1078825 research-article20222022 MSJ0010.1177/13524585221078825Multiple Sclerosis JournalJ Gärtner, SL Hauser MULTIPLE SCLEROSIS MSJ JOURNAL Original Research Paper Efficacy and safety of ofatumumab in recently Multiple Sclerosis Journal 1­–14 diagnosed, treatment-naive patients with DOI: 10.1177/ https://doi.org/10.1177/13524585221078825 13524585221078825 https://doi.org/10.1177/13524585221078825 multiple sclerosis: Results from ASCLEPIOS I © The Author(s), 2022. Article reuse guidelines: sagepub.com/journals- and II permissions Jutta Gärtner*, Stephen L Hauser* , Amit Bar-Or, Xavier Montalban, Jeffrey A Cohen , Anne H Cross , Kumaran Deiva, Habib Ganjgahi, Dieter A Häring, Bingbing Li, Ratnakar Pingili, Krishnan Ramanathan, Wendy Su, Roman Willi , Bernd Kieseier and Ludwig Kappos Abstract Correspondence to: L Kappos Background: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis Research Center for receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes Clinical Neuroimmunology and Neuroscience Basel than those receiving teriflunomide. (RC2NB) and MS Center, and Departments of Objectives: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, Medicine, Clinical Research, treatment-naive (RDTN) participants from ASCLEPIOS. Biomedicine and Biomedical Engineering, University Methods: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) Hospital of Basel, University or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the pro- of Basel, Petersgraben 4, Basel 4031, Switzerland. tocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening kapposl-pa@usb.ch (CDW), progression independent of relapse activity (PIRA) and adverse events. Jutta Gärtner Department of Paediatrics Results: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). and Adolescent Medicine, Division of Paediatric Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval Neurology, University (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 Medical Centre Göttingen, Georg August University (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings Göttingen, Göttingen, were manageable and consistent with those of the overall ASCLEPIOS population. Germany Stephen L Hauser Conclusion: The favourable benefit–risk profile of ofatumumab versus teriflunomide supports its consid- UCSF Weill Institute for eration as a first-line therapy in RDTN patients. Neurosciences, Department of Neurology, University of ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231). California – San Francisco, San Francisco, CA, USA Amit Bar-Or Keywords: Relapsing multiple sclerosis, recently diagnosed, treatment-naive, progression independent Center for Neuroinflammation and of relapse activity, no evidence of disease activity, neurofilament light chain Experimental Therapeutics and Department of Neurology, Perelman School Date received: 17 August 2021; revised: 14 December 2021; accepted: 20 January 2022 of Medicine, University of Pennsylvania, Philadelphia, PA, USA Introduction progression independent of relapse activity (PIRA) Xavier Montalban In young adults, MS is the most common chronic, both contribute to disability accrual from disease Department of Neurology- Neuroimmunology, Centre inflammatory, demyelinating and neurodegenerative onset, albeit in different proportions.4–6 Consistent d’Esclerosi Múltiple de CNS disease,1 and is a leading cause of non-traumatic with PIRA occurring from MS onset, findings from Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, disability.2 In patients with relapsing MS (RMS), dis- neuropathology, biomarker and imaging studies sug- Barcelona, Spain ability accrual was previously thought to be a sequen- gest that neuroaxonal loss, the main driver of neuro- Jeffrey A Cohen tial process, driven by poor recovery from relapses degeneration and irreversible progression in advanced Department of Neurology, Mellen MS Center, during the initial relapsing stage, followed by relapse- MS, may already be prominent in early RMS.7–9 Neurological Institute, independent progression in the secondary progressive Younger patients with RMS have higher clinical and Cleveland Clinic, Cleveland, OH, USA stage.3 However, accumulating clinical evidence indi- MRI disease activity, as well as more pronounced cates that relapses with incomplete recovery and acute axonal damage,7 than older patients.10 Moreover, journals.sagepub.com/home/msj 1 Multiple Sclerosis Journal 00(0) Anne H Cross Department of neuronal and brain volume loss begin early in the randomized, double-blind, double-dummy, active- Neurology, Section of disease.11,12 High levels of disability, high lesion load controlled, multicentre trials of identical design con- Neuroimmunology, Washington University and low brain volume are associated with poor MS ducted concurrently in participants with RMS. School of Medicine, St Louis, prognosis.13 Participants were randomized (1:1) to ofatumumab MO, USA 20 mg subcutaneously every 4 weeks (starting at Kumaran Deiva Department of Pediatric The effect of disease-modifying therapies (DMTs) on week 4, after initial dosing of 20 mg on days 1, 7 and Neurology, University worsening of MS disability is age-dependent, with 14) or teriflunomide 14 mg orally once daily for up to Hospitals Paris Saclay, Hôpital Bicêtre, National younger patients and those earlier in the disease 30 months.22 Protocols were approved by the relevant Reference Center for Rare course showing the greatest benefit.10,14–16 Therefore, institutional review board or ethics committee at Inflammatory Brain and Spinal Diseases, Le Kremlin- early