontinuation were excluded. NEDA-3 outcomes were compared between treatment groups (within the non-Hispanic Black, non-Hispanic Asian, Hispanic/Latino, non-Hispanic White, and other/unknown subgroups and the overall pooled population) using the Fisher exact test because of small sample sizes. No adjustments were made for multiple comparisons.
ARR was estimated using a negative binomial regression model with the cumulative number of confirmed relapses over the study period as the response variable and the natural log of time in the study (years) as an offset variable. Models were adjusted for study, treatment, and region as factors, and number of relapses in the year before the study, baseline EDSS, baseline number of Gd+ lesions, and patient's age at baseline as continuous covariates. The model tested for an interaction between treatment and race/ethnicity.
Rates of AEs are reported using the safety data set, defined as all participants who received ≥1 dose of study medication. Safety analyses include data up to and including the safety cutoff of 100 days after permanent study drug discontinuation.
The subgroup analyses were conducted post hoc, and no corrections were made for multiple comparisons. While p-values are reported (with p < 0.05 considered statistically significant), they are subject to the limitations of post hoc analyses.
Standard Protocol Approvals, Registrations, and Patient Consents
Both trials were approved by the relevant institutional review board or ethics committee at each participating site and conducted according to the provisions of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Both trials were registered on ClinicalTrials.gov (ASCLEPIOS I [NCT02792218]; ASCLEPIOS II [NCT02792231]). All participants provided written informed consent.
Data Availability
The ASCLEPIOS I and II trial data are available on reasonable request, provided that it is in line with current ethical and intellectual property requirements surrounding the use of data. Requests should be directed through ClinicalStudyDataRequest.com.
Results
Study Population
Complete details on the baseline characteristics of the overall population have been previously reported.19 Of the 1,882 participants in the pooled ASCLEPIOS population, 946 and 936 received ofatumumab and teriflunomide, respectively. Of the participants who received ofatumumab, 26 (2.7%) self-identified as non-Hispanic Black, 36 (3.8%) as non-Hispanic Asian, 76 (8.0%) as Hispanic/Latino, and 766 (81.0%) as non-Hispanic White; 42 (4.4%) participants were included in the other/unknown subgroup. Of those who received teriflunomide, 38 (4.1%) self-identified as non-Hispanic Black, 35 (3.7%) as non-Hispanic Asian, 69 (7.4%) as Hispanic/Latino, and 772 (82.5%) as non-Hispanic White; 22 (2.4%) participants were included in the other/unknown subgroup. Of the pooled ASCLEPIOS population, 393 (20.9%) participants were enrolled in the United States (eAppendix 1). Additional US participant demographics are presented in eTable 1.
The baseline participant demographics and characteristics were largely balanced across the race and ethnicity subgroups (Table 1). Compared with the other subgroups and the overall study population, non-Hispanic Black participants were more likely to be female, and non-Hispanic Asian participants in the teriflunomide group had a longer mean MS duration since diagnosis. In addition, Hispanic/Latino participants in the ofatumumab group had the highest mean number of Gd+ T1 lesions at screening.
Table 1.
Participant Characteristics and Demographics in Race/Ethnicity Subgroups From the ASCLEPIOS I and II Trials
| Characteristic | Non-Hispanic Black | Non-Hispanic Asian | Hispanic/Latino | Non-Hispanic White | Other/unknown | Overall | ||||||
| OMB (n = 26) | TER (n = 38) | OMB (n = 36) | TER (n = 35) | OMB (n = 76) | TER (n = 69) | OMB (n = 766) | TER (n = 772) | OMB (n = 42) | TER (n = 22) | OMB (n = 946) | TER (n = 936) | |
| Age, y | 39.6 (9.9) | 36.9 (8.7) | 35.4 (9.8) | 36.7 (8.2) | 37.5 (9.6) | 37.7 (9.0) | 38.5 (9.0) | 38.2 (9.3) | 39.7 (7.9) | 34.5 (8.9) | 38.4 (9.0) | 38.0 (9.2) |
| Female, n (%) | 19 (73.1) | 31 (81.6) | 23 (63.9) | 22 (62.9) | 50 (65.8) | 46 (66.7) | 516 (67.4) | 523 (67.7) | 29 (69.0) | 14 (63.6) | 637 (67.3) | 636 (67.9) |
| Race, n (%) | ||||||||||||
| Black/African American | 26 (100.0) | 38 (100.0) | 0 | 0 | 2 (2.6) | 0 | 0 | 0 | 0 | 0 | 28 (3.0) | 38 (4.1) |
| Asian | 0 | 0 | 36 (100.0) | 35 (100.0) | 0 | 0 | 0 | 0 | 0 | 0 | 36 (3.8) | 35 (3.7) |
| White | 0 | 0 | 0 | 0 | 63 (82.9) | 57 (82.6) | 766 (100.0) | 772 (100.0) | 0 | 0 | 829 (87.6) | 829 (88.6) |
| Other | 0 | 0 | 0 | 0 | 11 (14.5) | 11 (15.9) | 0 | 0 | 31 (73.8) | 17 (77.3) | 42 (4.4) | 28 (3.0) |
| Unknown | 0 | 0 | 0 | 0 | 0 | 1 (1.4) | 0 | 0 | 11 (26.2) | 5 (22.7) | 11 (1.2) | 6 (0.6) |
| MS duration since diagnosis, y | 5.7 (6.5) | 5.3 (5.3) | 5.6 (4.6) | 7.4 (6.7) | 5.9 (6.0) | 5.2 (5.0) | 5.7 (6.4) | 5.6 (6.2) | 4.2 (4.6) | 3.0 (3.1) | 5.7 (6.2) | 5.6 (6.1) |
| No. of relapses in past 12 mo | 1.1 (0.7) | 1.1 (0.5) | 1.1 (0.4) | 1.2 (0.8) | 1.2 (0.6) | 1.2 (0.6) | 1.3 (0.7) | 1.3 (0.7) | 1.2 (0.6) | 1.3 (0.5) | 1.3 (0.7) | 1.3 (0.7) |
| EDSS score | 2.9 (1.5) | 3.1 (1.3) | 3.3 (1.3) | 3.3 (1.5) | 3.1 (1.3) | 2.9 (1.2) | 2.9 (1.4) | 2.9 (1.4) | 2.8 (1.2) | 2.6 (1.1) | 2.9 (1.4) | 2.9 (1.4) |
| T2 lesion volume, cm3 | 17.2 (14.4) | 13.8 (13.0) | 18.6 (13.5) | 15.4 (14.3) | 16.4 (16.2) | 14.6 (15.6) | 13.1 (13.5) | 12.1 (13.6) | 14.7 (14.1) | 14.0 (15.4) | 13.7 (13.8) | 12.6 (13.8) |
| Free of Gd+ T1 lesions, n (%) | 15 (57.7) | 22 (57.9) | 19 (52.8) | 23 (65.7) | 42 (55.3) | 46 (66.7) | 463 (60.4) | 482 (62.4) | 22 (52.4) | 11 (50.0) | 561 (59.3) | 584 (62.4) |
| No. of Gd+ T1 lesions | 2.0 (3.8) | 1.3 (2.3) | 1.9 (4.1) | 1.1 (2.4) | 3.0 (6.1) | 1.2 (3.0) | 1.5 (4.5) | 1.3 (3.5) | 1.3 (2.3) | 3.0 (5.2) | 1.7 (4.5) | 1.3 (3.4) |
Abbreviations: EDSS = Expanded Disability Status Scale; Gd+ = gadolinium-enhancing; MS = multiple sclerosis; OMB = ofatumumab; TER = teriflunomide.
