Search

BACKGROUND: Spinal cord atrophy and whole brain volume (WBV) loss are associated with physical disability in patients with multiple sclerosis (MS). Medulla oblongata volume (MOV) as a surrogate for spinal cord volume and lateral ventricular volume (LVV) as a surrogate for WBV are easy-to-measure, validated biomarkers. LVV expansion of > 3.5% per year, which corresponds to WBV loss of > 0.4% per year, has been proposed to represent a pathological change in MS. A cutoff has not yet been identified for MOV. OBJECTIVES: To evaluate change at 1 year in MOV, LVV, and measures of physical disability among patients with early relapsing MS (RMS) treated with ozanimod in the ongoing ENLIGHTEN trial. METHODS: ENLIGHTEN (NCT04140305) is a prospective, multicenter, open-label study of ozanimod 0.92 mg in patients with early RMS. Participants are aged 18 to 65 years; are taking ≤ 1 MS disease-modifying therapy (DMT); have received a diagnosis of RMS within ≤ 5 years; and have an Expanded Disability Status Scale (EDSS) score of ≤ 3.5, no relapses within 30 days of screening, and ≤ 10 gadolinium-enhancing lesions on baseline brain MRI. For this analysis, MOV, LVV, Nine-Hole Peg Test (9-HPT), Timed 25-Foot Walk test (T25W), and EDSS scores at baseline and year 1 were evaluated (data cutoff: February 14, 2023). Change at 1 year was analyzed descriptively in the subset of patients with assessments at both time points. RESULTS: ENLIGHTEN participants (N = 185) were mostly women (78.4%), White (85. 9%), and DMT naive (72.4%), with a mean (SD) age of 39.5 (10.7) years at baseline, 4.1 (5.5) years since MS symptom onset, 1.1 (1.3) years since MS diagnosis, and a mean (SD) 0.8 (0.8) relapses in the year before the study. At baseline, the median MOV (n = 99) was 6.0 cm3, and LVV (n = 100) was 35.7 cm3. After 1 year of ozanimod, the change from baseline in these measures was small (median % change: MOV, --0.11%; LVV, 0.14% [n = 98 for both]). Patients' median time for completion of the 9-HPT (n = 106) was 22.0 seconds at baseline, and they completed it a median of 0.5 seconds faster after 1 year of ozanimod. For the T25W, (n = 105), median time at baseline was 5.2 seconds, with little change at year 1 (median change: 0.05 seconds). The median EDSS score (n = 122) was 2.0 at baseline and remained so at year 1 (median change: 0.0). CONCLUSIONS: During treatment with ozanimod, patients with early RMS had relatively stable MOV, LVV, and levels of physical disability over 1 year and improved their speed on the 9-HPT. The median percent change in LVV (0.14%) remained well below the 3.5% cutoff that is suggestive of pathologic change. FUNDING: Bristol Myers Squibb. Writing and editorial assistance was provided by Noud van Helmond of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy vs teriflunomide in the phase 3 ASCLEPIOS I/II (NCT02792218/ NCT02792231) trials in people with relapsing multiple sclerosis (PwRMS). Previously reported data for up to 5 years demonstrated sustained efficacy and a favorable safety profile in PwRMS. OBJECTIVES: To assess ofatumumab's longer-term safety and efficacy for up to 6 years in PwRMS. METHODS: Efficacy analyses will include all participants randomly assigned to cohorts in ASCLEPIOS I/II and their data from the first dose in ASCLEPIOS I/ II, whereas safety analyses will include all participants who received at least 1 dose of ofatumumab in ASCLEPIOS I/II, APOLITOS (NCT03249714), APLIOS (NCT03560739), or ALITHIOS (NCT03650114; cutoff: September 25, 2023). Efficacy will be analyzed by the randomized treatment in the core study, with those randomly assigned to ofatumumab being referred to as the continuous group and those randomly assigned to teriflunomide as the switch group. RESULTS: Mean baseline age in ASCLEPIOS I/II (N = 1882) was 38 years, 67.6% were female, and mean Expanded Disability Status Scale