Author Of 5 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.
P0192 - Benefit-risk of ofatumumab in treatment-naïve early relapsing multiple sclerosis patients (ID 1601)
Abstract
Background
Ofatumumab, a fully human anti-CD20 monoclonal antibody with a monthly 20 mg s.c. dosing regimen, demonstrated superior efficacy vs teriflunomide and a favorable safety profile in the Phase 3 ASCLEPIOS I/II relapsing multiple sclerosis (RMS) trials.
Objectives
To evaluate the benefit-risk profile of ofatumumab treatment in patients with early RMS in the Phase 3 ASCLEPIOS I/II trials.
Methods
Key efficacy and safety outcomes were assessed in the subgroup of 615 newly diagnosed (within 3 years before screening), treatment-naïve (no prior disease-modifying therapy [DMT] use) patients who received ofatumumab or teriflunomide as a first-line therapy in ASCLEPIOS I/II trials (32.7% of the total 1882 patients).
Results
Baseline characteristics of the newly diagnosed, treatment-naïve subgroup were typical of early MS patients (median age and MS duration since diagnosis (years) were 36 and 0.35, respectively). Compared to patients on teriflunomide, ofatumumab reduced ARR by 50.3% (0.09 vs 0.18; p<0.001), 3mCDW risk by 38% (10.1% vs 12.8%; p=0.065), 6mCDW risk by 46% (5.9% vs 10.4%; p=0.044), gadolinium-enhancing T1 lesions/scan by 95.4% (0.02 vs 0.39: p<0.001), and new/enlarging T2 lesions/year by 82.0% (0.86 vs 4.78, p<0.001). Treatment-emergent adverse events (AEs) occurred in 84.7% ofatumumab vs 86.0% teriflunomide-treated patients; serious AEs were reported in 7.0% and 5.3%, respectively. No cases of malignancies were reported in this newly diagnosed subgroup, randomized to either drug. Infection rates were comparable between ofatumumab (56.1%) and teriflunomide (56.5%); serious infections rates were 1.9% and 0.7%, respectively, and no opportunistic infections were reported. Systemic injection reactions were only imbalanced between ofatumumab and teriflunomide (with placebo injections) at the first injection given at the study site, and 99.8% of injection reactions were mild-to-moderate in this subgroup; after the 4th injection, >70% RMS patients self-injected at home. Compliance of all patients with ofatumumab was high (98.8%).
Conclusions
Ofatumumab is the first high efficacy DMT that can be self-administered at home, as demonstrated in Phase 3 ASCLEPIOS I/II trials. Ofatumumab showed superior efficacy vs teriflunomide in newly diagnosed, treatment-naïve patients with low absolute relapse rates, very low MRI lesion activity and prolonged time to disability worsening, consistent with the overall study population.
P0209 - Efficacy and safety of ofatumumab versus placebo in relapsing multiple sclerosis patients in Japan and Russia: Results from the Phase 2 APOLITOS study (ID 1656)
Abstract
Background
Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy versus teriflunomide with a favorable safety profile in the Phase 3 ASCLEPIOS I/II trials in relapsing multiple sclerosis (RMS) patients (Global, Ex-Japan). APOLITOS was designed to support ofatumumab registration for RMS treatment in Japan in conjunction with ASCLEPIOS.
Objectives
To evaluate the efficacy and safety of ofatumumab versus placebo in RMS patients and assess consistency of effect in Japanese and non-Japanese patients.
Methods
APOLITOS was a 24-week, double-blind, placebo-controlled study followed by an open-label extension up to week 48. Patients aged 18–55 years with confirmed MS diagnosis (2010 revised McDonald criteria), prior evidence of disease activity (≥1 relapse in the last 2 years AND MRI activity in the last year), and an EDSS score of 0–5.5 were randomized (2:1) to subcutaneous ofatumumab 20 mg or matching placebo (initial doses: Days 1, 7, 14, week 4; subsequent doses: every 4 weeks). Randomization was stratified by region (Japan or ex-Japan) and baseline gadolinium-enhancing (Gd+) T1 lesions (0 or ≥1). The primary endpoint was a reduction in cumulative number of Gd+ T1 lesions across weeks 12, 16, 20, and 24. Secondary outcomes included consistency in reduction of Gd+ T1 lesions across regions, annualized relapse rate (ARR), and safety.