Data are shown as mean (SD) or n (%).
Achievement of Overall NEDA-3
From months 0 to 24, ofatumumab was associated with an increased likelihood of NEDA-3 achievement compared with teriflunomide that was statistically significant for participants in the non-Hispanic Black, Hispanic/Latino, and non-Hispanic White subgroups (p-value for interactions was 0.607; Figure 1). These subgroups also saw statistically significantly increased odds of achieving NEDA-3 in months 0–12 and 12–24 (p-values for interactions were 0.308 and 0.968, respectively). For ofatumumab-treated non-Hispanic Asian participants, the odds of achieving NEDA-3 were statistically significant only for months 12–24. Across the race and ethnicity subgroups, NEDA-3 was achieved by similar proportions of participants treated with ofatumumab (Table 2). The proportion of teriflunomide-treated participants achieving NEDA-3 was also fairly consistent across subgroups, with the exception of comparatively lower achievement observed in the non-Hispanic Black subgroup. Across all time periods, participants treated with ofatumumab in the non-Hispanic Black subgroup demonstrated the greatest odds of achieving NEDA-3, with ORs ranging from 8.88 to 15.9. The proportion of US participants treated with ofatumumab who achieved NEDA-3 over the 2-year treatment period was consistent across the race and ethnicity subgroups (eTable 2). All interactions between treatment and race/ethnicity did not reach statistical significance.
Figure 1. Achievement of NEDA-3 in Race/Ethnicity Subgroups From the ASCLEPIOS I and II Trials.
Months 0–24 (A), 0–12 (B), and 12–24 (C). N′ represents the number of participants with evaluable NEDA-3 data. NEDA-3 = 3-parameter no evidence of disease activity; OR = odds ratio.
Table 2.
Proportion of Participants Achieving Individual NEDA-3 Components From the ASCLEPIOS I and II Trials
| NEDA-3 component | Non-Hispanic Black | Non-Hispanic Asian | Hispanic/Latino | Non-Hispanic White | Other/unknown | Overall | ||||||||||||
| OMB (n = 26) m/M (%) |
TER (n = 38) m/M (%) |
p Value | OMB (n = 36) m/M (%) |
TER (n = 35) m/M (%) |
p Value | OMB (n = 76) m/M (%) |
TER (n = 69) m/M (%) |
p Value | OMB (n = 766) m/M (%) |
TER (n = 772) m/M (%) |
p Value | OMB (n = 42) m/M (%) |
TER (n = 22) m/M (%) |
p Value | OMB (n = 946) m/M (%) |
TER (n = 936) m/M (%) |
p Value | |
| Months 0–24: proportion of participants with: | ||||||||||||||||||
| No confirmed relapses | 18/21 (85.7) | 19/29 (65.5) | 0.1906 | 23/28 (82.1) | 26/32 (81.3) | 1.0000 | 63/71 (88.7) | 47/59 (79.7) | 0.2218 | 555/687 (80.8) | 485/715 (67.8) | <0.0001 | 31/36 (86.1) | 13/20 (65.0) | 0.0918 | 690/843 (81.9) | 590/855 (69.0) | <0.0001 |
| No Gd+ lesions | 21/21 (100.0) | 19/29 (65.5) | 0.0028 | 28/28 (100.0) | 21/32 (65.6) | 0.0004 | 69/71 (97.2) | 41/59 (69.5) | <0.0001 | 670/687 (97.5) | 490/715 (68.5) | <0.0001 | 35/36 (97.2) | 14/20 (70.0) | 0.0064 | 823/843 (97.6) | 585/855 (68.4) | <0.0001 |
| No new or enlarging T2 lesions | 11/21 (52.4) | 6/29 (20.7) | 0.0334 | 16/28 (57.1) | 10/32 (31.3) | 0.0673 | 34/71 (47.9) | 18/59 (30.5) | 0.0498 | 358/687 (52.1) | 204/715 (28.5) | <0.0001 | 18/36 (50.0) | 8/20 (40.0) | 0.5796 | 437/843 (51.8) | 246/855 (28.8) | <0.0001 |
| No lesion activitya | 11/21 (52.4) | 6/29 (20.7) | 0.0334 | 16/28 (57.1) | 9/32 (28.1) | 0.0355 | 34/71 (47.9) | 18/59 (30.5) | 0.0498 | 356/687 (51.8) | 204/715 (28.5) | <0.0001 | 17/36 (47.2) | 8/20 (40.0) | 0.7798 | 434/843 (51.5) | 245/855 (28.7) | <0.0001 |
| No 6-mo CDW | 17/21 (81.0) | 24/29 (82.8) | 1.0000 | 24/28 (85.7) | 28/32 (87.5) | 1.0000 | 62/71 (87.3) | 47/59 (79.7) | 0.3386 | 614/687 (89.4) | 626/715 (87.6) | 0.3161 | 31/36 (86.1) | 17/20 (85.0) | 1.0000 | 748/843 (88.7) | 742/855 (86.8) | 0.2365 |
