Ofatumumab is the first fully human anti-CD20 monoclonal antibody to be approved for the treatment of relapsing multiple sclerosis. |
Rapid and sustained near-complete B-cell depletion can be achieved with ofatumumab treatment and maintained with monthly subcutaneous doses of 20 mg/0.4 ml. |
The tolerability profile and at-home self-administration of ofatumumab enables patients to be compliant with and persistent on therapy over time. |
The benefit–risk profile of ofatumumab supports its early initiation in the overall RMS population in order to maximize its long-term treatment benefits. |
Digital Features
Introduction
Properties of Ofatumumab
Clinical Development program of ofatumumab in MS and the 20 mg subcutaneous dosing regimen
Clinical study | Clinical phase | Mode of administration; ofatumumab dosing; treatment duration | Number of participants | Primary outcome measure | Other outcome measures | Results |
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IV infusion study [39] | Phase 2 | IV; 2 infusions, 100 mg, 300 mg, or 700 mg 2 weeks apart or placebo (at Week 24, patients crossed over to opposite treatment arm); 48 weeks | 38 | Cumulative number of new Gd + lesions, new and/or enlarging T2 lesions, and T1 hypointense lesions measured on monthly MRI | Proportion of relapse-free patients; relapse rate and change in EDSS and MSFC scores from baseline to Week 24 and from Week 24 to Week 48; safety (AE assessments, MRI, and clinical laboratory tests) | New brain MRI lesion activity was suppressed by > 99% in the first 24 weeks after ofatumumab administration across all doses, with statistically significant reductions (p < 0.001) favoring ofatumumab vs. placebo found in the number of new T1 Gd + lesions, total T1 Gd + lesions, and new and/or enlarging T2 lesions Ofatumumab did not provide significant benefit regarding T1 hypointense lesions Ofatumumab was associated with profound and selective reduction of B cells at each dose as measured by CD19 + expression No unexpected safety signals were identified for ofatumumab in the context of other indications, including rheumatoid arthritis |
MIRROR [40] | Phase 2b | SC; 3, 30, or 60 mg q12w or 60 mg q4w or placebo; 24 weeks | 232 | Cumulative number of new Gd + lesions (per brain MRI) at Week 12 | Cumulative number of new Gd + lesions at Week 24; cumulative number and total volume of new and new plus persisting Gd + lesions; new and/or newly enlarging T2 lesions; T1-hypointense lesions at Weeks 12 and 24; safety | The cumulative number of new lesions was reduced by 65% for all ofatumumab doses vs placebo (p < 0.001) Post-hoc analysis (excluding the Week 4 scan, consistent with the phase 2 approaches with other anti-CD20 products) revealed a clear dose–response and estimated a ≥ 90% lesion reduction vs. placebo (Week 12) for all cumulative ofatumumab doses ≥ 30 mg/12 weeks Dose-dependent CD19 B-cell depletion was observed SC ofatumumab demonstrated overall good tolerability and no new/unexpected safety findings No serious IRRs: IRRs were only seen at doses ≤ 30 mg/12 weeks |
