Author Of 2 Presentations
P0028 - Assessing the temporal relationship of serum neurofilament light and subclinical disease activity: Findings from APLIOS trial (ID 1641)
Abstract
Background
Several studies showed prognostic value of serum neurofilament light chain (sNfL) in relapsing multiple sclerosis (RMS). For the first time, we explored the association of sNfL and subclinical disease activity using data from the APLIOS trial.
Objectives
To evaluate the potential of sNfL as a patient-level biomarker for monitoring subclinical disease activity in RMS patients.
Methods
In the APLIOS open-label study of ofatumumab 20 mg s.c in RMS (n=284), frequent (14 time points over 12 weeks) sNfL measurements were performed (Siemens sNfL RUO assay on ADVIA Centaur®). MRI scans were done every 4 weeks. The potential monitoring value of sNfL was examined in 3 ways: 1) Age-adjusted geometric mean sNfL over time was estimated in 3 subgroups: patients who had on-study clinical relapses (r+), patients with presence of gadolinium-enhancing T1 (GdT1) lesions at or post-baseline but no clinical relapses (GdT1+r−) and patients with neither lesions nor clinical relapses (GdT1−r−); 2) As high-frequency sampling permitted an estimation of daily sNfL levels, every report of GdT1 lesion was linked to the estimated sNfL level at the time of the scan (using a recurrent-events analysis); and 3) Patient-level predictions of GdT1 lesion were done using the last sNfL value before the corresponding scan and compared with MRI-based predictions (in terms of across-scan average area under the receiver operating characteristics curve [AUC]).
Results
Over the study course, the age-adjusted geometric mean sNfL levels in the GdT1−r−group (n=153) were low compared to other two subgroups, with 95% CIs below those of the r+ (n=15) and GdT1+r– (n=116) groups. After adjusting for baseline age and MRI covariates, a between-patient difference of 50% higher sNfL at the time of GdT1 scan was associated with a 29% higher risk of persistent GdT1 lesion (p<0.0001). At the individual patient level, the predictive power of the last sNfL value (AUC=0.76) before scan for presence of GdT1 lesion was similar to that of baseline GdT1-count (AUC=0.77).
Conclusions
This study suggests sNfL may have utility for monitoring of subclinical disease activity in RMS patients as shown by its predictive value of GdT1 lesion activity. Assessments of sNfL could complement regular MRIs, and may provide an alternative in cases where standard MRI monitoring is infeasible.
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.