score was 2.9 in both groups. Previously reported 5-year data (cutoff: September 25, 2022) for ofatumumab showed a sustained, low annualized relapse rate (ARR) and sustained and almost complete suppression of MRI lesion activity in the continuous group. In the switch group, ARR was markedly reduced from years 2-3 (0.16- 0.06) and remained low through years 3-5 (0.05). MRI lesion activity was almost completely suppressed through years 3-5. At year 5, 9 of 10 patients reached no evidence of disease activity in both groups. Exposure-adjusted incidence rate of adverse events (AEs), serious AEs, serious infections, and malignancies remained consistent, with no increased risk over 5 years. Mean immunoglobulin (Ig) G levels remained stable (above the lower limit of normal [LLN]: 5.65 g/L), whereas mean IgM levels decreased but remained above the LLN (0.4 g/L). Updated 6-year efficacy and safety results will be presented at the annual meeting. CONCLUSIONS: These analyses will help inform physicians on the longer-term safety and efficacy profile of ofatumumab in PwRMS. [ABSTRACT FROM AUTHOR]

Background: In CARE-MS II (trial registration: NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved clinical/magnetic resonance imaging (MRI) outcomes vs subcutaneous interferon beta-1a (SC IFNβ-1a) over 2 years (y) in patients with RRMS with inadequate response to prior therapy. Efficacy was maintained in a 4-year extension study (NCT00930553), wherein patients could receive additional alemtuzumab courses (12 mg/ day on 3 days, ≥12 months apart) as needed for disease activity, or receive other disease-modifying therapy (DMT) per investigator discretion. Further follow-up was available in an additional 5-year extension, TOPAZ (NCT02255656). Objectives: Evaluate the efficacy and safety of alemtuzumab in CARE-MS II patients over 9 years. Methods: At investigator discretion, patients in TOPAZ can receive additional as-needed alemtuzumab (≥12 months apart, no criteria) or receive other DMT (at any time). Results: From core study baseline through year 9, 288/435 (66%) CARE-MS II alemtuzumab-treated patients remained on study; 41% received neither additional alemtuzumab nor another DMT through year 9. Annualized relapse rate was 0.19 in years 3-9. From core study baseline through year 9, 68% of patients had stable/improved Expanded Disability Status Scale (EDSS) scores, and mean change in EDSS was +0.32. Over 9 years, 60% of patients were free of 6-month confirmed disability worsening and 49% achieved 6-month confirmed disability improvement. On average, 69% of patients were free of MRI disease activity, 89% were free of new gadolinium-enhancing lesions, and 69% were free of new/enlarging T2 hyperintense lesions, annually from year 3-9. From core study baseline through year 9, median percent cumulative brain volume (BV) change was --1.22%; median percent BV change was ≤--0.19% annually over years 3-9. Incidence of overall adverse events (AEs) and infections declined through year 9; cumulative thyroid AE incidence was 43.7% and immune thrombocytopenia (ITP) incidence was 3.7% (1 new case of ITP, 14 months after the fourth alemtuzumab course, was observed at year 9). No new cases of nephropathy were reported. Efficacy and safety in SC IFNβ-1a--treated patients from the core study who switched to alemtuzumab in the extension were consistent with those treated with alemtuzumab both in the core and extension. Conclusions: Efficacy of alemtuzumab on clinical, MRI, and BV loss outcomes was maintained over 9 years in CARE-MS II patients, with 41% receiving no further treatment through year 9. Safety in year 9 in this study was consistent with that of previous years. [ABSTRACT FROM AUTHOR]

