Author Of 2 Presentations
P0236 - Serum immunoglobulin levels and infection risk in the Phase 3 trials of ofatumumab in relapsing multiple sclerosis (ID 1566)
Abstract
Background
Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy vs teriflunomide with a favorable safety profile in relapsing MS (RMS) patients in the Phase 3 ASCLEPIOS I/II trials. Reductions in serum immunoglobulin (Ig) M and IgG levels are associated with anti-CD20 therapies.
Objectives
To assess the effect of ofatumumab on serum Ig levels and evaluate potential association between a decrease in IgM/IgG levels and risk of infections.
Methods
Patients were randomized to receive subcutaneous ofatumumab 20 mg (initial doses: Days 1, 7, and 14; subsequent doses: every 4 weeks from Week (W) 4 onwards) or oral teriflunomide 14 mg once-daily for up to 30 months (m, mean follow-up duration: 18m). Serum IgM/IgG levels were monitored at baseline (BL), W4, W12, and every 12 weeks thereafter (ofatumumab, n=946; teriflunomide, n=936). Proportion of patients with IgM/IgG levels below the lower limit of normal (<LLN [g/L]: IgM, 0.4; IgG, 7.0), and association of IgM/IgG levels with incidence of infections that occurred up to 1m prior and 1m after any decrease in IgM/IgG levels (<LLN vs ≥LLN) were analyzed. Infections in conjunction with IgM/IgG <LLN and lymphopenia and/or neutropenia on the same visit were also analyzed.
Results
Mean IgM/IgG levels were well within reference ranges over time. Over all post-BL visits, a higher proportion of patients on ofatumumab had IgM<LLN (17.7% vs 6.6%), whilst a lower proportion had IgG<LLN (14.2% vs 22.9%) vs patients on teriflunomide. At W96, a similar trend was observed (IgM<LLN: 11.1% vs 1.9%; IgG<LLN: 2.7% vs 6.0%). Proportion of patients on ofatumumab who experienced ≥1 infection within 1m prior and until 1m after IgM<LLN was 31.1% (52/167; 2 serious) vs 51.5% (400/777) with IgM≥LLN (18 serious). Similarly, 27.6% (37/134) reported infections during a drop in IgG<LLN (3 serious) vs 50.6% (410/810) with IgG≥LLN (21 serious). The most common infection was nasopharyngitis. Overall, 1/11 patients with concurrent IgM<LLN and lymphopenia and/or neutropenia, and 7/20 patients with concurrent IgG<LLN and lymphopenia and/or neutropenia reported infections; none were serious.
Conclusions
Reduction in serum IgM levels was observed over time, but for the majority of patients, Ig levels remained above the lower limit of normal. No decrease in IgG levels was reported within the observation period (mean follow-up: 18m). There was no apparent association between decreased Ig levels and infections in conjunction with lymphopenia and/or neutropenia in ofatumumab-treated RMS patients.
P0396 - Sustained and rapid B-cell depletion with ofatumumab: Population pharmacokinetic B-cell modeling in relapsing MS patients (ID 1259)
Abstract
Background
In the Phase 3 ASCLEPIOS trials, ofatumumab 20 mg subcutaneous (s.c.; initial doses: Days 1, 7, 14; subsequent doses: every 4 weeks from Week 4 onwards) showed superior efficacy versus teriflunomide in relapsing MS patients.
Objectives
To characterize the pharmacokinetic (PK) relationship of ofatumumab for B-cell counts in RMS patients, assess the PK and B-cell dynamics given the Phase 3 dose regimen through PK-B cell simulations and explore the effect of covariates on PK and B cells.
Methods
The PK-B cell model was developed using data from Phase 2 (OMS115102, MIRROR, APLIOS) and Phase 3 (ASCLEPIOS I and II) trials. Nonlinear mixed effects modeling was performed using Monolix (v.2019R2) and R (v.3.6.1) programs. Simultaneous fitting was performed to assess the interaction between PK and B cells. A priori selected covariates were included in the covariate analysis and only those with significant effects based on a Wald test were included in the final model. The effect of body weight, age, administration route, s.c. injection device, and baseline B-cell count on PK and B-cell parameters were evaluated.
Results
In total, 9,168 plasma concentrations from 1,440 patients were included in the PK analysis and 17,158 B-cell counts from 1,486 patients in the B-cell analysis. A quasi-steady state binding model with two compartments and a first order absorption for s.c. administration with a time effect on the target synthesis rate adequately described ofatumumab PK. An indirect response model was used to describe the stimulation of B-cell lysis by free ofatumumab concentrations. Simulations demonstrated a rapid, median B-cell depletion to <10 cells/µL in 8.75 days; no signs of B-cell repletion occurred between doses, and that over 94% of patients had <10 cells/µL at B-cell steady state and pre-dose. Effect of weight on the steady state area under the curve was 71.8% higher and 52.0% lower for a 50 kg (5th percentile) and 110 kg (95th percentile) patient relative to a 70 kg patient (median), respectively. Steady state maximum concentrations were similar. Regardless of weight, all patients achieved low B-cell counts, similar to results observed in the Phase 3 ASCLEPIOS trials. Baseline age, B-cell counts and injection device had negligible effect on PK parameters.
Conclusions
The PK-B cell model showed early, rapid, and sustained B-cell depletion with ofatumumab, confirming the rationale for the chosen Phase 3 dosing regimen. No change in dosing schedule is warranted based on body weight effect on ofatumumab PK.