Author Of 7 Presentations
P0118 - Neurofilament light chain concentration predicts risk of relapse in participants with relapsing multiple sclerosis in phase 3 ozanimod trials (ID 1211)
Abstract
Background
In patients with multiple sclerosis (MS), neurofilament light chain concentration (NfL-c) is increased in blood and cerebrospinal fluid (CSF). Plasma and CSF NfL-c correlate and may serve as a biomarker for neurologic damage and disease activity in relapsing MS (RMS). Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, reduced annualized relapse rate (ARR) and plasma NfL-c (pNfL-c) vs interferon β-1a (IFN) in phase 3 RMS trials.
Objectives
To expand upon previously reported data showing that baseline (BL) pNfL-c predicts risk of on-treatment relapse, we analyzed the relationship between changes in pNfL-c and on-treatment risk of relapse with ozanimod vs IFN.
Methods
In this exploratory, post hoc analysis, pNfL-c was measured at BL and after 12 and 24 months of treatment with oral ozanimod 0.46 or 0.92 mg/d or intramuscular IFN β-1a 30 µg/wk in the phase 3 SUNBEAM (NCT02294058; ≥12 mo) and RADIANCE (NCT02047734; 24 mo) trials. The effect of treatment on pNfL-c was assessed, as were the relationships between BL pNfL-c and relapse rate and pNfL-c change from BL and ARR. NfL data are reported as median percentage change from BL. Poisson generalized linear models were used to fit the number of relapses as a function of BL pNfL-c and treatment group with an offset for duration. We calculated a predictive model of expected ARR based on median percentage change from BL in pNfL-c.
Results
At end of treatment, median pNfL-c was significantly reduced from BL by 20‒23% (P<0.01) and 23‒27% (P≤0.0001) with ozanimod 0.46 and 0.92 mg, respectively, and by 13‒15% with IFN. Higher BL p-NfL-c was associated with an increase in number of relapses (P<0.0001). Over a 12-month period, participants treated with either dose of ozanimod had significantly fewer relapses than those treated with IFN (P<0.05); the greatest effect was observed with ozanimod 0.92 mg. Further analyses reveal that treatment groups associated with a greater median reduction from BL pNfL-c are also associated with lower ARR. Predictive modeling estimated that a 25% reduction in pNfL-c, similar to that observed with ozanimod 0.92 mg, predicts an ARR (standard error [SE]) of 0.18‒0.23 (0.4); a 13% reduction, which was similar to that observed with IFN, predicts an ARR (SE) of 0.29‒0.37 (0.04).
Conclusions
Our findings further support pNfL-c as a biomarker for RMS disease activity. BL pNfL-c is related to relapse rate, as are changes in pNfL-c during treatment. Ozanimod causes dose-dependent reductions in pNfL-c and ARR compared with IFN.
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.
P0213 - Immune cell profiles and clinical and safety outcomes with fingolimod in the 12 month FLUENT study of patients with relapsing multiple sclerosis (ID 1750)
Abstract
Background
FLUENT investigated immune cell subset changes in the innate and adaptive immune systems during fingolimod therapy, and their associations with efficacy and safety outcomes.
Objectives
To report changes in immune cell profile, efficacy and safety of fingolimod 0.5 mg/day in adults with relapsing multiple sclerosis (RMS).
Methods
In FLUENT (NCT03257358), a prospective, 12 month, phase 4, multicenter, nonrandomized, open-label study, patients were stratified as fingolimod naive (Cohort 1) or previously treated with fingolimod 0.5 mg/day continuously for ≥2 years (Cohort 2). Primary outcome was change from Baseline to Month 12 in immune cell subsets. Secondary outcomes included Patient Determined Disease Steps (PDDS), anti-John Cunningham virus (anti-JCV) antibody status, serum neurofilament light chain (NfL) concentration, and adverse events (AEs) incidence. Data were analyzed from all patients completing Month 12 follow-up.