Background: Clinical trials of alemtuzumab have demonstrated its 9-year efficacy and safety, but real-world data are limited. PRO-ACT assesses patient-reported outcomes (PROs), safety, and treatment sequencing in adults with relapsing-remitting multiple sclerosis (RRMS) transitioning from prior disease-modifying therapy to alemtuzumab in the United States and Canada. Objectives: To report the 1-year interim results of the realworld PRO-ACT study. Methods: PRO-ACT is an ongoing 24-month, prospective, multicenter, noninterventional, single-arm, observational study. The primary end point evaluates change in overall satisfaction on the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM; scale 0-100; higher scores indicate greater satisfaction), after transitioning to alemtuzumab. Other PROs evaluated (lower scores indicate improved outcomes) are the MS Impact Scale-29 (MSIS-29; scale 0-100), Modified Fatigue Impact Scale-5 (MFIS-5; scale 0-20), Patient-Determined Disease Steps (PDDS; scale 0-8), and Health-Related Productivity Questionnaire (HRPQ)-MS v2. Results: As of September 2019, enrollment was complete (N = 200 patients) and PRO data were evaluable in 170 patients. Patients transitioned from natalizumab (37%), dimethyl fumarate (14%), fingolimod (13%), teriflunomide (12%), or other therapies (24%) to alemtuzumab. Mean TSQM scores improved from baseline to year (Y) 1 for overall satisfaction (50.3 vs 66.5; P < .0001) and effectiveness (49.3 vs 60.7; P < .0001) domains; scores were unchanged for side effects (77.6 vs 76.5) and convenience (70.3 vs 70.7). Mean scores for other PROs showed improvement at Y1 vs baseline: MSIS-29 physical impact scale (52.4 vs 47.8; P < .001), MSIS-29 psychological impact scale (53.4 vs 47.9; P < .001), and MFIS-5 (12.8 vs 11.7; P < .001). Scores remained stable on the PDDS (3.1 vs 3.2). Mean hours of weekly employment productivity lost decreased from 11.4 at baseline to 7.4 at Y1 (P < .05). Incidence of adverse events was 92% and serious adverse events was 11%. One death occurred (suicide). Conclusions: PROs improved during the first year of alemtuzumab treatment after transitioning from another therapy. Alemtuzumab safety in Y1 was consistent with the pivotal studies. [ABSTRACT FROM AUTHOR]

Background: Ublituximab (UTX) is a novel monoclonal antibody targeting a unique epitope on the CD20 antigen and glyco-engineered for enhanced B-cell targeting through antibody-dependent cellular cytotoxicity. Two phase 3 trials, ULTIMATE I and II, are fully enrolled and are investigating the efficacy and safety of UTX in relapsing forms of multiple sclerosis (RMS). Objectives: To evaluate the long-term safety and tolerability of UTX treatment in patients with RMS enrolled in the open-label extension (OLE) of a phase 2 trial. Methods: TG1101-RMS201 was a 52-week, phase 2, placebo-controlled, multicenter study of UTX in RMS. Subjects who completed RMS201 were eligible to continue treatment in the OLE, receiving 1-hour 450-mg UTX infusions every 24 weeks. Results: RMS201 enrolled 48 subjects and the primary end point was to evaluate B-cell depletion. Median B-cell depletion of >99% was observed at week 4 and maintained at week 48. At week 48, key observations included: 100% reduction in T1-Gd-enhancing lesions; 10.6% mean decrease in T2 lesion volume; 93% of subjects relapse free, and an annualized relapse rate (ARR) of 0.07. UTX was well tolerated; the most common adverse event (AE) was infusion-related reactions (all grade 1-2). No discontinuations due to AEs were reported. UTX continues to be well tolerated, with a median duration of follow-up of 124.7 weeks, no drugrelated discontinuations, and only 1 AE deemed at least possibly related to UTX that occurred in more than 1 patient, which was infusion-related reactions (IRR) all grade 1 or 2 in severity. At the time of presentation, long-term safety information will be presented for all patients on the OLE. Conclusions: The phase 2 OLE data support that UTX continues to be safe, well tolerated, and effective with 1-hour infusions. These results support the ongoing phase 3 ULTIMATE program in RMS. [ABSTRACT FROM AUTHOR]

