Author Of 2 Presentations
FC01.01 - Long-term efficacy and safety of eculizumab monotherapy in AQP4+ neuromyelitis optica spectrum disorder
Abstract
Background
In the randomized, double-blind, placebo-controlled, phase 3 PREVENT trial (NCT01892345), eculizumab was well tolerated and significantly reduced relapse risk vs placebo in patients with aquaporin-4 immunoglobulin G-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). The treatment effect observed in a prespecified subgroup of patients who received eculizumab monotherapy vs placebo alone (i.e. without concomitant immunosuppressive therapy [IST]) was consistent with the overall population.
Objectives
To examine the long-term efficacy and safety of eculizumab monotherapy in patients with AQP4+ NMOSD during PREVENT and/or its ongoing open-label extension (OLE; NCT02003144).
Methods
During PREVENT and its OLE, adults with AQP4+ NMOSD received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (PREVENT only) with/without concomitant IST. Relapses, hospitalizations, IST changes and adverse events (AEs) with eculizumab monotherapy (PREVENT and its OLE; interim data cut-off, July 31, 2019) or with placebo alone (PREVENT) were descriptively analyzed post hoc.
Results
During PREVENT and/or its OLE, 33 patients received eculizumab monotherapy for a total of 85.3 patient-years (PY). Adjudicated relapses occurred in 1/33 patients (annualized relapse rate [ARR], 0.012; 95% confidence interval [CI]: 0.002–0.082), vs 7/13 with placebo alone in PREVENT. At 192 weeks, 96.2% of patients who received eculizumab monotherapy were relapse-free (95% CI: 0.757–0.994) vs 93.8% of patients who received eculizumab with concomitant IST (95% CI: 0.867–0.972). No patients receiving eculizumab monotherapy required hospitalization for a relapse and none started an IST. The treatment-related AE rate with eculizumab monotherapy in PREVENT and its OLE was similar to that with placebo alone in PREVENT (181.0 and 186.0 events/100 PY, respectively), the infection rate was similar between these groups (174.1 vs 186.0 events/100 PY), and the treatment-related serious AE rate was lower with eculizumab monotherapy than with placebo alone (5.7 vs 23.3 events/100 PY). No meningococcal infections or deaths occurred among these patients.
Conclusions
A very high proportion of patients who had experienced 1–2 relapses in the pre-study year remained relapse-free through 192 weeks of eculizumab monotherapy. Long-term eculizumab monotherapy was well tolerated. These data support the long-term effectiveness of eculizumab monotherapy in reducing relapse risk in AQP4+ NMOSD.
FC01.02 - Efficacy and safety of eculizumab in patients with neuromyelitis optica spectrum disorder previously treated with rituximab: findings from PREVENT
Abstract
Background
In PREVENT, eculizumab was associated with a significant reduction in relapse risk versus placebo and was well tolerated. In total, 46 patients (26/96 in the eculizumab arm, 20/47 in the placebo arm) were previously treated with the monoclonal antibody rituximab.
Objectives
To describe the efficacy and safety of eculizumab in patients in the PREVENT trial (NCT01892345) who had previously received rituximab.
Methods
Adults with aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo with/without concomitant immunosuppressive treatment (except rituximab/mitoxantrone). A post hoc descriptive analysis was performed using data from patients with any prior rituximab treatment (within the previous year only for review of adverse events [AEs]) recorded more than 3 months before randomization.
Results
Baseline characteristics of the prior-rituximab subgroup were similar to those of the total PREVENT population; however, the subgroup included a lower proportion of Asian patients (10.9% vs 36.4% in total PREVENT) and greater representation from the Americas (58.7% vs 30.8%). In the subgroup, median times from last dose of rituximab to meningococcal vaccination and to first dose of study treatment were 31.7 and 38.7 weeks, respectively. Adjudicated relapses occurred in 1/26 patients (3.8%) and 7/20 patients (35.0%) in the eculizumab and placebo arms (hazard ratio: 0.093; 95% confidence interval: 0.011–0.755; p = 0.0055), respectively. Rates of AEs for eculizumab and placebo were 1025.8 and 1029.1 events/100 patient-years (100% of patients), respectively, and rates of serious AEs were 46.9 and 66.0 events/100 patient-years (38.9% and 47.1% of patients), respectively. Serious infections/infestations were recorded in 2/18 patients (11.1%) and 2/17 patients (11.8%) in the eculizumab and placebo arms, respectively.
Conclusions
In patients in PREVENT who had previously received rituximab, the risk of adjudicated relapse was significantly lower with eculizumab than with placebo. Rates of serious infections were similarly low with eculizumab and placebo.