treatment with high-efficacy DMTs that can each trial site, and all participants provided written Bicêtre, France slow disability accrual is essential.17,18 However, informed consent. Habib Ganjgahi there are barriers to early intervention with high- Oxford Big Data Institute, Li Ka Shing Centre for Health efficacy DMTs. Uncertainty early in the disease Information and Discovery, Nuffield Department of course regarding MS severity means that some Analysis populations Population Health, University patients are reluctant to accept long-term treatment Unless otherwise specified, analyses were performed of Oxford, Oxford, UK/ Statistics Department, with any DMT, including high-efficacy DMTs. Also, in the protocol-defined RDTN subpopulation of par- University of Oxford, safety concerns may cause clinicians to delay high- ticipants from the pooled full analysis set (FAS; all Oxford, UK efficacy DMT use, resulting in subclinical CNS randomized participants with assigned treatments) Dieter A Häring Krishnan Ramanathan damage compromising repair and compensation from ASCLEPIOS I and II. The full inclusion and key Roman Willi capacity, poor symptom control and eventually exclusion criteria for the FAS in ASCLEPIOS I and Bernd Kieseier Novartis Pharma AG, Basel, accrual of irreversible disability. Moreover, some II are listed in Supplementary Text 1. This sub- Switzerland high-efficacy therapies are restricted to later treat- population was defined as those participants who Bingbing Li ment lines by regulators, payers and healthcare man- had received an RMS diagnosis within the 36-month Ratnakar Pingili Wendy Su agement organizations. period before screening and had no prior treatment Novartis Pharmaceuticals with a DMT. As reported elsewhere,24 a modified FAS Corporation, East Hanover, NJ, USA Ofatumumab, a fully human anti-CD20 monoclonal was used for the analysis of no evidence of disease Ludwig Kappos antibody that selectively depletes B cells,19 is approved activity (NEDA) and it included all participants in the Research Center for in the USA, across Europe and in several other coun- FAS according to the intent-to-treat principle, but Clinical Neuroimmunology and Neuroscience Basel tries for the treatment of adults with RMS.20,21 In the excluded those who discontinued treatment early for (RC2NB) and MS Center, ASCLEPIOS I and II phase III trials, ofatumumab reasons other than ‘lack of efficacy’ or ‘death’ and and Departments of Medicine, Clinical Research, (20 mg subcutaneously every 4 weeks) was superior who had NEDA before early discontinuation. The Biomedicine and Biomedical to teriflunomide (14 mg orally once daily) in partici- safety set included all participants who received trial Engineering, University Hospital of Basel, University pants with RMS, significantly reducing relapse rate, drugs. of Basel, Basel, Switzerland disability worsening and MRI lesion activity with a *Jutta Gärtner and Stephen L Hauser are co-lead authors. favourable safety and tolerability profile that allowed for home administration without premedication.22 Endpoints and definitions The ASCLEPIOS trials and comparison across trials Efficacy endpoints to assess the benefit–risk of via network meta-analyses have shown that ofatu- ofatumumab versus teriflunomide treatment were: mumab is among the most highly efficacious treat- annualized relapse rate (ARR); confirmed disability ments for MS.22,23 worsening (CDW) at 3 months (3mCDW) and at 6 months (6mCDW); PIRA at 3 months (3mPIRA) and In this study, we assessed the benefit–risk profile of at 6 months (6mPIRA); the number of gadolinium- ofatumumab versus that of teriflunomide, analysing enhancing (Gd+) T1 lesions per MRI scan; the number clinical and MRI data in a subpopulation of partici- of new or enlarging T2 lesions per year; annual rate of pants with early RMS (recently diagnosed and treat- brain volume loss; the three-parameter NEDA (NEDA- ment-naive (RDTN)) from the combined ASCLEPIOS 3); and neurofilament light chain (NfL) concentration. I and II trial populations. Quantitation of NfL in human serum was done using the Quanterix Simoa NF-light assay advantage kit, which is a two-step quantitative digital immunoassay. Methods A technical assessment was performed to validate the performance claims of the Quanterix Simoa NfL kit in Trial design and participants a serum matrix for use as a clinical trial assay. Details of the ASCLEPIOS I (ClinicalTrials.gov identifier: NCT02792218) and II (NCT02792231) tri- ARR was the number of confirmed MS relapses als have been reported.22 ASCLEPIOS I and II were observed on the study, standardized to 1 year. 3mCDW 2 journals.sagepub.com/home/msj J Gärtner, SL Hauser et al. and 6mCDW were increased from baseline Expanded a repeated-measures model after log-transformation Disability Status Scale (EDSS) score (by ⩾1.5 points of the data; the treatment effect (i.e. percentage reduc- for a score of 0, by ⩾1 point for scores of 1–5 and by tion in NfL concentration) was the ratio of geometric ⩾0.5 points for a score ⩾5.5) sustained for at least 3 means (ofatumumab vs. teriflunomide) × 100. or 6 months, respectively; 3mPIRA and 6mPIRA used the same EDSS criteria as 3mCDW and 6mCDW, but Safety data were collected during the treatment included only cases in which the onset of progression period (screening to the end of the trial) and the did not occur during an investigator-reported relapse. safety follow-up period until a participant’s last visit. NEDA-3 criteria were no confirmed relapses, no After the last treatment dose, participants