Background: Peginterferon beta-1a is approved to treat relapsing forms of multiple sclerosis (RMS) based on results from the ADVANCE trial, which had a mean patient age of 36 years. US claims data show a mean age in the peginterferon beta-1a patient postmarketing population of 45-50 years, yet data on disease-modifying therapies for patients aged ≥50 with RMS are limited. The 5-year, phase 4 Plegridy Observational Program (POP) study explores the real-world safety and effectiveness of peginterferon beta-1a in patients with RMS, a third of whom are aged ≥50. Objectives: Report on baseline characteristics, safety outcomes, and clinical effectiveness of peginterferon beta-1a in patients ≥50 and <50 years of age enrolled in POP. Methods: The safety analysis population included 1126 patients; 375 (33%) were ≥50 and 751 (67%) were <50 years of age at baseline. The effectiveness analysis population included 1125 (≥50, 375; <50, 750) patients. Data reflect the third interim data cut as of September 2018. Data from the fourth interim data cut (September 2019) will be presented. Results: The mean (SD) ages of ≥50 and <50 patients were 58.0 (6.2) and 36.8 (8.2) years at baseline, respectively, and 45.2 (9.4) and 31.7 (7.6) years at multiple sclerosis (MS) diagnosis, respectively. The percentage of female patients was similar in the ≥50 (74.7%) and <50 (77.1%) subgroups. At baseline, the mean time since MS symptom onset was higher for the ≥50 group than the <50 group (17.1 vs 7.4 years). Patients ≥50 had fewer relapses in the year prior to baseline (mean: 0.3 vs 0.6) and in the 3 years prior to baseline (mean: 0.6 vs 1.0) than patients <50. At baseline, the mean Expanded Disability Status Scale score was higher in patients ≥50 (2.69) vs patients <50 (1.45). The incidence of treatment-emergent adverse events (AEs) in POP was similar in the ≥50 (63.2%) and <50 (62.7%) subgroups. A higher incidence of serious AEs (SAEs) was reported in patients ≥50 (9.6%) vs <50 (5.1%). The annualized relapse rate (ARR) was 0.08 in patients ≥50 and 0.15 in those <50. The percent of relapsefree patients over 3 years was 88.3% in patients ≥50 and 78.3% in patients <50. Conclusions: In both subgroups, the incidence of AEs was similar; the incidence of SAEs was higher in patients aged ≥50. ARR was low and the percentage of relapse-free patients was high in both subgroups, indicating that peginterferon beta-1a has the potential to provide treatment benefits to patients with RMS, including those aged ≥50. [ABSTRACT FROM AUTHOR]

Background: Adherence to therapy in multiple sclerosis (MS) leads to improved clinical outcomes. Persistence to therapy and discontinuation rates contribute to adherence. Diroximel fumarate (DRF) is a novel oral fumarate recently approved in the United States for relapsing forms of MS, administered as 2 capsules twice daily. Objectives: To compare adherence with DRF vs dimethyl fumarate (DMF) in EVOLVE-MS-2 and describe long-term adherence and efficacy outcomes with DRF in EVOLVEMS-1. Methods: Adherence was assessed in patients with relapsing- remitting MS who received DRF or DMF in the 5-week, randomized EVOLVE-MS-2 study (trial registration: NCT03093324) and in those who received DRF in the ongoing, 96-week, open-label EVOLVE-MS-1 study (NCT02634307). All EVOLVE-MS-2 patients received 2 capsules twice daily. Adherence was determined by pill count (number taken divided by the number prescribed x 100). In patients who discontinued treatment, adherence was based on duration of treatment and not the full study period. Efficacy outcomes were assessed in EVOLVE-MS-1. Results: In the completed EVOLVE-MS-2 study, mean adherence was high (DRF 97.1%, n = 252; DMF 97.0%, n = 251); 97.4% of patients were ≥80% adherent to