Results
165 patients enrolled in Cohort 1; 217 in Cohort 2. Proportionally more patients in Cohort 1 than Cohort 2 relapsed in the year before baseline. At Baseline, patients in Cohort 1 had proportionally more naive and central memory CD4+ and CD8+ T cells and memory B cells, and proportionally fewer effector memory CD4+ and CD8+ T cells and regulatory B cells, than those in Cohort 2. At Month 12, between-cohort differences in the proportions of these lymphocyte types/subtypes were much reduced or negligible. Levels were essentially unchanged in Cohort 2, indicating reductions in naive T cells and increases in effector memory T cells and regulatory B cells in Cohort 1. Mean baseline PDDS scores were low (Cohort 1, 1.7; Cohort 2, 1.8), and changed little by Month 12. Median change from Baseline in anti-JCV antibody index was small in both cohorts. Proportions of patients with positive JCV serology remained stable at Month 12 (61% and 67% in Cohorts 1 and 2 vs 57% and 65% at Baseline). Mean serum NfL level was higher in Cohort 1 than Cohort 2 at Baseline (12.2 vs 9.6 pg/mL); levels were similar at Month 12 (8.7 vs 9.8 pg/mL), having reduced substantially in Cohort 1. Proportionally more patients in Cohort 1 than in Cohort 2 had treatment-emergent AEs (54.6% vs 44.2%), and discontinued study treatment (12.3% vs 5.5%); 5.5% of patients in each cohort reported serious AEs.
Conclusions
These data expand our knowledge of changes in immune cell profiles over time in patients with RMS treated with fingolimod in the short or long term.
P0217 - Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1−3 trials (ID 991)
Abstract
Background
Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in the US and EU for the treatment of relapsing forms of multiple sclerosis (RMS).
Objectives
To characterize the long-term safety and efficacy of ozanimod in participants with RMS in an ongoing open-label extension (OLE) trial.
Methods
Participants with RMS who completed a phase 1, 2, or 3 ozanimod clinical trial were eligible to enroll in DAYBREAK (NCT02576717), where they received ozanimod 0.92 mg/d (equivalent to ozanimod HCl 1 mg). The primary objective was to evaluate safety in the overall population; treatment-emergent adverse events (TEAE) were monitored. Efficacy was evaluated with annualized relapse rate (ARR), calculated via negative binomial regression and pooled for all parent-trial treatment groups. Number of new/enlarging T2 and gadolinium-enhancing (GdE) MRI brain lesions were reported for the subset of participants who entered the OLE from an active-controlled phase 3 trial.
Results
In total, 2639 participants completed the parent trials; this interim analysis (data cut 20 December 2019) included 2494 participants with mean (range) ozanimod exposure of 35.4 (0.03–50.2) months in the OLE. Adjusted ARR in the OLE was 0.112 (95% confidence interval, 0.093‒0.135). At months 24 and 36, 79% and 75% of participants, respectively, were relapse free in the OLE. Three- and 6-month confirmed disability progression was observed in 10.8% and 8.6% of participants in the OLE, respectively. Mean number of new/enlarging T2 lesions per scan at 24 months was similar, regardless of parent-trial treatment group (range, 1.57–1.90), as were mean number of GdE lesions at month 24 (range, 0.2 ‒0.4). In the OLE, 2039 participants (81.8%) had any TEAE, 236 (9.5%) had a serious TEAE (SAE), and 56 (2.2%) discontinued due to a TEAE. Similar rates of TEAEs and SAEs occurred when assessed by parent-trial treatment group. The most common TEAEs were nasopharyngitis (17.9%), headache (14%), upper respiratory tract infection (9.9%), and lymphopenia (9.6%). TEAEs were generally similar to parent trial observations. There were no serious opportunistic infections. Exposure-adjusted incidence rates of TEAEs and SAEs have decreased over time.
Conclusions
In DAYBREAK, ozanimod was associated with low ARR and low new/enlarging T2 and GdE lesion counts over time. Most participants were relapse free and did not experience disability progression. Ozanimod was generally well tolerated and no new safety concerns emerged with long-term use.
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.