Results
In total, 64 patients were randomized (32 each from Japan and Russia; by treatment: ofatumumab, N=43; placebo, N=21), and 59 completed the double-blind phase. The majority of patients had high baseline disease activity ([mean] 1.5 relapses in the last year, 1.2 Gd+ T1 lesions) and 69% received prior disease-modifying therapies. At week 24, ofatumumab significantly reduced Gd+ T1 lesions versus placebo by 93.6% (p<0.001); the results were consistently in favor of ofatumumab across regions. Ofatumumab reduced the ARR versus placebo by 58.0% (p=0.119). Adverse events occurred in 69.8% of patients with ofatumumab and 81.0% with placebo; injection-related reactions were the most common (20.9% and 19.0%, respectively). One ofatumumab-treated patient was diagnosed with serious chronic inflammatory demyelinating polyradiculoneuropathy after completing the study. No deaths, opportunistic infections, or malignancies occurred during the study.
Conclusions
Ofatumumab demonstrated superior efficacy versus placebo in a RMS population with recent disease activity in Japanese and non-Japanese patients. No new safety signals were observed and the results were consistent with the Phase 3 ASCLEPIOS I/II trials.
P0316 - Dose-dependent tolerability of intravenous and subcutaneous ofatumumab in clinical studies (ID 1585)
Abstract
Background
Ofatumumab, a fully human anti-CD20 monoclonal antibody with monthly 20 mg subcutaneous (s.c.) dosing regimen, demonstrated superior efficacy vs teriflunomide and a favorable safety profile in relapsing MS (RMS) patients in the Phase 3 ASCLEPIOS I/II trials. Prior studies evaluated the effect of >20 mg ofatumumab doses, s.c. and intravenous (i.v.), in both MS and rheumatoid arthritis (RA) patients. Injection/infusion-related reactions (IRRs) were the most frequently reported adverse events in these studies.
Objectives
To assess the dose-dependent tolerability of different ofatumumab doses (s.c. and i.v.) in both patients with MS and with RA.
Methods
For MS, data were pooled from ASCLEPIOS I/II, APLIOS (s.c. ofatumumab 20 mg, N=1873 including long-term data), Phase 2 dose-finding (i.v. ofatumumab 100 mg, N=12; 300 mg, N=15; 700 mg, N=11) and MIRROR studies (s.c. ofatumumab every 12 weeks [q12w]: 3 mg, N=34; 30 mg, N=32; 60 mg, N=34; 60 mg every 4 weeks [q4w], N=64). For RA, data were pooled from Phase 1/2/3 studies administered with atleast 1 dose of i.v. ofatumumab (300 mg, N=70; 700 mg, N=282; 1000 mg, N=64) up to Week 24. IRRs were reported within 24 hours of dose administration. Tolerability was measured as IRR-related drug interruption, discontinuation, severity and seriousness.
Results
In MS patients, the incidence of IRRs was lowest with s.c. 20 mg (23.2%) vs all other effective doses. The majority (99.8%) of IRRs with s.c. 20 mg were Grade 1/2 in severity. Grade 3 IRRs were lower with s.c. 20 mg (0.2%) vs all other doses (1.6–18.2%). No drug interruptions were observed across s.c. doses while the drug was interrupted (paused and restarted) in 41.7–72.7% patients with i.v. doses. A lower proportion of patients withdrew treatment with s.c. 20 mg (0.1%) vs other doses (1.6–6.7%). Serious IRRs were low with s.c. 20 mg (0.1%) vs 60 mg doses (q12w, 2.9%; q4w, 3.1%); none were reported with all other doses. Two serious IRRs (of 1873 patients) with s.c. 20 mg occurred at first injection, resolved without treatment withdrawal and with no recurrences. Cytokine release syndrome was reported in 3 patients (s.c. 60 mg q12w, n=1 [hospitalized for observation]; i.v. 300 mg, n=2 [non-serious]). In RA patients, the incidence of IRRs was higher with i.v. 1000 mg (at first infusion: 71.9%), vs 300 mg (55.7%) and 700 mg (36.9%). The majority of IRRs were Grade 1/2 in severity (95.2%), non-serious (96.9%) and subsided with treatment; 8.4% discontinued treatment due to IRRs.
Conclusions
Ofatumumab 20 mg s.c. was well tolerated compared to higher s.c. and i.v. doses. IRRs were predominant with first injection and similar to matching-placebo with subsequent injections. Most IRRs were non-serious and mild-to-moderate in severity. The IRRs were manageable with low withdrawal rate and recovered with symptomatic treatment, even in absence of premedication. For MS, low dose s.c. injections have a better tolerability profile with higher compliance.
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.