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Background: Ofatumumab is the first fully human anti-CD20 monoclonal antibody, administered with a monthly 20 mg subcutaneous dosing regimen. Objectives: To investigate the efficacy and safety of ofatumumab vs teriflunomide in patients with relapsing multiple sclerosis (MS). Methods: ASCLEPIOS I and II were 2 identical phase 3, double-blind, double-dummy, active comparator-controlled, parallel-group, innovative, adaptive-design (with flexible duration), multicenter trials in patients aged 18-55 years with an Expanded Disability Status Scale score of 0-5.5 at screening. Patients were randomized (1:1) to receive subcutaneous ofatumumab 20 mg (loading dose: days 1, 7, and 14; maintenance dose: every 4 weeks from week 4) or oral teriflunomide 14 mg once daily, for up to 30 months. The primary end point was annualized relapse rate. Key secondary end points included 3- and 6-month confirmed disability worsening (3mCDW/6mCDW), 6-month confirmed disability improvement (6mCDI), magnetic resonance imaging--related outcomes, and serum neurofilament light chain (NfL) levels. Safety and tolerability were also assessed. Results: Of 1882 enrolled patients (ASCLEPIOS I/II: N = 927/955), 1578 completed the core study. Ofatumumab reduced annualized relapse rate (ASCLEPIOS I and II: 50.5% and 58.5%), gadolinium-enhancing T1 lesions (97.5% and 93.8%), and new/enlarging T2 lesions (82.0% and 84.5%) vs teriflunomide (all, P < .001). In the pre-specified ASCLEPIOS I/II pooled analysis, ofatumumab reduced the risk of 3mCDW by 34.4% (P = .002) and 6mCDW by 32.5% (P = .012), and numerically increased the probability to achieve 6mCDI by 35.2% (P = .094), vs teriflunomide. Ofatumumab reduced serum NfL levels vs teriflunomide in the first measurement at month 3 (ASCLEPIOS I, P = .011; ASCLEPIOS II, P < .001) and in all subsequent assessments (all, P < .001). No difference in the slope of brain volume change from baseline was observed between treatments (P = .116 [ASCLEPIOS I] and 0.129 [ASCLEPIOS II] vs teriflunomide). Adverse events occurred in 83.6% and 84.2% of patients receiving ofatumumab and teriflunomide, respectively. Systemic injection-related reactions occurred in 20.6% and 15.3% of ofatumumab and teriflunomide-treated patients, respectively. Rates of serious infections (ofatumumab, 2.5%; teriflunomide, 1.8%) and malignancies (0.5% and 0.3%, respectively) were low. Conclusions: Ofatumumab demonstrated superior efficacy vs teriflunomide, with an acceptable safety profile, in patients with relapsing MS. [ABSTRACT FROM AUTHOR]

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy vs teriflunomide in patients with relapsing multiple sclerosis (RMS) in the phase 3 ASCLEPIOS I/II trials. A decline in serum immunoglobulin (Ig) levels was observed with other anti-CD20 therapies. Objectives: To determine serum IgG and IgM levels and investigate associations between IgG/IgM levels and risk of infections in ofatumumab-treated patients. Methods: In the ASCLEPIOS trials, patients received subcutaneous ofatumumab 20 mg on days 1, 7, and 14, week 4, and every 4 weeks thereafter or once-daily oral teriflunomide 14 mg for up to 30 months (average follow-up duration: 18 months). Serum IgG/IgM levels were monitored at baseline, weeks 4 and 12, and every 12 weeks thereafter (ofatumumab, n = 946; teriflunomide, n = 936). A notable decline in IgG/IgM levels was defined as 50% of the lower limit of normal (LLN) at any time (IgG, 3.5 g/L; IgM, 0.2 g/L). Outcomes included the proportion of patients with IgG/IgM levels <50% LLN, and association between low IgG/IgM levels and incidence of infections. Results: At week 120, no patients reached IgG levels <50% LLN with ofatumumab (median IgG [g/L]: ASCLEPIOS I and II, 10.57 and 9.57, respectively) or teriflunomide (10.01 and 9.65). The proportion of patients who reached IgM levels <50% LLN was 2.1% (n = 20/944) with ofatumumab (median IgM [g/L]: 0.91 and 0.59) and 0.6% (n = 6/933) with teriflunomide (0.84 and 0.92) at week 120. Of these patients, 5 had infections with ofatumumab, mostly nonserious (grade 1/2 in severity), except one grade 3 recurrent urinary tract infection, but all infections were resolved. One patient on teriflunomide who had nasopharyngitis had not recovered at the time of last follow-up. Conclusions: A reduction in serum IgG levels <50% LLN was not observed with either treatment. IgM levels showed reductions with both ofatumumab and teriflunomide treatments; there was no apparent association with increased rate of serious/nonserious infections in patients with RMS. [ABSTRACT FROM AUTHOR]