| No evidence of disease activity | 7/21 (33.3) | 1/29 (3.4) | 0.0067 | 12/28 (42.9) | 7/32 (21.9) | 0.1008 | 26/71 (36.6) | 11/59 (18.6) | 0.0315 | 257/687 (37.4) | 119/715 (16.6) | <0.0001 | 11/36 (30.6) | 3/20 (15.0) | 0.3343 | 313/843 (37.1) | 141/855 (16.5) | <0.0001 |
| Months 12–24: proportion of participants with: | ||||||||||||||||||
| No confirmed relapses | 18/20 (90.0) | 20/24 (83.3) | 0.6731 | 25/27 (92.6) | 29/32 (90.6) | 1.0000 | 67/69 (97.1) | 45/50 (90.0) | 0.1293 | 599/646 (92.7) | 564/642 (87.9) | 0.0034 | 29/32 (90.6) | 14/17 (82.4) | 0.4055 | 738/794 (92.9) | 672/765 (87.8) | 0.0007 |
| No Gd+ lesions | 20/20 (100.0) | 18/24 (75.0) | 0.0246 | 27/27 (100.0) | 22/32 (68.8) | 0.0012 | 69/69 (100.0) | 38/50 (76.0) | <0.0001 | 635/646 (98.3) | 501/642 (78.0) | <0.0001 | 31/32 (96.9) | 11/17 (64.7) | 0.0048 | 782/794 (98.5) | 590/765 (77.1) | <0.0001 |
| No new or enlarging T2 lesions | 20/20 (100.0) | 9/24 (37.5) | <0.0001 | 26/27 (96.3) | 18/32 (56.3) | 0.0006 | 66/69 (95.7) | 24/50 (48.0) | <0.0001 | 609/646 (94.3) | 293/642 (45.6) | <0.0001 | 31/32 (96.9) | 7/17 (41.2) | <0.0001 | 752/794 (94.7) | 351/765 (45.9) | <0.0001 |
| No lesion activitya | 20/20 (100.0) | 8/24 (33.3) | <0.0001 | 26/27 (96.3) | 17/32 (53.1) | 0.0002 | 66/69 (95.7) | 24/50 (48.0) | <0.0001 | 605/646 (93.7) | 290/642 (45.2) | <0.0001 | 30/32 (93.8) | 6/17 (35.3) | <0.0001 | 747/794 (94.1) | 345/765 (45.1) | <0.0001 |
| No 6-mo CDW | 18/20 (90.0) | 24/24 (100.0) | 0.2008 | 27/27 (100.0) | 31/32 (96.9) | 1.0000 | 64/69 (92.8) | 50/50 (100.0) | 0.0731 | 623/646 (96.4) | 613/642 (95.5) | 0.3992 | 32/32 (100.0) | 16/17 (94.1) | 0.3469 | 764/794 (96.2) | 734/765 (95.9) | 0.7953 |
| No evidence of disease activity | 16/20 (80.0) | 5/24 (20.8) | 0.0002 | 24/27 (88.9) | 16/32 (50.0) | 0.0019 | 61/69 (88.4) | 21/50 (42.0) | <0.0001 | 547/646 (84.7) | 250/642 (38.9) | <0.0001 | 27/32 (84.4) | 5/17 (29.4) | 0.0003 | 675/794 (85.0) | 297/765 (38.8) | <0.0001 |
Abbreviations: CDW = confirmed disease worsening; Gd+ = gadolinium-enhancing; NEDA-3 = 3-parameter no evidence of disease activity; OMB = ofatumumab; TER = teriflunomide.
m: Number of participants who responded; M: Total number of participants in the treatment group with the response variable defined.
Lesion activity is defined as either Gd+ lesions or new or enlarging T2 lesions. Participants free of lesion activity had to be free of Gd+ lesions and free of new or enlarging T2 lesions.
Individual Efficacy Components
Free of Confirmed Relapses and ARR
For all subgroups except the non-Hispanic White and the overall pooled populations, the proportion of participants free of confirmed MS relapses was numerically greater, but not statistically significantly different, for ofatumumab-treated participants vs teriflunomide-treated participants over the 2-year treatment period (Table 2). There was only a slight difference between treatment groups in the non-Hispanic Asian population.
Participants in the non-Hispanic Black, Hispanic/Latino, and non-Hispanic Asian subgroups had numerically lower adjusted ARRs in both treatment arms than those in the non-Hispanic White subgroup (Table 3). The reduction in relative relapse rate in the overall pooled population was statistically significant for ofatumumab vs teriflunomide treatment. Across all subgroups, ofatumumab treatment resulted in relative reductions in relapse rate vs teriflunomide; however, differences were statistically significant only for the non-Hispanic White subgroup. Relative reductions in relapse rate with ofatumumab were numerically greater in the non-Hispanic Black and Hispanic/Latino participants than in non-Hispanic White participants. Non-Hispanic Asian participants had the lowest relative reductions in relapse rate. The other/unknown subgroup had a relative reduction in relapse rate of ∼65%. The interaction between treatment and race/ethnicity did not reach statistical significance.
Table 3.