Phase 3 | SC; 20 mg q4w after 20-mg loading doses at Days 1, 7, and 14 or teriflunomide; 30 months | 1882 | ARR | 3- or 6-month CDW; 6-month CDI; number of Gd + lesions per T1-weighted MRI scan; annualized rate of new or enlarging lesions on T2-weighted MRI scan; serum NfL chain levels at Month 3; change in brain volume; safety | ARRs in the ofatumumab and teriflunomide groups were 0.1 and 0.2, respectively, in Trial 1 (difference, − 0.1; 95% CI, − 0.2 to − 0.1; p < 0.001) and 0.1 and 0.3 in Trial 2 (difference, − 0.2; 95% CI, − 0.2 to − 0.1; p < 0.001) 10.9% and 15.0% of patients on ofatumumab and teriflunomide, respectively, experienced 3-month CDW (HR, 0.7; p = 0.002) 8.1% and 12.0% of patients experienced 6-month CDW (HR, 0.7; p = 0.01) 11.0% and 8.1% of patients experienced 6-month CDI (HR, 1.4; p = 0.09) The mean number of Gd + lesions per T1-weighted MRI scan (1 lesion per 50 scans) was reduced by 97% and 94% with ofatumumab vs. teriflunomide (p < 0.001) in trial 1 and trial 2, respectively The annualized rate of lesions on T2-weighted MRI and serum NfL chain levels were reduced with ofatumumab vs. teriflunomide AEs that occurred in at least 10% of patients on ofatumumab were IRRs, nasopharyngitis, headache, injection-site reaction, upper respiratory tract infection, and urinary tract infection – AEs and AE rates were similar with ofatumumab and teriflunomide treatment; SAEs were reported in 9.1% of patients on ofatumumab and 7.9% of patients on teriflunomide In the ofatumumab group, two cases of basal-cell carcinoma, one case of malignant melanoma in situ, one case of recurrent non-Hodgkin’s lymphoma, and one case of invasive breast carcinoma were reported There was also one case of myocardial infarction in the ofatumumab group In the teriflunomide group, two cases of basal-cell carcinoma, one case of cervix carcinoma and one case of fibrosarcoma were reported Analysis of efficacy and safety of ofatumumab vs teriflunomide in the subgroup of RDTN patients (n = 615) from ASCLEPIOS I/II found ofatumumab to be an appropriate treatment option also in early patients | |
APLIOS (17) | Phase 2 | SC; 20 mg q4w after 20-mg loading doses at Days 1, 7, and 14; 12 weeks | 256 | Area under the plasma concentration–time curve over the dosing interval and Cmax after drug administration | Plasma concentration–time curve over the dosing interval and Cmax; proportion of patients with anti-ofatumumab Abs; MRI lesion activity; safety (AEs, including injection-related systemic reactions and laboratory abnormalities) | Abdominal ofatumumab PK exposure was bioequivalent for autoinjector and PFS [geometric mean area under the plasma concentration–time curve over the dosing interval, 487.7 vs. 474.1 h × μg/mL (ratio 1.0); Cmax, 1.4 vs. 1.4 μg/mL (ratio 1.0)] B-cell counts (median cells/μL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14) The mean number of new/persisting Gd + T1 lesions decreased from 1.5 at baseline to 0.8, 0.3, and 0.1 by Weeks 4, 8, and 12, respectively; the proportion of patients free of Gd + T1 lesions increased over time in all
ofatumumab groups Ofatumumab had favorable safety and tolerability profiles, in line with those reported in the ASCLEPIOS I/II trials |
APOLITOS [42] | Phase 2 | SC; 20 mg q4w after 20-mg loading doses at Days 1, 7, and 14 or placebo; total duration 48 weeks (placebo-controlled initial 24 weeks) | 64 | Number of Gd + T1 lesions per scan over 24 weeks | Consistency of efficacy of ofatumumab on the cumulative number of Gd + T1 lesions on MRI scans at Weeks 12, 16, 20, and 24 across regions (Japan and Russia); the efficacy of ofatumumab vs. placebo on the annualized rate of new or enlarging T2 lesions; ARR; time to first relapse; safety | Ofatumumab reduced Gd + T1 lesions vs. placebo by 93.6% (p < 0.001); results were consistent across regions Ofatumumab reduced annualized T2 lesion and relapse rate vs. placebo by Week 24 Both groups showed a benefit from ofatumumab in the APOLITOS extension-part (up to 48 weeks) Incidence of AEs was lower with ofatumumab vs. placebo (69.8% vs. 81.0%); IRRs were most common No deaths, opportunistic infections, or malignancies |
