Table 1.
Summary of studies in the ofatumumab clinical program in MS
| Clinical study | Clinical phase | Mode of administration; ofatumumab dosing; treatment duration | Number of participants | Primary outcome measure | Other outcome measures | Results |
|---|---|---|---|---|---|---|
| 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 |
| ASCLEPIOS I and II [16, 41] | 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 |
| ALITHIOS [43, 44] | 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 |
Ab antibody, AE adverse event, ARR annualized relapse rate, CDI confirmed disability improvement, CDW confirmed disability worsening, CI confidence interval, Cmax maximum plasma concentration, ECG electrocardiogram, EDSS Expanded Disability Status Scale, Gd+ gadolinium-enhancing, HR hazard ratio, IRR injection-related reaction, IV intravenous, MRI magnetic resonance ratio, MSFC Multiple Sclerosis Functional Composite, NfL neurofilament light, PFS pre-filled syringe, PK pharmacokinetic, q4w every 4 weeks, q12w every 12 weeks, RDTN recently diagnosed and treatment-naïve, SAE serious adverse event, SC subcutaneous