were fol- 6mCDW and no MRI activity (i.e. Gd+T1 lesions or lowed up for at least 9 months. Data collected on or enlarging T2 lesions on any MRI scan vs. baseline). before 100 days after the last dose of study medica- tion were included in the analysis except for SAEs, Safety endpoints to assess the benefit–risk of ofatu- for which all data collected until the end of the trial mumab versus teriflunomide treatment were adverse were included. events (AEs), AEs leading to study discontinuation, and serious AEs (SAEs); AEs were recorded at all Analyses of individual endpoints in RDTN partici- visits and graded using the Common Terminology pants were undertaken post hoc. Criteria for Adverse Events.25 Results Statistical analyses Participant characteristics at baseline were summa- Participants rized descriptively by treatment in the RDTN subpop- Of the 1882 participants randomly assigned to treat- ulation and in the pooled FAS. Percentage compliance ment in ASCLEPIOS I and II, 615 (32.7%) were was calculated in the safety set as the duration of RDTN (ofatumumab, 314; teriflunomide, 301). RDTN exposure to study drug (days)/treatment duration participants had a median of 0.35 and 0.36 years from (days). diagnosis for the ofatumumab and teriflunomide treated patients, respectively, with a range of 0.1–2.9 years ARR was analysed using a negative binomial regres- from diagnosis for both groups. Demographic and sion model, with an offset to adjust for variable study disease characteristics were similar between treat- duration in years. Disability-related endpoints (CDW ment groups and across trials (Table 1). Comparison and PIRA) were analysed using a Cox proportional by treatment group with the overall ASCLEPIOS hazards model. 3mPIRA and 6mPIRA were analysed population showed that RDTN participants in both in: (1) RDTN participants with no confirmed on-study groups were – as expected – younger with lower dis- relapses and (2) RDTN participants with no con- ability scores and lower total T2 lesion volume. firmed relapses on study or before a CDW event. More stringent sensitivity analyses of these two The median duration of exposure to study treatment groups included only participants without confirmed was 1.7 years for those receiving ofatumumab, and or unconfirmed on-study relapses, and with CDW 1.6 years for those receiving teriflunomide. 90% of defined such that confirmation could not be within patients received study treatment for more than 1 year, 90 days of a relapse. Numbers of Gd+T1 lesions and and more than 25% of participants received treatment of new or enlarging T2 lesions were assessed using for more than 2 years (Supplementary Figure 1). negative binomial regression models; the number of available MRI scans was the offset for analysis of Compliance in RDTN participants was high (ofatu- Gd+T1 lesions; and the time in years between base- mumab, 98.8%; teriflunomide, 98.9%), 100% com- line scan and last available scan was the offset for pliance being achieved by 171 of 314 (54.5%) and analysis of T2 lesions. The annual rate of brain vol- 176 of 301 (58.5%) in the two groups, respectively; at ume loss was estimated as the marginal slope estimate least 90% compliance was achieved by 307 of 314 from a random coefficient model with random inter- (97.8%) ofatumumab-treated participants. cept and slope based on assessments of brain volume percentage change from baseline at month 12, month 24 and end of treatment and/or trials. Efficacy in RDTN participants NEDA-3 was analysed in the modified FAS using Ofatumumab reduced ARR by 50% versus terifluno- logistic regression. Serum NfL concentration was mide (ARR: 0.09 vs. 0.18; rate ratio (95% confidence measured at months 3, 12 and 24, and analysed using interval; CI): 0.50 (0.33, 0.74); p < 0.001) (Table 2). journals.sagepub.com/home/msj 3 Multiple Sclerosis Journal 00(0) Table 1. Participant characteristics and demographics in RDTN participants and in the overall population from the ASCLEPIOS I and II trials (FAS). Characteristic RDTN participants from All participants from ASCLEPIOS I and IIa ASCLEPIOS I and II Ofatumumab Teriflunomide Ofatumumab Teriflunomide (n = 314) (n = 301) (N = 946) (N = 936) Age, mean (SD)b, years 36.8 (9.4) 35.7 (9.0) 38.4 (9.0) 38.0 (9.2) Women, n (%) 217 (69.1) 195 (64.8) 637 (67.3) 636 (67.9) Type of MS, n (%) RRMS 311 (99.0) 296 (98.3) 890 (94.1) 884 (94.4) SPMS 3 (1.0) 5 (1.7) 56 (5.9) 52 (5.6) Time since diagnosis, mean (SD), years 0.58 (0.63) 0.53 (0.51) 5.68 (6.21) 5.56 (6.10) Relapses in previous 12 months, mean (SD) 1.3 (0.7) 1.4 (0.7) 1.2 (0.7) 1.3 (0.7) Relapses in previous 12–24 months, mean (SD) 0.6 (0.8) 0.5 (1.0) 0.8 (1.0) 0.9 (1.1) EDSS score at baseline, mean (SD)c 2.30 (1.20) 2.28 (1.20) 2.93 (1.35) 2.90 (1.37) Participants with Gd+T1 lesions, mean (SD) n = 306 n = 298 n = 923 n = 922 1.8 (4.4) 1.4 (2.8) 1.7 (4.5) 1.3 (3.4) Participants with Gd+T1 lesions, n (%) 141 (44.9) 130 (43.2) 385 (40.7) 352 (37.6) Total volume of T2 lesions, mean (SD), cm3 n = 311 n = 300 n = 934 n = 930 10.11 (12.23) 8.31 (8.83) 13.72 (13.80) 12.55 (13.81) NfL concentration, mean (SD), pg/mL n = 297 n = 279 n = 893 n = 853 15.19 (18.57) 13.66 (14.52) 13.98 (15.86) 12.54 (11.94) Normalized brain volume, mean (SD), cm3 n = 310 n = 300 n = 929 n = 927 1472.6 (72.3) 1472.9 (66.1) 1439.8 (78.9) 1444.0 (77.8) EDSS: Expanded Disability Status Scale; FAS: full analysis set; Gd+: gadolinium-enhancing; NfL: neurofilament light chain; RDTN, recently diagnosed, treatment-naive; RRMS: relapsing–remitting MS; SD: standard