ARR in Race/Ethnicity Subgroups From the ASCLEPIOS I and II Trials
| Non-Hispanic Black | Non-Hispanic Asian | Hispanic/Latino | Non-Hispanic White | Other/unknown | Overalla | |||||||||
| Equally distributed margins | Observed margins | |||||||||||||
| OMB (n = 25) | TER (n = 38) | OMB (n = 34) | TER (n = 35) | OMB (n = 72) | TER (n = 66) | OMB (n = 751) | TER (n = 760) | OMB (n = 41) | TER (n = 22) | OMB (n = 923) | TER (n = 921) | OMB (n = 923) | TER (n = 921) | |
| Adjusted ARR (95% CI) | 0.07 (0.02–0.23) | 0.20 (0.10–0.38) | 0.08 (0.03–0.22) | 0.08 (0.03–0.21) | 0.04 (0.02–0.10) | 0.11 (0.06–0.20) | 0.12 (0.10–0.14) | 0.26 (0.22–0.29) | 0.10 (0.04–0.24) | 0.28 (0.13–0.61) | 0.08 (0.06–0.10) | 0.17 (0.13–0.22) | 0.11 (0.09–0.13) | 0.23 (0.20–0.26) |
| Relative relapse reduction, OMB vs TER (p value) | 65.2% (0.1208) | 6.7% (0.9225) | 58.6% (0.1010) | 53.5% (<0.0001) | 64.6% (0.0773) | 53.8% (<0.0001) | 53.8% (<0.0001) | |||||||
Abbreviations: ARR = annualized relapse rate; CDW = confirmed disease worsening; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium-enhancing; OMB = ofatumumab; TER = teriflunomide.
Confirmed relapses are those accompanied by a clinically relevant change in the EDSS. ARR was estimated using a negative binomial regression model with the cumulative number of confirmed relapses over the study period as the response variable and the natural log of time in the study (years) as an offset variable. Models were adjusted for study, treatment, race/ethnicity, and region as factors and number of relapses in the year before the study, baseline EDSS, baseline number of Gd+ lesions, and baseline age as continuous covariates. The model tested for an interaction between treatment and race/ethnicity.
Overall treatment effects were estimated from a model without a treatment-by-race interaction. The ARR estimate based on equally distributed margins presumes the same number of patients in all race/ethnicity categories. The ARR estimate using observed margins is based on the actual number of patients per race/ethnicity category. Modification of margins results in a multiplication of both rates by the same factor; therefore, the rate ratio remains unchanged.
Free of Gd+ T1 Lesions
From months 0 to 24, for participants treated with ofatumumab, the percentage of participants free of Gd+ T1 lesions was similar across the race and ethnicity subgroups and the overall pooled population and was higher than the rate observed in teriflunomide-treated participants across all subgroups (Table 2). Consistent with the overall pooled population, the between-treatment differences for Gd+ T1 lesions were statistically significant in all race and ethnicity subgroups.
Free of New or Enlarging T2 Lesions
Similarly, more ofatumumab-treated participants had no new or enlarging T2 lesions from months 0 to 24 vs teriflunomide-treated participants (Table 2). The between-treatment differences in this end point were statistically significant in the overall population and in non-Hispanic Black, Hispanic/Latino, and non-Hispanic White subgroups.
Free of 6-Month CDW
From months 0 to 24, no statistically significant differences between treatment groups were observed for 6-month CDW across the race and ethnicity subgroups (Table 2).
Safety
Rates of AEs, SAEs, and AEs resulting in discontinuation were similar between the teriflunomide and ofatumumab treatment arms across the race and ethnicity subgroups, but the highest rates of AEs and SAEs were observed in the non-Hispanic Black subgroup (Table 4). The most common AEs reported included injection-related reaction, nasopharyngitis, headache, upper respiratory tract infection, alopecia, urinary tract infection, and diarrhea. Notably, 33.3% (12/36) of non-Hispanic Asian participants receiving ofatumumab reported pyrexia.
Table 4.
Summary of AEs in Race/Ethnicity Subgroups From the ASCLEPIOS I and II Trials
| Event, n (%) | Non-Hispanic Black | Non-Hispanic Asian | Hispanic/Latino | Non-Hispanic White | Other/unknown | Overall | ||||||
| OMB (n = 26) | TER (n = 38) | OMB (n = 36) | TER (n = 35) | OMB (n = 76) | TER (n = 69) | OMB (n = 766) | TER (n = 772) | OMB (n = 42) | TER (n = 22) | OMB (n = 946) | TER (n = 936) | |
| Any AE | 24 (92.3) | 35 (92.1) | 25 (69.4) | 29 (82.9) | 62 (81.6) | 58 (84.1) | 656 (85.6) | 651 (84.3) | 29 (69.0) | 16 (72.7) | 796 (84.1) | 789 (84.3) |
| Any SAE | 3 (11.5) | 3 (7.9) | 2 (5.6) | 1 (2.9) | 7 (9.2) | 6 (8.7) | 78 (10.2) | 63 (8.2) | 3 (7.1) | 3 (13.6) | 93 (9.8) | 76 (8.1) |