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, with a monthly 20 mg subcutaneous (s.c.) dosing regimen, demonstrated superior efficacy (reductions in clinical relapses by 51%-59%, disability worsening by 33%-34%, and gadolinium-enhancing lesions by 94%-98%) vs teriflunomide in the two phase 3 ASCLEPIOS I/II relapsing multiple sclerosis (RMS) trials. Injection-related reactions (IRRs) were the most common adverse events (AEs) observed. Objectives: To characterize the risk of IRRs (systemic and local site reactions) observed with ofatumumab in patients with RMS. Methods: In the pooled ASCLEPIOS I/II trials, patients were randomized (1:1) to receive s.c. ofatumumab 20 mg (n = 946) (loading dose: days 1, 7 and 14; maintenance dose: every 4 weeks from week 4) or oral teriflunomide 14 mg once daily (n = 936), for up to 30 months. Patients in the teriflunomide group received matching placebo injections. All patients received the first 4 injections at the clinic and subsequent injections at home. Premedication was recommended, but not mandatory. Both systemic (during and within 24 hours postinjection) and local site IRRs (at any time) were reported. Results: 20.6% (n = 195) of the patients in the ofatumumab group and 15.3% (n = 143) in the teriflunomide group had ≥1 systemic IRR. Incidence of systemic IRRs with the first injection was 14.4% with ofatumumab vs 7.5% with teriflunomide. The incidence of systemic IRRs decreased with subsequent doses and was similar to the matching placebo injections in the teriflunomide group. Most IRRs (99.8%) were grade 1/2 in severity; grade 3 IRRs were observed in 2 patients (0.2%) with ofatumumab at the first injection (1 of which was reported as a serious AE) vs none with teriflunomide. One additional IRR (grade 1) was also reported as a serious AE with ofatumumab. The serious IRRs (0.2%) were manageable, and patients continued treatment with no recurrences. No life-threatening IRRs were reported during the study. The most frequent (≥2%) IRR symptoms observed with ofatumumab were fever, headache, myalgia, chills, and fatigue. Most local site IRRs were mild to moderate in severity and nonserious in nature; the most frequently reported symptoms (≥2%) included erythema, pain, itching, and swelling. Conclusions: Systemic and local IRRs with ofatumumab 20 mg s.c. were mostly mild to moderate in severity. Beyond the first injection, IRRs were no more frequent with ofatumumab vs matching placebo injections. [ABSTRACT FROM AUTHOR]

Background: Ofatumumab (OMB), the first fully human anti-CD20 monoclonal antibody, administered with a monthly 20-mg subcutaneous (s.c.) dosing regimen, demonstrated superior efficacy vs teriflunomide (TER) in the two phase 3 ASCLEPIOS I and ASCLEPIOS II trials in relapsing multiple sclerosis. Patients who completed the double-blind phase of the trials on study drug were eligible for transition to the ongoing openlabel extension study ALITHIOS. Objectives: To evaluate treatment discontinuation and compliance with OMB and TER treatment in the phase 3 ASCLEPIOS I/II trials and to assess patients' acceptance of transitioning to the ALITHIOS study. Methods: In ASCLEPIOS I/II, patients were randomized (1:1) to OMB 20 mg s.c. (loading doses, administered at clinic: days 1, 7, and 14; maintenance doses, administered at home: every 4 weeks from week 4) or TER 14 mg (orally once daily), for up to 30 study months. Here we report on treatment discontinuation and compliance (defined as exposure to study drug [days]/on-treatment period [days] x 100%) in ASCLEPIOS trials and percentage of eligible ASCLEPIOS patients who accepted to transition to the ALITHIOS study and the compliance in this study. Results: In ASCLEPIOS I, 759/927 (81.9%) randomized patients (OMB: 400/465 [86.0%]; TER: 359/462 [77.7%]) completed the study on study drug. The proportion of patients discontinuing treatment were OMB, 14.0%; TER, 21.2%. The most common reasons for discontinuation (>2% in any group) were patient/guardian decision (OMB: 4.9%; TER: 8.2%), adverse event (OMB: 5.2%; TER: 5.0%), and physician decision (OMB: 2.2%; TER: 6.5%). In ASCLEPIOS II, 753/955 (78.8%) randomized patients (OMB: 383/481 [79.6%]; TER: 370/474 [78.1%]) completed the study on study drug. Proportion of patients discontinuing treatment were OMB, 20%; TER, 21.5%; reasons for discontinuation were patient/guardian decision (OMB: 7.3%; TER: 7.8%), adverse event (OMB: 5.6%; TER: 4.9%), and physician decision (OMB: 5.2%; TER: 6.8%). In both trials compliance was high (>95% of patients falling in the ≥90% compliance category) across treatment groups. Approximately 90% of eligible patients consented to participate in the open-label study; compliance data will be presented. Conclusions: In ASCLEPIOS trials compliance with home-administered s.c. OMB was high and fewer patients discontinued OMB as compared to TER. Most eligible patients accepted transition to the open-label ALITHIOS extension study. [ABSTRACT FROM AUTHOR]