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.
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.
P0218 - Long-term safety, compliance, and effectiveness of ofatumumab in patients with relapsing multiple sclerosis: ALITHIOS Phase 3b study (ID 1580)
Abstract
Background
Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy versus teriflunomide along with a favorable safety profile in the Phase 3 ASCLEPIOS trials in relapsing multiple sclerosis (RMS) patients. Assessment of the long-term use of subcutaneous (s.c.) ofatumumab 20 mg is important to further understand its benefit-risk profile.
Objectives
To present the design of the ALITHIOS extension study of ofatumumab and evaluate treatment compliance, including treatment discontinuations, in patients transitioning to the ALITHIOS study.
Methods
ALITHIOS is an ongoing Phase 3b, open-label, umbrella extension study which has enrolled eligible patients (approximately 1700 patients) completing the Phase 3 ASCLEPIOS I/II, Phase 2 APOLITOS and APLIOS trials from >300 sites worldwide. ALITHIOS consists of three parts: screening, loading, and open-label treatment. Ofatumumab 20 mg is administered at the site on Day 1 (patients from ASCLEPIOS have a blinded loading part with two additional ofatumumab/matching placebo s.c. injections on Days 7 and 14; no blinding is required for those from the APOLITOS and APLIOS studies) followed by open-label treatment every 4 weeks from Week 4 for up to 5 years. The primary endpoint is the proportion of patients with adverse events (AEs); abnormal laboratory, vital signs or electrocardiogram results; and the proportion of patients meeting predefined criteria of suicidal behavior as per the Columbia Suicide Severity Rating Scale. Secondary endpoints include relapse rate, disability (worsening and improvement), and magnetic resonance imaging outcomes. Patient-reported outcomes was included as an exploratory endpoint. The proportion of eligible patients who accepted transition to ALITHIOS from the Phase 2/3 trials and treatment compliance (defined as exposure to study drug [days]/duration of on-treatment period [days]×100%) are recorded.
Results
As of May 2020, 1692 patients from 37 countries and 294 sites were screened, and 1671 (98.8%) were enrolled into ALITHIOS; 1615 patients are ongoing and 56 (3.3%) patients discontinued. The most common reasons for discontinuation were patient/guardian decision (0.9%), AEs (0.5%), and physician decision (0.2%). The study is expected to complete in 2025. Study design details and compliance data will be presented at the congress.
Conclusions
The ALITHIOS study is designed to allow patients who participated in prior ofatumumab studies to continue with the treatment, and to further assess the benefit-risk profile of ofatumumab in RMS and tolerability in long-term use.
P0234 - Safety experience with extended exposure to ofatumumab in patients with relapsing multiple sclerosis from Phase 2 and 3 clinical trials (ID 1638)
Abstract
Background
Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy versus teriflunomide in Phase 3 ASCLEPIOS I/II relapsing multiple sclerosis (RMS) trials. Long-term data to assess the safety and benefit-risk profile of ofatumumab 20 mg per month is required.
Objectives
To report the overall safety data of all patients treated with subcutaneous (s.c.) ofatumumab 20 mg for RMS, including patients who continued treatment and those who were newly switched in the ongoing open-label Phase 3b ALITHIOS study.
Methods
The overall safety population was divided into 2 groups 1) Continuous: Patients randomized to ofatumumab in the core Phase 2 APLIOS (12 weeks) or Phase 3 ASCLEPIOS I/II (up to 30 months) trials and continued in ALITHIOS, or completed core study and continued with the safety follow-up, and 2) Newly-switched: Patients randomized to teriflunomide in ASCLEPIOS I/II and switched to ofatumumab in ALITHIOS. All adverse events (AEs), serious AEs (SAEs) and deaths up to and including the safety cut-off of 100 days after last administration of ofatumumab are included in this safety analysis until 30 November 2019.
Results
A total of 1873 patients (continuous: 1230; newly-switched: 643) were exposed to ofatumumab ([median duration] continuous: 21.0 months; newly-switched: 4.4 months) for 2118.6 patient-years (continuous: 1903 patient-years; newly-switched: 215.6 patient-years). 71.4% of patients (continuous: 82%; newly-switched: 51%) experienced at least one AE; most were mild-to-moderate. AEs led to ofatumumab discontinuation in 3.0% of patients. SAEs were observed in 6.2% of patients. Incidence of infections was 38.5% (continuous: 49.3%, newly-switched: 18.0%). Serious infections occurred in 1.8% of patients. Incidence of injection-related reactions (IRRs) was 23.7% (continuous: 24.9%; newly-switched: 21.3%); most IRRs were non-serious, grade 1 or 2 and none led to ofatumumab discontinuation. Hepatitis B reactivation, progressive multifocal leukoencephalopathy or deaths have not been reported. No cases of opportunistic infections have been identified. Incidence of malignancies was 0.3% (with confounding) and no new cases have been reported in either continuous or newly-switched patients as of the data cut-off time.
Conclusions
No new safety signals were identified in this extended analysis. The safety profile of ofatumumab in RMS patients remains consistent with data reported in the core studies, including the ASCLEPIOS I/II trials.
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.