Author Of 4 Presentations
P0452 - Continued increase of multiple sclerosis and neuromyelitis optica and the north-south gradient in Japan; updates from the 5th nationwide survey (ID 775)
Abstract
Background
In Japan, nationwide survey for multiple sclerosis (MS) including neuromyelitis optica spectrum disorders (NMOSD) has regularly been conducted since 1972, and the past 4 surveys conducted before the discovery of anti-aquaporin 4 antibodies demonstrated the rapid increase of MS.
Objectives
To investigate the epidemiological characteristics of MS and NMOSD in Japan simultaneously through the 5th nationwide survey.
Methods
Preliminary survey was conducted to ascertain the approximate number of patients with either MS (pwMS) or NMOSD (pwNMOSD) who had seen at the selected facilities in 2017. Preliminary survey packages were sent to departments of neurology, internal medicine, ophthalmology, and pediatrics, at the facilities randomly selected using pre-determined sampling rates stratified based on the hospital bed counts. Secondary questionnaire was sent to the facilities with the cases to collect the detailed clinical information of each patient.
Results
Out of 3,799 departments where we sent preliminary survey, 2,284 (60.1%) replied and 645 departments reported the presence of the patients with the diseases. Second questionnaire form was sent to the 645 departments for 13,067 cases, and 6,990 (53.5%) forms were returned for further analysis. Estimated number of pwMS and pwNMOSD were 24,118 in total, which is more than 10-fold higher than that (2,280) of the 1st survey in 1972. The crude prevalence for both MS and NMOSD was 19.6/100,000 (14.3 for MS and 5.3 for NMOSD). Male: female ratios of MS and NMOSD were 1: 2.2 and 1: 4.1, respectively. The onset ages (mean ± standard deviation, year) of MS and NMOSD were 32.3 ± 11.6 and 44.2 ± 16.1, respectively. The Expanded Disability Status Scale scores and disease durations were 2.7 ± 2.4 in 12.9 ± 9.0 years for MS and 3.7 ± 2.4 in 10.9 ± 9.5 years for NMOSD. Disease-modifying therapy had been used for 77.2% in MS. The proportion of pwNMOSD against pwMS was 1: 0.37. Based on the prefectures at birth, the distribution of pwMS demonstrated north-south gradient (ρ = 0.39, p = 0.008), although no significant gradient was observed in pwNMOSD. Based on the registered sites, the proportion of pwMS among both pwMS and pwNMOSD showed north-south gradient (ρ = 0.4, p = 0.004).
Conclusions
As the combined prevalence of MS and NMOSD was 7.7/100,000 in the 4th survey (4.4 for conventional MS and 3.3 for others including opticospinal form), the prevalence of both MS and NMOSD appears to be still increasing. Disease severity may have become milder in MS and NMOSD compared with the 4th survey (3.5 ± 2.9 in conventional MS and 4.3 ± 2.7 in opticospinal form), though the disease durations in the two studies were comparable. Higher latitude is a risk for MS but not NMOSD in Japanese.
P0692 - Benefit of eculizumab for a broad range of patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: findings from PREVENT (ID 408)
Abstract
Background
Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in neuronal injury. The terminal complement inhibitor eculizumab is the first treatment approved for use in patients with AQP4 immunoglobulin G-positive NMOSD, based on PREVENT data.
Objectives
To determine whether the beneficial effect of eculizumab in reducing relapse risk in patients with NMOSD is associated with time since diagnosis, relapse history, disability burden or prior immunosuppressant therapy (IST) use, based on data from the phase 3 trial PREVENT (NCT01892345)
Methods
In PREVENT, patients received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo, with stable-dose concomitant IST (except rituximab and mitoxantrone) permitted. PREVENT was not powered for subgroup analyses; post hoc descriptive analysis was performed on subgroups defined by time since diagnosis, total number of historical relapses, baseline Expanded Disability Status Scale (EDSS) score and prior IST use.
Results
The proportions of patients experiencing an adjudicated relapse were lower with eculizumab than with placebo in all subgroups. Proportions for eculizumab and placebo, respectively, were: 2/31 versus 6/12 for < 1 year since diagnosis and 1/65 versus 14/35 for ≥ 1 year since diagnosis; 1/39 versus 10/24 for 2–4 historical relapses and 2/57 versus 10/23 for ≥ 5 historical relapses; 0/14 versus 3/6 for baseline EDSS scores ≤ 2.0 and 3/82 versus 17/41 for baseline EDSS scores ≥ 2.5 to ≤ 7.0; 0/15 versus 2/5 for no prior IST use (except corticosteroids alone); and 3/81 versus 18/42 for prior IST use. Relapse-risk reductions were consistent and statistically significant in all subgroups.