Ongoing open-label extension of ASCLEPIOS I/II, APLIOS, APOLITOS | SC; 20 mg q4w for up to 5 years | 1367 | Number of patients that experience an AE or abnormal laboratory, vital and/or ECG results and positive suicidality outcomes | ARRs; confirmed 3- and 6- month disability worsening; confirmed 6-, 12- and 24-month disability improvement and improvement until end of study; safety | 86.2% (n = 1698) of patients experienced at least one AE in the ASCLEPIOS I/II + extension studies Overall rate of AEs and SAEs remained consistent with the rates observed during ASCLEPIOS I/II No new safety signals, compared to those reported in the ASCLEPIOS I and II trials, were identified In the between-group analysis, there was a 43.4% reduction in the number of confirmed relapses and near complete suppression of MRI lesions in the continuous ofatumumab group vs. the teriflunomide-ofatumumab switch group |
Efficacy and Safety of Ofatumumab SC in RMS
Patients with at least one event, n (%) | ASCLEPIOS I/II ofatumumab (n = 946) | ASCLEPIOS I/II teriflunomide (n = 936) | Long-term (core + ALITHIOS extension) overall ofatumumab (n = 1969)a | |||
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n (%) | EAIR (95% CI) | n (%) | EAIR (95% CI) | n (%) | EAIR (95% CI) | |
Patients with at least one AE | 791 (83.6) | 188.6 [175.9, 202.2] | 788 (84.2) | 188.9 [176.2, 202.6] | 1698 (86.2) | 135.1 [128.8, 141.7] |
Patients with at least one SAE | 83 (8.8) | 5.6 [4.5, 6.9] | 73 (7.8) | 4.9 [3.9, 6.2] | 242 (12.3) | 5.0 [4.4, 5.6] |
AEs leading to treatment discontinuation | 54 (5.7) | – | 49 (5.2) | – | 128b (6.5) | – |
Infections | 488 (51.6) | 51.1 [46.8, 55.9] | 493 (52.7) | 52.6 [48.1, 57.4] | 1149 (58.4) | 41.0 [38.7, 43.4] |
Serious infections | 24 (2.5) | 1.6 [1.0, 2.3] | 17 (1.8) | 1.1 [0.7, 1.8] | 78 (4.0) | 1.5 [1.2, 1.9] |
Injection-related systemic reactions | 195 (20.6) | 15.5 [13.5, 17.8] | 143 (15.3) | 10.9 [9.3, 12.8] | 492 (25.0) | 12.4 [11.3, 13.5] |
Injection site reactions | 103 (10.9) | 7.2 [5.9, 8.7] | 52 (5.6) | 3.5 [2.7, 4.7] | 233 (11.8) | 5.0 [4.4, 5.7] |
Malignancies | 5 (0.5) | 0.3 [0.1, 0.8] | 4 (0.4) | 0.3 [0.1, 0.7] | 17 (0.9) | 0.3 [0.2, 0.5] |
Deaths | 0 | 0 | 1 (0.1) | – | 6c (0.3) | – |
Confirming the Optimal Dose Regimen for Ofatumumab: Pharmacokinetic–Pharmacodynamic Model Simulations of the Ofatumumab SC Dose
B-Cell Repletion Kinetics
Longer-Term Safety Profile of Ofatumumab SC and Immune Maintenance
Immune Maintenance with Ofatumumab SC
Immune Maintenance with Ofatumumab SC and COVID-19
Tolerability of IV Versus SC Ofatumumab
Patients with at least one event, n (%) | SC doses | IV doses | ||||||
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3 mg q12wa (n = 34) | 20 mg q4w (n = 1873) | 30 mg q12wa (n = 32) | 60 mg q12wa (n = 34) | 60 mg q4wa (n = 64) | 100 mg (n = 12) | 300 mg (n = 15) | 700 mg (n = 11) | |
Injection- or infusion-related reactions | 13 (38.2) | 435 (23.2) | 11 (34.4) | 14 (41.2) | 30 (46.9) | 8 (66.7) | 12 (80.0) | 10 (90.9) |
Injection- or infusion-related reactions with first injection/infusion | 3 (8.8) | 322 (17.2) | 9 (28.1) | 7 (20.6) | 15 (23.4) | 6 (50.0) | 9 (60.0) | 6 (54.5) |
Serious reaction | 0 | 2 (0.1) | 0 | 1 (2.9) | 2 (3.1) | 0 | 0 | 0 |
Treatment discontinuation | 1 (2.9) | 1 (0.1) | 1 (3.1) | 0 | 1 (1.6) | 0 | 1 (6.7) | 0 |
Treatment interrupted | 0 | 0 | 0 | 0 | 0 | 5 (41.7)b | 9 (60.0)b | 8 (72.7)b |
Severe injection- or infusion-related reactions (Grade ≥ 3) | 1 (2.9) | 4 (0.2) | 0 | 1 (2.9) | 1 (1.6) | 0 | 0 | 2 (18.2) |
Cytokine release syndrome | 0 | 0 | 0 | 1 (2.9) | 0 | 0 | 2 (13.3) | 0 |