| Any serious infection | 3 (11.5) | 0 | 1 (2.8) | 0 | 3 (3.9) | 2 (2.9) | 17 (2.2) | 15 (1.9) | 0 | 1 (4.5) | 24 (2.5) | 18 (1.9) |
| Any AE resulting in discontinuation | 0 | 1 (2.6) | 0 | 0 | 2 (2.6) | 2 (2.9) | 28 (3.7) | 23 (3.0) | 0 | 0 | 30 (3.2) | 26 (2.8) |
| Most common (≥10%) AEs by preferred term | ||||||||||||
| Injection-related reaction | 5 (19.2) | 2 (5.3) | 7 (19.4) | 3 (8.6) | 6 (7.9) | 11 (15.9) | 169 (22.1) | 127 (16.5) | 8 (19.0) | 0 | 195 (20.6) | 143 (15.3) |
| Nasopharyngitis | 2 (7.7) | 5 (13.2) | 2 (5.6) | 1 (2.9) | 7 (9.2) | 8 (11.6) | 153 (20.0) | 139 (18.0) | 6 (14.3) | 4 (18.2) | 170 (18.0) | 157 (16.8) |
| Headache | 2 (7.7) | 8 (21.1) | 3 (8.3) | 3 (8.6) | 14 (18.4) | 7 (10.1) | 106 (13.8) | 98 (12.7) | 5 (11.9) | 3 (13.6) | 130 (13.7) | 119 (12.7) |
| Upper respiratory tract infection | 2 (7.7) | 4 (10.5) | 4 (11.1) | 2 (5.7) | 4 (5.3) | 5 (7.2) | 88 (11.5) | 108 (14.0) | 2 (4.8) | 1 (4.5) | 100 (10.6) | 120 (12.8) |
| Alopecia | 2 (7.7) | 3 (7.9) | 2 (5.6) | 0 | 3 (3.9) | 12 (17.4) | 46 (6.0) | 124 (16.1) | 1 (2.4) | 1 (4.5) | 54 (5.7) | 140 (15.0) |
| Urinary tract infection | 5 (19.2) | 6 (15.8) | 2 (5.6) | 2 (5.7) | 9 (11.8) | 7 (10.1) | 80 (10.4) | 62 (8.0) | 2 (4.8) | 0 | 98 (10.4) | 77 (8.2) |
| Diarrhea | 2 (7.7) | 7 (18.4) | 0 | 5 (14.3) | 6 (7.9) | 9 (13.0) | 42 (5.5) | 93 (12.0) | 2 (4.8) | 0 | 52 (5.5) | 114 (12.2) |
| Injection site reaction | 4 (15.4) | 2 (5.3) | 1 (2.8) | 0 | 10 (13.2) | 3 (4.3) | 80 (10.4) | 47 (6.1) | 8 (19.0) | 0 | 103 (10.9) | 52 (5.6) |
| Nausea | 3 (11.5) | 6 (15.8) | 2 (5.6) | 0 | 3 (3.9) | 6 (8.7) | 52 (6.8) | 54 (7.0) | 3 (7.1) | 0 | 63 (6.7) | 66 (7.1) |
| Influenza | 3 (11.5) | 3 (7.9) | 0 | 0 | 11 (14.5) | 5 (7.2) | 42 (5.5) | 47 (6.1) | 2 (4.8) | 1 (4.5) | 58 (6.1) | 56 (6.0) |
| Depression | 1 (3.8) | 2 (5.3) | 1 (2.8) | 1 (2.9) | 8 (10.5) | 8 (11.6) | 33 (4.3) | 38 (4.9) | 0 | 1 (4.5) | 43 (4.5) | 50 (5.3) |
| Paresthesia | 2 (7.7) | 3 (7.9) | 0 | 1 (2.9) | 2 (2.6) | 5 (7.2) | 23 (3.0) | 42 (5.4) | 1 (2.4) | 1 (4.5) | 28 (3.0) | 52 (5.6) |
| Anxiety | 5 (19.2) | 0 | 0 | 1 (2.9) | 5 (6.6) | 4 (5.8) | 34 (4.4) | 28 (3.6) | 2 (4.8) | 0 | 46 (4.9) | 33 (3.5) |
| Dizziness | 3 (11.5) | 2 (5.3) | 0 | 0 | 4 (5.3) | 4 (5.8) | 33 (4.3) | 26 (3.4) | 0 | 1 (4.5) | 40 (4.2) | 33 (3.5) |
| Pyrexia | 0 | 2 (5.3) | 12 (33.3) | 5 (14.3) | 1 (1.3) | 2 (2.9) | 24 (3.1) | 17 (2.2) | 0 | 0 | 37 (3.9) | 26 (2.8) |
| Hypoesthesia | 3 (11.5) | 7 (18.4) | 1 (2.8) | 1 (2.9) | 2 (2.6) | 2 (2.9) | 19 (2.5) | 23 (3.0) | 0 | 2 (9.1) | 25 (2.6) | 35 (3.7) |
| Muscle spasms | 3 (11.5) | 2 (5.3) | 0 | 0 | 0 | 4 (5.8) | 21 (2.7) | 25 (3.2) | 0 | 0 | 24 (2.5) | 31 (3.3) |
| Vomiting | 3 (11.5) | 2 (5.3) | 0 | 0 | 2 (2.6) | 1 (1.4) | 12 (1.6) | 31 (4.0) | 2 (4.8) | 0 | 19 (2.0) | 34 (3.6) |
| Constipation | 3 (11.5) | 1 (2.6) | 1 (2.8) | 0 | 1 (1.3) | 0 | 19 (2.5) | 17 (2.2) | 1 (2.4) | 0 | 25 (2.6) | 18 (1.9) |
| Neck pain | 3 (11.5) | 5 (13.2) | 1 (2.8) | 0 | 3 (3.9) | 2 (2.9) | 11 (1.4) | 8 (1.0) | 0 | 2 (9.1) | 18 (1.9) | 17 (1.8) |
| Pain | 4 (15.4) | 1 (2.6) | 0 | 1 (2.9) | 0 | 1 (1.4) | 9 (1.2) | 5 (0.6) | 1 (2.4) | 0 | 14 (1.5) | 8 (0.9) |
Abbreviations: AE = adverse event; OMB = ofatumumab; SAE = serious adverse event; TER = teriflunomide.
A patient with multiple occurrences of an AE is counted only once for that AE. MedDRA version 23.1 was used for the reporting of AEs.
The ASCLEPIOS I and II trials used a double-dummy study design; injection site reactions were reported in both ofatumumab and teriflunomide-treated participants but were more frequent with ofatumumab across race and ethnicity subgroups and the overall population compared with teriflunomide. Injection site reactions were seen in 15.4% (4/26) and 5.3% (2/38) of non-Hispanic Black participants treated with ofatumumab and teriflunomide, 13.2% (10/76) and 4.3% (3/69) of Hispanic/Latino participants, 10.4% (80/766) and 6.1% (47/772) of non-Hispanic White participants, and 10.9% (103/946) and 5.6% (52/936) of overall participants, respectively. In the non-Hispanic Asian and other/unknown subgroups, 1 of 36 (2.8%) and 8 of 42 (19.0%) ofatumumab-treated participants, respectively, and no teriflunomide-treated participants reported injection site reactions.
Serious infections were reported in 2.5% (24/946) and 1.9% (18/936) of participants treated with ofatumumab and teriflunomide, respectively.