deviation; SPMS: secondary progressive MS. Unless otherwise stated in individual rows, the number of participants with available data at baseline is indicated in the column header. aRDTN were those who had not received a prior MS disease-modifying therapy and who had received a diagnosis in the 36 months before screening. bAge at baseline was calculated from the date of the first administration of trial drug and the birth year (no exact birth date was captured for data privacy reasons). Eligibility for trial entry was assessed at the screening visit. cEDSS score at baseline was defined as the EDSS score at the last assessment before administration of the first dose of trial drug. EDSS scores range from 0 to 10.0, with higher scores indicating a higher degree of disability. Ofatumumab reduced the risk of 3mCDW numeri- p = 0.049) (Figure 2(a) and (b)). The findings in the cally by 38% (hazard ratio (HR) (95% CI): 0.62 (0.37, subgroup without confirmed on-study relapses 1.03); p = 0.065) and of 6mCDW by 46% (HR (95% before 3mPIRA or 6mPIRA events were similar and CI): 0.54 (0.30, 0.98); p = 0.044) versus teriflunomide significant (3mPIRA: 6.9% vs. 10.2%; HR (95% (Figure 1 and Table 2). CI): 0.51 (0.26, 1.00); p = 0.049; 6mPIRA: 4.0% vs. 8.9%; HR (95% CI): 0.41 (0.19, 0.89); p = 0.023) Over half of all 3mCDW events (ofatumumab, (Figure 2(c) and (d)). In the sensitivity analyses 13/24; teriflunomide, 20/37) and 6mCDW events (with PIRA defined such that CDW could not be (ofatumumab, 9/17; teriflunomide, 17/30) occurred within 90 days of a relapse), the hazard of a 3mPIRA in the absence of confirmed on-study relapses and and 6mPIRA event was numerically lower with ofa- were considered PIRA. In the subgroup of partici- tumumab than with teriflunomide (3mPIRA, HR pants without confirmed on-study relapses, the pro- (95% CI): 0.62 (0.27, 1.43); p = 0.263; 6mPIRA, HR portion of participants with 3mPIRA events was (95% CI): 0.55 (0.23, 1.36); p = 0.197). Findings in numerically lower, and the proportion with 6mPIRA the subgroup of participants without any confirmed events significantly lower, with ofatumumab than on-study relapses before 3mPIRA or 6mPIRA were with teriflunomide (3mPIRA: 6.6% vs. 9.1%; HR similar (3mPIRA, HR (95% CI): 0.63 (0.28, 1.40); (95% CI): 0.55 (0.27, 1.11); p = 0.096); 6mPIRA: p = 0.254; 6mPIRA, HR (95% CI): 0.57 (0.24, 1.33); 3.6% vs. 7.7%; HR (95% CI): 0.44 (0.20, 1.00); p = 0.194). 4 journals.sagepub.com/home/msj J Gärtner, SL Hauser et al. Table 2. Clinical, MRI and biomarker outcomes in the subpopulation of RDTN participants from the ASCLEPIOS I and II trials (FAS). Outcome RDTN participantsa Ofatumumab Teriflunomide p value Relapses No. of participants evaluated 314 301 Total no. of relapses 45 88 No. of patient-years 509 494 Adjusted ARR (95% CI) 0.09 (0.07, 0.12) 0.18 (0.14, 0.23) Rate ratio (95% CI) 0.50 (0.33, 0.74) <0.001 Disability-related outcomes 3mCDW    No. of events during the trial/no. of participants (%) 24/312 (7.7) 37/300 (12.3)    HR (95% CI) 0.62 (0.37, 1.03) 0.065 6mCDW    No. of events during the trial/no. of participants (%) 17/312 (5.4) 30/300 (10.0)    HR (95% CI) 0.54 (0.30, 0.98) 0.044 MRI-related outcomes Gd+T1 lesions    No. of participants evaluated 296 284    No. of Gd+lesions 10 212    No of evaluable scans 561 540    Mean no. of lesions per scan (95% CI) 0.02 (<0.01, 0.04) 0.39 (0.28, 0.53)    Rate ratio (95% CI) 0.05 (0.02, 0.10) <0.001 New or enlarging T2 lesions    No. of participants evaluated 300 287    No. of new or enlarging T2 lesions 418 2179    No. of patient-years 481 469    Mean no. of lesions per year (95% CI) 0.86 (0.70, 1.05) 4.78 (3.97, 5.76)    Rate ratio (95% CI) 0.18 (0.14, 0.24) <0.001 Brain volume change    No. of participants evaluated 295 280    Annual rate of changeb (95% CI) –0.30 (–0.37, –0.23) –0.31 (–0.38, –0.24)    Difference in percentage points (95% CI) 0.01 (–0.10, 0.11) 0.9 NEDA-3 Months 0–12   No. of participants achieving NEDA-3/no. of participantsc (%) 134/285 (47.0) 71/288 (24.7)    Odds ratio (95% CI) 3.31 (2.24, 4.90) <0.001 Months 12–24   No. of participants achieving NEDA-3/no. of participantsc (%) 258/280 (92.1) 131/280 (46.8)    Odds ratio (95% CI) 14.68 (8.76, 24.61) <0.001 Months 0–24   No. of participants achieving NEDA-3/no. of participantsc (%) 127/285 (44.6) 51/288 (17.7)    Odds ratio (95% CI) 4.63 (3.05, 7.03) <0.001 Biomarker outcomes Serum NfL concentration   At 3 months     No. of participants evaluated 294 280     Geometric mean (95% CI), pg/mL 8.72 (8.20, 9.26) 9.13 (8.58, 9.72)     Geometric mean ratio (95% CI) 0.95 (0.88, 1.03) 0.258 (Continued) journals.sagepub.com/home/msj 5 Multiple Sclerosis Journal 00(0) Table 2. (Continued) Outcome RDTN participantsa Ofatumumab Teriflunomide p value   At 12 months     No. of participants evaluated 285 274     Geometric mean (95% CI), pg/mL 6.60 (6.25, 6.98) 8.61 (8.14, 9.11)     Geometric mean ratio (95% CI) 0.77 (0.71, 0.83) <0.001   At 24 months     No. of participants evaluated 254 253     Geometric mean (95% CI), pg/mL 6.47 (6.11, 6.85) 8.10 (7.64, 8.58)     Geometric mean ratio (95% CI) 0.80 (0.74, 0.86) <0.001 3mCDW: 3-month confirmed disability worsening; 6mCDW: 6-month confirmed disability worsening; ARR: annualized relapse rate; CI: confidence interval; FAS: full analysis set; Gd+: gadolinium-enhancing; HR: hazard ratio; NEDA: no evidence of disease activity; NfL: neurofilament light chain; RDTN: recently diagnosed, treatment-naive. aRDTN participants were those who had not received a prior disease-modifying therapy and who had received a