P0225 - Phase 3 Study Results Assessing the Efficacy and Safety of ADS-5102 (Amantadine) Extended Release Capsules in MS Patients with Walking Impairment (ID 1919)
Abstract
Background
ADS-5102, FDA-approved as Gocovri, to treat dyskinesia in Parkinson’s disease, has a unique PK profile, such that once daily bedtime dosing provides higher amantadine concentrations from morning throughout the day and lower at night. Based on results from a 60-subject, 4-week, Phase-2 study, INROADS was designed to confirm benefit of ADS-5102 on walking in MS patients.
Objectives
To evaluate the efficacy and safety of ADS-5102 (amantadine) extended release capsules in patients with multiple sclerosis with walking impairment.
Methods
INROADS comprised a 4-week placebo run-in, followed by a 12-week double-blind period. Five hundred ninety-four MS patients with walking impairment from the US or Canada enrolled, and 560 were randomized, 1:1:1, to 274 mg ADS-5102 (n=185), 137 mg ADS-5102 (n=187), or placebo (n=186). The primary endpoint was the proportion of responders (≥20% improvement from baseline measured in ft/sec) in timed 25-foot walk [T25FW] at Week 16, comparing 274 mg ADS-5012 versus placebo. Subjects who did not have a Week 16 assessment were counted as non-responders. Additional outcomes included timed up and go test, 2-minute walk test, and MS walking scale-12. Prespecified subgroups, including prior dalfampridine use, were analyzed.
Results
Baseline characteristics were similar across treatment arms, with mean time since diagnosis 15.9 years, median EDSS 6.0, and mean T25FW 12.4 seconds; 52.5% reported prior dalfampridine use. At Week 16, 274 mg ADS-5102 demonstrated a statistically significantly greater response rate, 21.1% (P=.01) than placebo (11.3%); the response rate for 137 mg ADS-5102 was 17.6% (P=.08). For subjects who completed the study, the response rates were 28.3% (P< .001) for 274 mg, and 19.6% (P=.049) for 137 mg, vs. 11.9% for placebo. Response rates were consistent for subjects with (20.0%, 15.9%, vs. 11.0%) and without (22.5%, 19.2%, vs. 11.6%) prior dalfampridine use. The most commonly reported (>5%) adverse events (AEs) were peripheral edema, dry mouth, fall, constipation, UTI, and insomnia; AEs led to study drug discontinuation for 20.5% (274 mg), 6.4% (137 mg) and 3.8% (placebo) of subjects.
Conclusions
INROADS met its primary objective of showing clinically meaningful benefit in MS walking speed for 274 mg ADS-5102. A dose-response was seen for both efficacy and tolerability. AEs were consistent with the known safety profile of amantadine. Results suggest a role for ADS-5102 to improve walking in patients with MS, particularly those who have tried and discontinued dalfampridine.
P0606 - MRI changes over the disease course in a large multiple sclerosis clinical cohort (ID 1318)
Abstract
Background
Quantitative MRI measures are proposed as biomarkers of disease course and therapeutic response. Understanding the evolution of these metrics is key for interpretation of change in clinical practice.
Objectives
To describe longitudinal changes in T2 lesion volume (T2LV), whole brain (WBF) and gray matter (GMF) fraction, and thalamic volume (TV) over the disease course in a large multiple sclerosis (MS) cohort.
Methods
Demographics, disease history, and MRI were collected from MS patients at a single site. Patients with ≥2 MRI assessments were included. T2LV, WBF, GMF, and TV annualized rate of change and raw values compared to the first available scan were analyzed. Multivariate mixed-effects models were used to evaluate longitudinal MRI changes, adjusting for age at disease onset, sex, and patient-determined disease steps category (PDDS) with a random intercept for patient and an autoregressive covariance structure. For each outcome, three models were generated: a linear model, a second-order B-spline model, and a third-order B-spline model were tested for nonlinearity in the relationship between MRI outcome and disease duration and were compared based on Akaike Information Criterion.