therapy. Discontinuation rates were lower with DRF (3.2%) than DMF (7.2%), primarily due to differences in gastrointestinal tolerability. In EVOLVE-MS-1 as of November 30, 2018 (median [range] exposure, 84 [0-100] weeks; n = 888), mean adherence was 93.4% (n = 877); 92.0% of patients were ≥80% adherent. Overall, 16.3% of patients discontinued treatment. Median (range) exposure for patients with ≥80% vs <80% adherence was 84 (1-100) and 22 (0-97) weeks, respectively. In patients with ≥80% adherence, adjusted annualized relapse rate was 0.15 (95% CI 0.13-0.19), representing a 79.4% (95% CI 75.0-83.0; P < .0001) reduction from the 12 months before study entry. Mean (SD) change in Expanded Disability Status Scale score from baseline to week 96 in patients with ≥80% adherence was 0.07 (0.59; n = 310). The small sample size (n = 70 at baseline, n = 2 at week 96) of patients with <80% adherence limits the ability to draw conclusions on the correlation between adherence and efficacy outcomes. Conclusions: High adherence and low discontinuation rates demonstrate documented treatment adherence and persistence to DRF. Adherence rates with DRF and DMF in EVOLVE-MS-2 were sustained in DRF-treated patients from EVOLVE-MS-1 for up to 96 weeks, demonstrating little impact of a 2-capsules-twice-daily dosing regimen. DRF-treated patients in EVOLVE-MS-1 had improved effi- cacy outcomes from baseline. [ABSTRACT FROM AUTHOR]

Background: Injection site reactions (ISRs) are a common adverse event associated with peginterferon beta-1a treatment and may lead to discontinuation. This analysis of the Plegridy Observational Program (POP), a 5-year, phase 4 real-world study, assessed the relationship between ISRs and discontinuation of peginterferon beta-1a. Objectives: Assess the risk of treatment discontinuation associated with ISRs in new and experienced users of peginterferon beta-1a. Methods: Using POP third interim data from November 2014 to September 2018, patients were classified as new users if they initiated peginterferon beta-1a ≤31 days prior to, on, or after study consent; and experienced users if they initiated peginterferon beta-1a >31 days prior to study consent. Treatment discontinuation was based on physician report, and only the first discontinuation was analyzed. Demographics and baseline characteristics were summarized with descriptive statistics. Frequencies and proportions of individuals who experienced ≥1 ISR were calculated for each group. Fisher exact test assessed the relative risk (RR) of discontinuation in those with or without ISRs. Kaplan-Meier analysis assessed the cumulative risk of discontinuation. Data from the fourth interim POP analysis (as of September 2019) will be presented. Results: Of the 1126 patients included in this analysis, 576 (51%) were new and 550 (49%) were experienced users of peginterferon beta-1a. Among new and experienced users, 280 (49%) and 147 (27%) reported ≥1 ISR, respectively. In the new-user cohort, 148 (53%) patients with ISRs and 135 (46%) patients without ISRs discontinued peginterferon beta-1a treatment (RR: 1.16 [95% CI: 0.98, 1.37]). In experienced users, 44 (30%) patients with ISRs and 124 (31%) patients without ISRs discontinued peginterferon beta-1a treatment (RR: 0.97 [95% CI: 0.73, 1.30]). Over 12 months of treatment in the new-user cohort, the cumulative probability of peginterferon beta-1a discontinuation was 0.38 in patients with ≥1 ISR and 0.31 in patients without an ISR. Conclusions: These preliminary findings suggest an increased risk of discontinuation in new users of peginterferon beta-1a with ISRs, whereas in experienced users no impact of ISRs on discontinuation was observed. New users of peginterferon beta-1a treatment may benefit from additional information on ISR mitigation and management through discussions with their health care professionals. [ABSTRACT FROM AUTHOR]