diagnosis in the 36 months before screening. bThe annual rate of brain volume change was estimated according to the slope from a random coefficient model based on assessment of the percentage change from baseline in brain volume performed at month 12, month 24 and the end of treatment and/or trial. cThe total number of participants in the treatment group for whom the response variable was defined. MRI-related outcomes. Ofatumumab reduced the treatment groups (ofatumumab, 84.7%; terifluno- mean number of Gd+T1 lesions per scan from base- mide, 86.0%). AEs that occurred in at least 10% of line to the end of the trial by 95% versus teriflunomide participants with ofatumumab were nasopharyngitis, (0.02 vs. 0.39; rate ratio (95% CI): 0.05 (0.02, 0.10); injection-related systemic reactions, headache and p < 0.001) (Table 2; Figure 3). Ofatumumab also upper respiratory tract infections; and with teriflu- reduced the annualized rate of new or enlarging T2 nomide were nasopharyngitis, alopecia, upper res- lesions by 82% versus teriflunomide (Table 2). There piratory tract infection, injection-related systemic was no between-group difference in annual percentage reactions, headache and fatigue. SAEs were reported change in brain volume from baseline (Table 2). in 22 participants (7.0%) receiving ofatumumab and 16 (5.3%) receiving teriflunomide. There were no No evidence of disease activity 3. Ofatumumab sig- deaths. nificantly increased the odds of achieving NEDA-3 versus teriflunomide in all study periods evaluated Injection-related reactions. Injection-related systemic (Table 2). The proportions of ofatumumab-treated and reactions were reported for 62 participants (20.1%) teriflunomide-treated participants achieving NEDA-3 receiving ofatumumab and 45 participants (15.0%) in were: 47.0% and 24.7% in year 1, 92.1% and 46.8% the teriflunomide group receiving placebo injec- in year 2 and 44.6% and 17.7% from baseline through tions. Incidence of injection-site reactions was 14.0% year 2, respectively. (n = 44) and 7.0% (n = 21), respectively. After the first injection, the frequency of injection-related sys- Serum NfL concentration. There was no significant temic reactions was similar in both groups (Figure 4). difference in mean serum NfL concentration with Nearly all (99.4%) injection-related reactions (sys- ofatumumab and teriflunomide at month 3 (8.72 temic and site) were mild to moderate in severity (no vs. 9.13 pg/mL; ratio (95% CI): 0.95 (0.88, 1.03); Grade 4 injection-related reactions were reported). p = 0.258) (Table 2). However, mean serum NfL con- Only one participant receiving ofatumumab experi- centration was significantly lower (both p < 0.001) in enced a Grade 3, non-serious injection-related the ofatumumab group than in the teriflunomide group systemic reaction and discontinued the study treat- at month 12 (6.60 vs. 8.61 pg/mL; ratio (95% CI): ment. This participant experienced abdominal pain, 0.77 (0.71, 0.83)) and month 24 (6.47 vs. 8.10 pg/mL; asthenia, pruritis general and urticaria that resolved ratio (95% CI): 0.80 (0.74, 0.86)) (Table 2). within 1 day after treatment with an antihistamine. No anaphylaxis related to ofatumumab treatment was observed. Participants received training and self- Safety in RDTN participants administered ofatumumab at day 7, day 14 and month Safety outcomes are summarized in Table 3; similar 1 visits, under the supervision of a healthcare pro- proportions of participants experienced AEs in both vider. From the fifth injection, 48–95% of participants 6 journals.sagepub.com/home/msj J Gärtner, SL Hauser et al. (a) 24 Ofatumumab 20 mg Teriflunomide 14 mg 20 K-M estimate of cumulative 16 event rate (%) 12 8 4 0 0 3 6 9 12 15 18 21 24 27 30 33 Months Number of patients at risk 312 298 292 284 277 271 192 100 51 16 1 0 300 292 282 272 254 245 171 99 48 16 0 0 (b) 24 Ofatumumab 20 mg Teriflunomide 14 mg 20 K-M estimate of cumulative 16 event rate (%) 12 8 4 0 0 3 6 9 12 15 18 21 24 27 30 33 Months Number of patients at risk 312 298 292 285 279 273 196 103 54 17 1 0 300 292 282 274 258 251 174 102 51 17 0 0 Figure 1. Kaplan–Meier estimates of percentage of patients with disability worsening confirmed at: (a) 3 and (b) 6 months. Disability worsening confirmed at 3 or 6 months was defined as an increase from baseline in the Expanded Disability Status Scale (EDSS) score (on a scale from 0 to 10.0, with higher scores indicating worse disability) that was sustained for at least 3 or 6 months. For patients with a baseline EDSS score of 0, an increase in the EDSS score of at least 1.5 points was required; for patients with a baseline EDSS score of 1.0 to 5.0, the criterion was an increase of at least 1.0 points; and for patients with a baseline EDSS score of at least 5.5 points, the criterion was an increase of at least 0.5 points. self-injected at home, increasing to 60%–95% from Nasopharyngitis and upper respiratory tract infection injection 10 onwards. were the most common and were mostly mild to mod- erate in severity. Six participants (1.9%) receiving Infections. Similar proportions of participants in ofatumumab and two (0.7%) receiving teriflunomide both treatment groups experienced infections (ofatu- had serious infections. No opportunistic infections mumab, 56.1%; teriflunomide, 56.5%) (Table 3). were reported. journals.sagepub.com/home/msj 7 Multiple Sclerosis Journal 00(0) (a) (b) 20 20 Proportion of participants (%) Proportion of participants (%) Ofatumumab 20 mg Ofatumumab 20 mg 15 Teriflunomide 14 mg 15 Teriflunomide 14 mg 10 10 5 5 0 0 0 3 6 9 12 