Novartis Pharma AG

Author Of 5 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0028 - Assessing the temporal relationship of serum neurofilament light and subclinical disease activity: Findings from APLIOS trial (ID 1641)

Speakers
Presentation Number
P0028
Presentation Topic
Biomarkers and Bioinformatics

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 (GdT1r); 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 GdT1rgroup (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.

Collapse
Biomarkers and Bioinformatics Poster Presentation

P0033 - Baseline serum neurofilament light levels have prognostic value for on-study MRI activity: Results from ASCLEPIOS trials (ID 1669)

Speakers
Presentation Number
P0033
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

In the ASCLEPIOS I/II trials, ofatumumab significantly lowered serum neurofilament light (sNfL) levels, a marker of disease activity and treatment response, in the first assessment at month 3 and at all subsequent visits versus teriflunomide.

Objectives

To investigate the prognostic value of baseline sNfL for on-study disease activity and worsening in patients with relapsing MS, particularly in newly diagnosed, treatment-naïve patients.

Methods

Patients (pooled N=1882) were randomized to ofatumumab or teriflunomide, receiving treatment for up to 30 months. Patients were stratified by median baseline sNfL levels. We assessed annual on-study T2 lesion formation and brain volume loss (BVL, Jacobian integration) by sNfL category in all patients and in the subgroup of newly diagnosed within 3 year of screening without prior disease-modifying treatment (representing natural course of sNfL and disease at baseline) at month 24 or end of study. The annualized rate of new or enlarging T2 (neT2) lesions in year-2 versus year-1 was assessed in all patients by sNfL category (negative binomial model with time [in year] as offset).

Results

Patients with high sNfL (>median) levels at baseline developed more neT2 lesions per year on study than patients with low (≤median) sNfL levels (adjusted mean rate: ofatumumab: 0.95 vs 0.39, relative increase 143%, p<0.001; teriflunomide 5.28 vs 3.02, relative increase 74.5%, p<0.001). The prognostic value of baseline sNfL persists for year-2 (high vs low, ofatumumab: 0.09 vs 0.06, 64.5%, p=0.124; teriflunomide 4.53 vs 3.12, 45.6%, p=0.003. A single sNfL assessment at baseline had no prognostic value for on-study relapses and disability worsening. Patients with high baseline sNfL had higher annualized rate of BVL than patients with low sNfL (ofatumumab: 0.32% vs 0.23%, relative difference 37.3%, p=0.045; teriflunomide: 0.43% vs 0.29%, relative difference 49.4%, p<0.001). The results were consistent in the subgroup of newly diagnosed, treatment-naïve patients. The relative treatment effect of ofatumumab versus teriflunomide was similar across all measures in both the high and low sNfL groups.

Conclusions

Baseline sNfL levels were prognostic for on-study lesion formation and BVL for at least 2 years, in all patients and in the subgroup of newly diagnosed, treatment-naïve patients. sNfL levels can supplement clinical assessments and help identify patients at high risk for future disease activity.

Collapse
Clinical Trials Poster Presentation

P0192 - Benefit-risk of ofatumumab in treatment-naïve early relapsing multiple sclerosis patients (ID 1601)

Speakers
Presentation Number
P0192
Presentation Topic
Clinical Trials

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.

Collapse
Clinical Trials Poster Presentation

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)

Speakers
Presentation Number
P0209
Presentation Topic
Clinical Trials

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.

Collapse
Clinical Trials Poster Presentation

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.

Collapse