Rapid and sustained B-cell depletion with subcutaneous ofatumumab in relapsing multiple sclerosis: APLIOS, a randomized phase-2 study

Abstract

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS).

Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion.

Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUC_τ) and maximum plasma concentration (C_max) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed.

Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUC_τ, 487.7 vs 474.1 h × µg/mL (ratio 1.03); C_max, 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated.

Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.

Keywords: Ofatumumab; autoinjector pen; bioequivalence; multiple sclerosis; pharmacokinetics; pre-filled syringe.

Figure 1.

APLIOS patient flow chart. One patient in the PFS-abdomen group discontinued the study following a Grade-2 AE (blood IgM level decreased). Two patients in the PFS-abdomen group, including the patient who discontinued the study, did not contribute to the bioequivalence analysis because they missed the dose at Week 8 and had no data available for the dosing interval (Weeks 8–12). AE: adverse event; AI: autoinjector; PFS: pre-filled syringe; PK, pharmacokinetic.

Figure 2.

Plasma concentrations of ofatumumab by nominal visit. The blue vertical arrows indicate the timing of dose administration. The shaded region indicates the Week 8−12 dosing interval that was considered for bioequivalence testing. AI: autoinjector; PFS: pre-filled syringe.

Figure 3.

(a) Median number of B-cells over 12 weeks with subcutaneous ofatumumab 20 mg (N = 284), (b) proportion of patients with B-cells < 10 µL over time (N = 284), and (c) proportion of patients with B-cells < 10 µL over time stratified by body-weight quartile. The blue vertical arrows indicate the timing of dose administration. The analysis considered data until 30 days after the last injection. The shaded bands in parts (a) and (b) are 95% confidence intervals calculated using the Clopper–Pearson method. Q: quartile.

Figure 4.

(a) Number of new or persistent Gd+ T1 lesions and (b) proportion of patients free of Gd+ T1 lesions over 12 weeks with ofatumumab treatment. Pre-dose MRI assessments are displayed as time 0 on the x-axis. The analysis considers scans collected until 30 days after the last injection date. Gd+ T1 lesion counts from scans collected in the 14 days after termination of steroid therapy are excluded from the analysis. The shaded bands are 95% confidence intervals calculated (a) from bootstrap and (b) using the Clopper–Pearson method. Gd+: gadolinium-enhancing.