15 18 21 24 27 30 33 0 3 6 9 12 15 18 21 24 27 30 33 Months Months No. of participants No. of participants 274 267 262 257 251 247 179 93 44 14 0 274 267 262 257 252 248 181 94 46 15 0 230 226 220 215 206 198 133 75 38 14 0 230 226 220 215 207 200 134 76 39 14 0 (c) (d) 20 20 Proportion of participants (%) Proportion of participants (%) Ofatumumab 20 mg Ofatumumab 20 mg 15 Teriflunomide 14 mg 15 Teriflunomide 14 mg 10 10 5 5 0 0 0 3 6 9 12 15 18 21 24 27 30 33 0 3 6 9 12 15 18 21 24 27 30 33 Months Months No. of participants No. of participants 275 267 262 257 251 247 179 93 44 14 0 275 267 262 257 252 248 181 94 46 15 0 233 228 220 215 206 198 133 75 38 14 0 233 228 220 215 207 200 134 76 39 14 0 Figure 2. Kaplan–Meier analyses of time to PIRA in RDTN participants: (a) time to 3mPIRA in participants without confirmed relapses on study, (b) time to 6mPIRA in participants without confirmed relapses on study, (c) time to 3mPIRA in participants without confirmed relapses on study or before 3mCDW and (d) time to 6mPIRA in participants without confirmed relapses on study or before 6mCDW. 3mCDW: 3-month confirmed disability worsening; 3mPIRA: 3-month progression independent of relapse activity; 6mCDW: 6 month confirmed disability worsening; 6mPIRA: 6-month progression independent of relapse activity; PIRA: progression independent of relapse activity; RDTN: recently diagnosed, treatment-naive. Other safety findings. Two malignancies (0.6%) were achieved for 90% of patients by week 4, and 98% of reported in the ofatumumab group, and one (0.3%) in patients by week 12 (Supplementary Figure 2). The the teriflunomide group (all basal cell carcinomas). No effect of ofatumumab on B-cell depletion was consis- congenital abnormalities or birth defects were reported tent across body weight quartiles. After the last ofatu- among participants exposed to either treatment during mumab dose in participants who stopped treatment pregnancy (ofatumumab, two participants; terifluno- for any reason, B-cell repletion (levels above the mide, three participants). Neutropenia, a known risk LLN) was observed in 12 of 27 participants (44%) by associated with teriflunomide, occurred more fre- week 24, 13 of 21 (62%) by week 36, 6 of 8 (75%) by quently in the teriflunomide group (four participants) week 48 and 8 of 8 (100%) by week 60. than in the ofatumumab group (two participants). B- cell levels. B-cell depletion to below the lower limit Discussion of normal (LLN) (40 cells/µL) was achieved quickly In RDTN participants from the phase III ASCLEPIOS with ofatumumab. By week 2, 97% of participants I and II trials, ofatumumab was superior to teriflu- had B-cell levels below the LLN and this proportion nomide in reducing relapse rates, delaying all-cause remained constant until the end of the trial. B-cell disability worsening, including PIRA, with a near- depletion of less than or equal to 10 cells/µL was complete abrogation of new focal inflammatory 8 journals.sagepub.com/home/msj J Gärtner, SL Hauser et al. Figure 3. Empirical lesion incidence maps for Gd+T1 lesions in all RDTN participants: (a) at baseline (N = 615); (b) 12 months after initiation of treatment with ofatumumab (N = 314); and (c) 12 months after initiation of treatment with teriflunomide (N = 301). Gd+, gadolinium-enhancing; RDTN: recently diagnosed, treatment-naive. journals.sagepub.com/home/msj 9 Multiple Sclerosis Journal 00(0) Table 3. AEs in RDTN participants from the ASCLEPIOS I and II trials (safety analysis set). Safety event Ofatumumab (N = 314) Teriflunomide (N = 301) AEs 266 (84.7) 259 (86.0) AEs leading to treatment discontinuation 19 (6.1) 7 (2.3) Most common AEs (⩾10% in any group) Nasopharyngitis 78 (24.8) 70 (23.3) Injection-related systemic reaction 63 (20.1) 45 (15.0) Headache 45 (14.3) 47 (15.6) Upper respiratory tract infection 40 (12.7) 49 (16.3) Fatigue 28 (8.9) 30 (10.0) Alopecia 16 (5.1) 50 (16.6) Infections (all) 176 (56.1) 170 (56.5) SAEs 22 (7.0) 16 (5.3) Infectionsa 6 (1.9) 2 (0.7) Malignancy 2 (0.6)b 1 (0.3)c Deaths 0 (0.0) 0 (0.0) AE: adverse event; N: total number of participants included in the analysis; RDTN: recently diagnosed, treatment-naive; SAE: serious AE. Data are shown as the number of participants (%) with at least one event. aThree cases of appendicitis, one case of influenza, one case of neutropenic sepsis, one case of upper respiratory tract infection in the ofatumumab group, one case of appendicitis and one case of pneumonia in the teriflunomide group. bAll malignancies were basal cell carcinomas. cOne case of basal cell carcinoma was not listed as an SAE. 16 Ofatumumab 20 mg Grade 1 Grade 2 Grade 3 14 Teriflunomide 14 mg Grade 1 Grade 2 Proportion of participants (%) 12 10 8 6 4 2 0 1 2 3 4 5 6 7 8 9 10 Injection number No. of participants 314 301 311 301 311 301 310 301 307 300 303 299 299 295 298 293 297 290 294 287 Figure 4. Proportion of RDTN participants with injection-related systemic reactions following the first 10 injections in the study. RDTN: recently diagnosed, treatment-naive. Only Common Terminology Criteria for Adverse Events grades that were observed in the data are shown. Only reactions/symptoms occurring within 24 hours after injections are included (i.e. time to onset of reaction ⩽ 24 hours). As teriflunomide is taken as an oral medication, injection-related systemic reactions in participants treated with teriflunomide are in response to placebo injections. activity. These findings are consistent with those Among patients early in the MS disease course, disa- observed in the overall