Ig Levels
Mean serum IgG and IgM levels remained relatively stable over time across race and ethnicity subgroups and the overall population (Table 5 and Figure 2). Most of the participants had IgG above the lower limit of normal (LLN) throughout the study period. Of note, 4.3% (3/69) of teriflunomide-treated Hispanic/Latino participants and 1.4% (11/765) of ofatumumab-treated non-Hispanic White participants had IgG levels 20% below the LLN at least once. No participants in the non-Hispanic Black or non-Hispanic Asian subgroups had low IgG levels. Similarly, serum IgM levels remained above the LLN for most participants. Low IgM levels were most frequently reported in non-Hispanic Asian participants treated with ofatumumab; 25.7% (9/35) of participants had IgM levels 10% below the LLN. In non-Hispanic Black participants, low IgM was more commonly observed in teriflunomide than ofatumumab-treated participants. However, in the overall pooled population, low IgM levels were observed at a higher rate in participants treated with ofatumumab than in those treated with teriflunomide (10% below LLN: 14.4% [136/944] vs 4.5% [42/933]).
Table 5.
Mean Serum IgG and IgM (g/L) at Baseline, Month 12, and Month 24 (Safety Analysis Set)
| Non-Hispanic Black | Non-Hispanic Asian | Hispanic/Latino | Non-Hispanic White | Other/unknown | Overall | |||||||
| OMB (n = 26) | TER (n = 38) | OMB (n = 36) | TER (n = 35) | OMB (n = 76) | TER (n = 69) | OMB (n = 766) | TER (n = 772) | OMB (n = 42) | TER (n = 22) | OMB (n = 946) | TER (n = 936) | |
| IgG, g/L | ||||||||||||
| Baseline | 11.34 (1.87) n = 26 |
11.10 (1.67) n = 35 |
11.50 (2.97) n = 35 |
11.59 (2.37) n = 35 |
10.23 (2.47) n = 75 |
10.04 (1.99) n = 69 |
9.80 (2.01) n = 761 |
9.47 (1.84) n = 767 |
9.79 (2.58) n = 42 |
9.62 (1.45) n = 22 |
9.94 (2.15) n = 939 |
9.66 (1.92) n = 928 |
| Month 12 | 11.44 (2.28) n = 23 |
11.15 (1.79) n = 30 |
11.55 (2.79) n = 32 |
11.29 (2.66) n = 32 |
10.30 (2.49) n = 72 |
9.56 (1.91) n = 59 |
9.55 (1.97) n = 722 |
8.79 (1.73) n = 724 |
9.44 (1.81) n = 36 |
8.84 (1.35) n = 20 |
9.73 (2.11) n = 885 |
9.01 (1.89) n = 865 |
| Month 24 | 13.62 (1.98) n = 11 |
12.16 (2.77) n = 21 |
12.87 (3.69) n = 12 |
13.13 (2.70) n = 21 |
10.52 (2.45) n = 29 |
9.97 (2.09) n = 27 |
10.42 (2.12) n = 381 |
9.88 (1.96) n = 364 |
10.43 (2.37) n = 25 |
9.48 (1.58) n = 8 |
10.57 (2.28) n = 458 |
10.14 (2.20) n = 441 |
| IgM, g/L | ||||||||||||
| Baseline | 1.09 (0.53) n = 26 |
1.21 (0.72) n = 35 |
1.33 (0.87) n = 35 |
1.44 (0.61) n = 35 |
1.19 (0.50) n = 75 |
1.30 (0.63) n = 69 |
1.23 (0.64) n = 762 |
1.29 (0.73) n = 766 |
1.37 (0.70) n = 42 |
1.15 (0.40) n = 22 |
1.23 (0.64) n = 940 |
1.29 (0.71) n = 927 |
| Month 12 | 0.84 (0.44) n = 23 |
1.05 (0.76) n = 30 |
1.03 (0.90) n = 32 |
1.18 (0.64) n = 32 |
0.84 (0.36) n = 72 |
1.14 (0.58) n = 59 |
0.93 (0.55) n = 722 |
1.11 (0.68) n = 724 |
0.94 (0.46) n = 36 |
0.96 (0.31) n = 20 |
0.92 (0.55) n = 885 |
1.11 (0.67) n = 865 |
| Month 24 | 0.76 (0.47) n = 11 |
1.04 (0.60) n = 21 |
0.76 (0.65) n = 12 |
1.30 (0.45) n = 21 |
0.70 (0.34) n = 29 |
1.00 (0.43) n = 27 |
0.81 (0.48) n = 381 |
1.15 (0.82) n = 364 |
0.84 (0.33) n = 25 |
0.93 (0.34) n = 8 |
0.80 (0.47) n = 458 |
1.13 (0.78) n = 441 |
Abbreviations: Ig = immunoglobulin; OMB = ofatumumab; TER = teriflunomide.
Data are given as mean (SD); n represents the number of participants with an IgG or IgM value at both baseline and the time point evaluated.
Figure 2. Mean Serum IgG (A) and IgM (B) Levels From Baseline Over Time in Ofatumumab-Treated Participants From the ASCLEPIOS I and II Trials.
Ig = immunoglobulin.
Treatment Discontinuation
AEs leading to treatment discontinuation were infrequent with both therapies in all race and ethnicity subgroups and the overall population, with no discontinuations seen in non-Hispanic Asian participants receiving teriflunomide or ofatumumab and in non-Hispanic Black participants receiving ofatumumab (Table 4). No general pattern of AEs leading to ofatumumab discontinuation was detected. Observed rates of discontinuation because of AEs with teriflunomide were comparable across the overall population and race and ethnicity subgroups (range 2.6%–3.0% when excluding the subgroups with no discontinuations).
The proportions of participants in the overall population who discontinued the study drug were 17.1% (162/946) for ofatumumab and 21.5% (201/936) for teriflunomide. The proportions of participants (ofatumumab and teriflunomide) who discontinued in each race and ethnicity group are presented in eTable 3. Overall, the most common reasons for discontinuation of ofatumumab and teriflunomide, respectively, were patient/guardian decision (5.0% and 9.0%), AEs (3.2% and 2.7%), physician decision (1.9% and 1.7%), and lost to follow-up (2.0% and 1.1%).
Classification of Evidence
This study provides Class II evidence that among patients aged 18–55 years with RMS, the improvement in NEDA-3 with ofatumumab was comparably better than with teriflunomide among patients self-identified as non-Hispanic Black, non-Hispanic Asian, non-Hispanic White, Hispanic/Latino, and other/unknown.