Results
1012 patients were included (69.2% female, 72.9% relapsing-remitting MS, mean ± SD age at disease onset 34.4±10.3, age at baseline MRI 43.8±11.1, disease duration 9.4±5.8 years, mean number of MRIs 3.1±1.2, median [IQR] PDDS 1.0 [0.0-3.0]). Male sex (B=4.9) and PDDS>3 (B=7.0) were associated with greater T2LV accumulation over the disease course (best fit: linear model). T2LV annualized rate of change peaked at 5-6 years of disease duration (rate 9%/year) (best fit: third-order B spline). Male sex, older age, and PDDS>3 were associated with lower WBF, TV (best fit: linear model), and GMF (best fit: second-order B spline), all p<0.05. No non-linear effect of disease duration on WBF, TV, and GMF were observed. There was no statistically significant change in the annualized rate of change of WBF, TV, and GMF over the disease course.
Conclusions
The dynamics of T2LV accumulation are variable throughout the disease course, whereas the rate of change of WBF, TV, and GMF were more stable. These results suggest T2LV accumulation reflecting focal lesion activity predominates early in the disease while WBF, TV, and GMF loss reflecting underlying neurodegeneration is present at disease onset and continues throughout the course.
Presenter Of 1 Presentation
P0225 - Phase 3 Study Results Assessing the Efficacy and Safety of ADS-5102 (Amantadine) Extended Release Capsules in MS Patients with Walking Impairment (ID 1919)
Abstract
Background
ADS-5102, FDA-approved as Gocovri, to treat dyskinesia in Parkinson’s disease, has a unique PK profile, such that once daily bedtime dosing provides higher amantadine concentrations from morning throughout the day and lower at night. Based on results from a 60-subject, 4-week, Phase-2 study, INROADS was designed to confirm benefit of ADS-5102 on walking in MS patients.
Objectives
To evaluate the efficacy and safety of ADS-5102 (amantadine) extended release capsules in patients with multiple sclerosis with walking impairment.
Methods
INROADS comprised a 4-week placebo run-in, followed by a 12-week double-blind period. Five hundred ninety-four MS patients with walking impairment from the US or Canada enrolled, and 560 were randomized, 1:1:1, to 274 mg ADS-5102 (n=185), 137 mg ADS-5102 (n=187), or placebo (n=186). The primary endpoint was the proportion of responders (≥20% improvement from baseline measured in ft/sec) in timed 25-foot walk [T25FW] at Week 16, comparing 274 mg ADS-5012 versus placebo. Subjects who did not have a Week 16 assessment were counted as non-responders. Additional outcomes included timed up and go test, 2-minute walk test, and MS walking scale-12. Prespecified subgroups, including prior dalfampridine use, were analyzed.
Results
Baseline characteristics were similar across treatment arms, with mean time since diagnosis 15.9 years, median EDSS 6.0, and mean T25FW 12.4 seconds; 52.5% reported prior dalfampridine use. At Week 16, 274 mg ADS-5102 demonstrated a statistically significantly greater response rate, 21.1% (P=.01) than placebo (11.3%); the response rate for 137 mg ADS-5102 was 17.6% (P=.08). For subjects who completed the study, the response rates were 28.3% (P< .001) for 274 mg, and 19.6% (P=.049) for 137 mg, vs. 11.9% for placebo. Response rates were consistent for subjects with (20.0%, 15.9%, vs. 11.0%) and without (22.5%, 19.2%, vs. 11.6%) prior dalfampridine use. The most commonly reported (>5%) adverse events (AEs) were peripheral edema, dry mouth, fall, constipation, UTI, and insomnia; AEs led to study drug discontinuation for 20.5% (274 mg), 6.4% (137 mg) and 3.8% (placebo) of subjects.
Conclusions
INROADS met its primary objective of showing clinically meaningful benefit in MS walking speed for 274 mg ADS-5102. A dose-response was seen for both efficacy and tolerability. AEs were consistent with the known safety profile of amantadine. Results suggest a role for ADS-5102 to improve walking in patients with MS, particularly those who have tried and discontinued dalfampridine.