ASCLEPIOS population22 bility accrual was previously thought to be exclu- and show that ofatumumab can delay disability wors- sively attributable to incomplete recovery from ening in early MS. relapses. However, in agreement with other studies of 10 journals.sagepub.com/home/msj J Gärtner, SL Hauser et al. patients with RMS on DMT,4–6 we observed that, and second year of treatment, respectively, versus when relapses and acute symptoms were suppressed, teriflunomide. Notably, 9 of 10 ofatumumab-treated proportionally more disability events occurred in the participants achieved NEDA-3 during year 2, which form of progression events detected in the course of might better reflect the long-term preventive effect regular 3-monthly neurological assessments by EDSS on disease activity and worsening of disability. raters blinded to treatment. In the RDTN group, most Achieving NEDA-3 during the first 2 years of treat- patients (92.3% in the ofatumumab arm versus 87.7% ment has been associated with lower odds of disability in the teriflunomide arm) remained clinically stable at 7–8 years.18,30 and did not experience any 3mCDW events during the entire study. Approximately half of the observed The safety and tolerability profile of ofatumumab in CDW events in RDTN patients occurred in the RDTN participants was consistent with that in the absence of overt relapses, although an effect of sub- overall ASCLEPIOS population,22 with no safety clinical relapse biology cannot be ruled out. events that would prevent the use of ofatumumab Progression independent of relapse activity in early early in MS. Injection-related systemic reactions were relapsing–remitting MS is thought to be related to mostly mild to moderate and limited to the first injec- neurodegenerative processes such as continuous tion with ofatumumab; reactions with subsequent neuroaxonal damage and brain volume loss pro- injections were largely similar to those observed with cesses that have been shown to be present from the placebo injections in the teriflunomide arm. After ini- initial stages of RMS.10,26 In patients with RMS, a tial training, most participants self-injected at home. high baseline T2 lesion volume has been consistently The short-term safety and tolerability profile of ofatu- identified as an important risk factor for on-study mumab also seems to compare favourably with that brain volume26 and neuronal27 loss. This suggests that of other treatments considered suitable for use in MS lesion prevention should be a target in the treat- early MS, such as interferon-β and glatiramer ace- ment of MS, as it is likely to underlie insidious dis- tate, although long-term safety data for ofatumumab ease progression.28,29 are not yet available.31,32 Compliance with ofatu- mumab in RDTN participants was high, consistent Ofatumumab delayed disability accrual compared with the rates seen in the overall ASCLEPIOS I and with teriflunomide in RDTN participants by reducing II population. The high compliance with ofatumumab the risk of CDW and PIRA, albeit not significantly in in this study lasting 30 months, as compared with sensitivity analyses that used a more rigorous defini- other injectable DMTs,33,34 might be explained by the tion of PIRA requiring no relapses within 90 days of low frequency of injections and lack of need for a disability event. The ASCLEPIOS studies were accompanying medications to prevent or mitigate powered to show an effect in the overall combined injection-related adverse events. trials, not in subgroups. Thus, the small sample size and relatively low number of events using the more stringent definitions may explain the lack of statisti- Conclusion cal significance despite a clinically meaningful effect Ofatumumab had a superior benefit–risk profile in size. RDTN patients compared with teriflunomide, with an almost complete abrogation of inflammatory disease The findings of this comparative analysis of ofatu- activity and no unexpected safety signals, supporting mumab versus teriflunomide efficacy in early RMS its use as a first-line treatment in early MS. are consistent with those from a network analysis that suggested a benefit for ofatumumab versus other Acknowledgements first-line therapies.23 ARR comparisons in RDTN The authors thank the participants for their involve- participants suggest that, on average, patients would ment in and commitment to the ASCLEPIOS trials experience neurological symptoms manifesting in and the clinical study team for the conduct of the mostly temporary EDSS score changes once in study. The authors are grateful to Angela Pozo Ramajo 11 years with ofatumumab and once in 5.5 years with (Oxford PharmaGenesis, Oxford, UK) for providing teriflunomide. MRI findings indicate almost complete medical writing support. These services were funded abrogation of focal inflammatory disease with ofatu- by Novartis Pharma AG. mumab and a substantial associated reduction in annual accrual of lesion burden. Consistent with these Author Contributions clinical and radiological findings, RDTN participants J. G. contributed to data interpretation; manuscript receiving ofatumumab had a 3 and 15 times greater review for intellectual content; and final manuscript likelihood of achieving NEDA-3 during the first approval. S.L.H. contributed to trial design; data journals.sagepub.com/home/msj 11 Multiple Sclerosis Journal 00(0) collection and responses to queries; data review; Declaration of Conflicting Interests data interpretation; manuscript review for intellec- The author(s) declared the following potential con- tual content; and final manuscript approval. A.B.