Discussion
Determining whether there are significant differences in response to therapies for MS is of great potential importance in guiding therapeutic decision making. In this post hoc analysis of the phase 3 ASCLEPIOS I and II trials, ofatumumab was associated with statistically significantly greater odds of achieving NEDA-3 across race and ethnicity subgroups compared with teriflunomide in adult participants with RMS. The exception was the non-Hispanic Asian population, who were at least 2-fold more likely to achieve NEDA with ofatumumab than teriflunomide but with odds that were only statistically significant for the second year of treatment (months 12–24). NEDA-3 achievement in teriflunomide-treated participants was largely consistent across race and ethnicity subgroups and the overall population, being lowest for non-Hispanic Black participants across all time periods (months 0–12, 12–24, and 0–24) and highest for non-Hispanic Asian participants. The reason for low NEDA-3 achievement among teriflunomide-treated non-Hispanic Black participants is unclear but may be related to the comparatively higher prevalence and disease burden reported for Black and African American patients with MS,25 which could suggest a therapeutic benefit for administering high-efficacy DMTs in this population.
It is important to note that this is a post hoc analysis and that the study was not originally powered for racial and ethnic subgroup analyses. When limiting the analyses to participants in the United States and US health care delivery systems, the findings were consistent with the overall pooled population (eAppendix 1). Greater proportions of ofatumumab-treated participants achieved the individual NEDA-3 components of no confirmed relapses, no Gd+ T1 lesions, no new or enlarging T2 lesions, and no 6-month CDW compared with teriflunomide. The effect of ofatumumab remained relatively consistent, with no notable differences between the race and ethnicity subgroups and the overall pooled population.
The safety profile of ofatumumab in the race and ethnicity subgroups was consistent with observations in the overall ASCLEPIOS population.19 No new or unexpected safety signals were identified. Hispanic/Latino and non-Hispanic Asian participants had slightly lower rates of any AEs and SAEs than the overall population, whereas the rates of AEs were highest in the non-Hispanic Black population. AEs resulting in ofatumumab discontinuation were uncommon and occurred mostly in the Hispanic/Latino (2.6%) and non-Hispanic White (3.7%) subgroups. Rates of any AEs, SAEs, and AEs resulting in discontinuation were largely balanced between treatments across the subgroups. Pyrexia was seen more commonly reported among non-Hispanic Asian participants. Further work to confirm this observation would be of potential value in determining whether antipyretic pretreatment is indicated with ofatumumab subcutaneous injections. Mean serum IgG levels remained consistent and did not significantly decline across the race and ethnicity subgroups and the overall population, remaining above the LLN in most participants. Serum IgM levels were similarly consistent over the study period.
Non-Hispanic Black participants receiving teriflunomide had the highest rates of treatment discontinuation. The most common reason for their discontinuation (alongside lost to follow-up) was physician decision, which could have been the result of various factors, such as poor tolerability or response. A comparative study of age and sex-matched individuals with MS (n = 300) reported that Black individuals had the highest rates of treatment-limiting AEs compared with White and Hispanic individuals.26 This is consistent with findings from this analysis, where slightly higher rates of AEs, SAEs, and serious infections were reported in ofatumumab-treated non-Hispanic Black participants than in other race and ethnicity groups. In addition, it has been reported that Black and Hispanic individuals have higher rates of disease progression and experience more frequent medication changes, regardless of DMT choice, relative to White individuals.26
Data on the efficacy and safety of currently approved MS treatments in racial and ethnic minorities are limited. A systematic literature review found that trial representation of ethnically diverse individuals was lacking compared with White individuals.11 However, for the studies where there was diverse enrollment, investigators found that DMT efficacy for interferon did not differ in Asian participants compared with White participants. It was also reported that Black participants may be at a greater risk of disability than White participants when receiving treatment with interferon or glatiramer acetate.11 Hispanic patient recruitment in large phase 3 clinical trials was particularly low, with only 7% enrollment in studies for fingolimod or dimethyl fumarate. Compared with glatiramer acetate, Hispanic participants had a greater preference for fingolimod, as evidenced by higher rates of persistence and lower discontinuation rates. No significant differences in efficacy were identified between Hispanic participants and other race and ethnic subgroups.11 Furthermore, when ocrelizumab was evaluated in Black and African American and Hispanic/Latino participants in the phase 4 CHIMES study, the overall efficacy was found to align with that observed in the OPERA pivotal trials, with no noticeable differences in safety across racial subgroups.27
The findings of this analysis reveal that ofatumumab was overall efficacious and well tolerated across the race and ethnicity subgroups included in the ASCLEPIOS trials and these measures were numerically consistent with the overall study population. High-efficacy DMTs, such as ofatumumab, may be an optimal treatment choice for participants with MS of different ethnic backgrounds. To optimize disease management, the design of clinical trials is an important factor in improving the understanding of how participants of different racial and ethnic groups respond to novel MS therapies.
Under-representation of diverse populations, especially racial and ethnic minorities, in clinical trials remains a serious challenge.28 To improve representation in research, it is important to provide financial resources for research teams, initiate proactive outreach, establish long-term infrastructure in communities, identify and use media outlets frequented by underserved communities so as to spread knowledge of research participation opportunities, and prespecify diversity targets.29 It is also essential to offer material and social support for community advocates and organizations and educate scientists, community members, and relevant stakeholders about the significance of these efforts.29 Encompassing many of these proposals, the International Advisory Committee on Clinical Trials in MS and the US Food and Drug Administration (FDA) have issued draft guidance on a diversity plan to improve enrollment of participants from under-represented racial and ethnic populations in clinical trials.30,31 Requirements for such plans will become part of a new FDA mandate that will begin by 2025.