-O. flicts of interest with respect to the research, author- contributed to trial design; data collection and ship and/or publication of this article: J.G., in the past responses to queries; data review; data interpreta- 3 years, has received fees for lectures and consultancy tion; manuscript review for intellectual content; and fees from Bayer, Biogen, Merck, Novartis and Sanofi, final manuscript approval. X.M. contributed to trial as well as funding for a research project from Novartis. design; data collection and responses to queries; data S.L.H. has received personal compensation from review; data interpretation; manuscript review for Alector, Annexon Biosciences, Bionure and Neurona intellectual content; and final manuscript approval. Therapeutics; he has also received travel reimburse- J.A.C. contributed to trial design; data collection ment from F. Hoffmann-La Roche and Novartis for and responses to queries; data review; data interpre- CD20-related meetings and presentations. A.B.-O. tation; manuscript review for intellectual content; has participated as a speaker in meetings sponsored and final manuscript approval. A.H.C. contributed by and received consulting fees and/or grant support to trial design; data collection and responses to que- from Atara Biotherapeutics, Biogen Idec, Celgene/ ries; data review; data interpretation; manuscript Receptos, Janssen/Actelion, MedImmune, Merck/ review for intellectual content; and final manuscript EMD Serono, Novartis, Roche/Genentech and approval. K.D. contributed to data interpretation; Sanofi Genzyme. X.M. has received speaking fees manuscript review for intellectual content; and final and travel expenses for participation in scientific manuscript approval. H.G. contributed to data analy- meetings, has been a steering committee member for sis; manuscript review for intellectual content; and clinical trials, or has participated in advisory boards final manuscript approval. D.A.H. contributed to for clinical trials in the past years with Actelion, trial design; statistical analysis; data review; data Alexion Pharmaceuticals, Bayer, Biogen, Celgene, interpretation; planning of this manuscript; review EMD Serono, EXCEMED, Genzyme, Immunic, of the manuscript for intellectual content; and final MedDay, Merck, the MS International Federation, manuscript approval. B.L. contributed to trial Mylan, NervGen Pharma, the National Multiple design; statistical analysis; data review; data inter- Sclerosis Society, Novartis, Roche, Sanofi Genzyme, pretation; review of the manuscript for intellectual Teva Pharmaceuticals and TG Therapeutics. J.A.C. content; and final manuscript approval. R.P. con- has received personal compensation for consulting tributed to trial design; data review; data interpreta- from Adamas Pharmaceuticals, Atara Biotherapeutics, tion; review of the manuscript for intellectual Bristol Myers Squibb, Convelo Therapeutics, MedDay content; and final manuscript approval. K.R. con- and Mylan, and for serving as an editor of the Multiple tributed to trial design; data review; data interpreta- Sclerosis Journal. A.H.C. has consulted for Biogen, tion; review of the manuscript for intellectual Celgene, EMD Serono, Genentech/Roche, Novartis content; and final manuscript approval. W.S. con- and TG Therapeutics. K.D. has received personal tributed to data review; data interpretation; review of compensation for speaker activities from Novartis and the manuscript for intellectual content; and final Sanofi. In the past 3 years, L.K.’s institution (University manuscript approval. R.W. contributed to trial Hospital of Basel) has received steering committee, design; data review; data interpretation; review of advisory board and consultancy fees used exclu- the manuscript for intellectual content; and final sively for research support in the department, as well manuscript approval. B.K. contributed to data inter- as support of educational activities, from Actelion, pretation; review of the manuscript for intellectual Allergan, Almirall, Baxalta, Bayer, Biogen, Celgene/ content; and final manuscript approval. L.K. con- Receptos, CSL Behring, Desitin, Eisai, EXCEMED, tributed to trial design; data collection and responses F. Hoffmann-La Roche, Genzyme, Japan Tobacco, to queries; data review; data interpretation; manu- Merck, Minoryx Therapeutics, Novartis, Pfizer, script review for intellectual content; and final man- Sanofi Aventis, Santhera Pharmaceuticals and Teva uscript approval. Pharmaceuticals, and license fees for Neurostatus- UHB products. Research at the MS Center in Basel Data Availability Statement has been supported by grants from Bayer, Biogen, the ASCLEPIOS I and II trial data are available on reason- European Union, Inno-Suisse, Novartis, the Swiss MS able request provided the reason for the request is in Society, the Swiss National Research Foundation and line with current ethical and intellectual property require- Roche research foundations. D.A.H., K.R., R.W. and ments surrounding the use of data. Requests should B.K. are employees of Novartis Pharma AG, Basel, be directed through ClinicalStudyDataRequest.com. Switzerland. B.L., R.P. and W.S. are employees of 12 journals.sagepub.com/home/msj J Gärtner, SL Hauser et al. Novartis Pharmaceutical Corporation, East Hanover, progression in disease activity-free relapsing multiple NJ, USA. sclerosis. Ann Neurol 2019; 85(5): 653–666. 7. Pfeifenbring S, Bunyan RF, Metz I, et al. 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