As previously noted, this was a post hoc analysis, and no allowance was made for multiple comparisons. The ASCLEPIOS I and II trials were not originally powered to examine efficacy and safety in subpopulations based on race and ethnicity, and recruitment did not account for a diverse population. Therefore, the small sample sizes of the race and ethnicity subpopulations did not appropriately power this post hoc analysis to identify small differences in treatment effect. These small cohort numbers may in part explain why numerical differences observed between race and ethnicity subgroups for some comparisons failed to achieve statistical significance, which argues for future studies enrolling greater number of Black, Asian, Hispanic/Latino, and other under-represented racial and ethnic populations. Notwithstanding this, our analysis was able to demonstrate differences between treatment interventions because of the large effect size seen with ofatumumab compared with teriflunomide.
This analysis relied upon the self-identification of race and ethnicity by study participants, which can be influenced by social and cultural beliefs. Specific details regarding regionality and/or nationality of participants were not collected at screening (e.g., Asian participants could only select the prespecified racial category of Asian). Owing to the highly heterogeneous nature of the Asian and Black subgroups, an examination of the impact of regional and/or geographic differences on treatment responses in these populations should be considered for future analyses. In addition, the inclusion of an other/unknown subgroup precluded race and ethnicity-based conclusions to be drawn for these participants. Furthermore, data on genetic ancestry and SDoH were not collected. The use of US census race and ethnicity categories in this study may not precisely align with categories or terms used in other countries and regions. Finally, the under-representation of each race and ethnicity in each country was not examined in this study.
In conclusion, ofatumumab demonstrated greater efficacy than teriflunomide across non-Hispanic Black, non-Hispanic Asian, Hispanic/Latino, and non-Hispanic White participants with RMS enrolled in the ASCLEPIOS I and II trials. Observed differences between the race and ethnicity subgroups and the overall pooled population in the efficacy and safety outcomes were small and not considered clinically meaningful. Thus, this analysis provides further evidence supporting use of ofatumumab in these participant subgroups. Under-representation of diverse populations is a recurring issue in clinical trials for MS, and future studies should strive to enroll racially and ethnically diverse groups, including Black and African American, Asian, and Hispanic/Latino individuals, to better inform treatment decisions and outcomes for these populations.
Acknowledgment
Additional medical writing support was provided by Nancy Nguyen, PharmD (formerly of Envision Pharma, Inc.), and was funded by Novartis Pharmaceuticals Corporation. Xiangyi Meng, PhD (formerly of Novartis Pharmaceuticals Corporation, East Hanover, NJ) provided statistical support for this post hoc analysis. This manuscript was developed in accordance with Good Publication Practice (GPP4) guidelines.
Glossary
- AE
adverse event
- ARR
annualized relapse rate
- CDW
confirmed disease worsening
- DMT
disease-modifying therapy
- EDSS
Expanded Disability Status Scale
- FDA
US Food and Drug Administration
- Gd+
gadolinium-enhancing
- Ig
immunoglobulin
- LLN
lower limit of normal
- MS
multiple sclerosis
- NEDA-3
3-parameter no evidence of disease activity
- OR
odds ratio
- RMS
relapsing MS
- SAE
serious AE
- SDoH
social determinants of health
Appendix. Authors
| Name | Location | Contribution |
| Mitzi J. Williams, MD | Joi Life Wellness MS Center, Atlanta, GA | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Lilyana Amezcua, MD | University of Southern California, Los Angeles | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Stanley L. Cohan, MD, PhD | Providence Multiple Sclerosis Center, Providence Brain and Spine Institute, Portland, OR | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Jeffrey A. Cohen, MD | Cleveland Clinic Mellen Center, OH | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Silvia R. Delgado, MD | Department of Neurology, University of Miami Miller School of Medicine, FL | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Le H. Hua, MD | Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Elisabeth B. Lucassen, MD | Novartis Pharmaceuticals Corporation, East Hanover, NJ | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
| Rebecca S. Piccolo, PhD | Novartis Pharmaceuticals Corporation, East Hanover, NJ | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data; additional contributions (in addition to one or more of the above criteria) |
| Chloe R. Koulouris, PhD | Envision Pharma, Inc., Horsham, United Kingdom | Drafting/revision of the manuscript for content, including medical writing for content |
| James Stankiewicz, MD | Novartis Pharmaceuticals Corporation, East Hanover, NJ | Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data |
Footnotes
Editorial, page e209730
Study Funding
This study was funded by Novartis Pharmaceuticals Corporation. Novartis Pharmaceuticals Corporation supported the development of this manuscript and provided data analyses according to the direction of the authors. The authors had full control of the content and made the final decision on all aspects of this publication.
Disclosure
M.J. Williams has received consulting/speaking fees from Alexion, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Janssen, Novartis, Sanofi Genzyme, and TG Therapeutics and has received research support from Biogen, Genentech, and Novartis. L. Amezcua has received personal compensation for serving as a consultant for Biogen, EMD Serono, and Novartis, has received personal compensation for serving on a scientific advisory or data safety monitoring board for Genentech, and has received research support from Biogen, Bristol Myers Squibb Foundation, Genentech, NIH/National Institute of Neurological Disorders and Stroke, National Multiple Sclerosis Society, and Race to Erase MS. S.L. Cohan has served on advisory boards or steering committees for AbbVie, Biogen, Bristol Myers Squibb, EMD Serono, Novartis, Roche/Genentech, and Sanofi Genzyme, has received research support from AbbVie, ADAMAS, Biogen, EMD Serono, MedDay, Novartis, Opexa, Roche/Genentech, and Sanofi Genzyme, and has received speaker honoraria from Biogen, Bristol Myers Squibb, EMD Serono, Roche/Genentech, and Sanofi Genzyme. J.A. Cohen has received personal compensation for consulting from Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI and has received personal compensation for serving as an Editor of Multiple Sclerosis Journal. S.R. Delgado has received research support from EMD Serono and Novartis. L.H. Hua has received personal fees for speaking, consulting, and advisory board activities from Alexion, Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Greenwich Biosciences, Horizon, and Novartis, and has received research support from Biogen (paid to institution). E. Lucassen is an employee of and stockholder in Novartis. R. Piccolo is an employee of and stockholder in Novartis. J. Stankiewicz is an employee of and stockholder in Novartis. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The ASCLEPIOS I and II trial data are available on reasonable request, provided that it is in line with current ethical and intellectual property requirements surrounding the use of data. Requests should be directed through ClinicalStudyDataRequest.com.