Conclusions
The data from this post hoc subgroup analysis suggest that eculizumab reduced relapse risk in PREVENT compared with placebo, regardless of time since NMOSD diagnosis, relapse history, disability burden or prior IST use.
P0718 - Impact of relapse on disability and quality of life in patients with neuromyelitis optica spectrum disorder: findings from the Phase 3 PREVENT study (ID 701)
Abstract
Background
Neuromyelitis optica spectrum disorder (NMOSD) is a rare, inflammatory disorder associated with relapse activity that may lead to poor recovery. The phase 3 PREVENT study was a randomized controlled trial with an open-label extension (OLE) that evaluated the efficacy of eculizumab in patients with aquaporin-4 immunoglobulin G-positive (AQP4-IgG+) NMOSD. Patients on eculizumab had a significantly lower risk of adjudicated relapse versus patients on placebo and reported improved health-related quality of life (HRQoL). Additional analyses on the impact of relapses on disease progression can provide a basis for the strategic treatment of patients with NMOSD.
Objectives
A post hoc analysis of data from the PREVENT study and its OLE assessed the impact of relapses on disability and HRQoL in patients with AQP4-IgG+ NMOSD.
Methods
Neurological disability was measured via the Expanded Disability Status Scale (EDSS). HRQoL was assessed using the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the 36-Item Short-Form Health Survey (SF-36). Changes in mean scores and the proportion of patients having clinically meaningful worsening (SF-36: 5-point decrease; EDSS: ≥2-point increase if the baseline score was 0, ≥1-point increase if the baseline score was 1 to 5, and ≥0.5-point increase if the baseline score was ≥5.5) from prerelapse to 30, 90, and 120 days post relapse were analysed.
Results
Overall, 27 patients were identified as having ≥1 adjudicated relapse. Compared with prerelapse measures, mean SF-36 PCS and MCS scores were significantly worse at 30 days post relapse, the mean EDSS score was significantly worse at 90 days post relapse, and the mean score for the SF-36 MCS was significantly worse at 120 days post relapse. Between 30 and 90 days post relapse, the proportion of patients with clinically meaningful worsening increased by 7%, 8%, and 11% for the EDSS, SF-36 PCS, and SF-36 MCS, respectively. Between 90 and 120 days post relapse, the proportion of patients decreased by 11% for the EDSS to reach 30%, and increased only by 4% for both the SF-36 PCS and SF-36 MCS to reach 31% and 50%, respectively, suggesting a stabilization of the relapse symptoms.
Conclusions
In the PREVENT study and its OLE, patients with AQP4-IgG+ NMOSD had significant, sustained (120 days) worsening of disability and HRQoL outcomes following adjudicated relapses. One-quarter to one-half of relapsing patients experienced stable, clinically meaningful worsening.
P0727 - Long-term efficacy and safety of eculizumab in AQP4+ neuromyelitis optica spectrum disorder (ID 555)
Abstract
Background
Neuromyelitis optica spectrum disorder (NMOSD) relapses can cause significant and irreversible neurologic disability. In PREVENT, eculizumab reduced the risk of relapse in patients with aquaporin-4 immunoglobulin G-positive (AQP4+) NMOSD by 94.2% vs placebo (hazard ratio 0.058; 95% confidence interval [CI]: 0.017–0.197; p < 0.0001) and adjudicated annualized relapse rate (ARR) for eculizumab was 0.02. The rate of adverse events (AEs)/100 patient-years (PY) was 749.3 for eculizumab and 1160.9 for placebo.
Objectives
To present the long-term efficacy and safety of eculizumab in patients with AQP4+ NMOSD during PREVENT (NCT01892345) and its ongoing open-label extension (OLE; NCT02003144).
Methods
During PREVENT, adults with AQP4+ NMOSD received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo with/without concomitant immunosuppressive therapy (IST). Patients who completed PREVENT could enroll in the OLE to receive eculizumab. Eculizumab safety and efficacy data from PREVENT and its OLE (interim data cut, July 31, 2019) were combined for this analysis.
Results
Overall, 137 patients received eculizumab, and were observed for a median (range) of 133.29 (5.1– 276.9) weeks, for a combined total of 362.3 PY. The estimated percentage of patients who were relapse free at 192 weeks (3.7 years) was 94.4% (95% CI: 88.6–97.3). The adjudicated ARR was 0.025 (95% CI: 0.013–0.048) and the annualized relapse-related hospitalization rate (ARRHR) was 0.03/PY (95% CI: 0.017–0.055). Rates of AEs and serious AEs (SAEs)/100 PY were 732.5 and 33.7, respectively. Common AEs included headache (29.2%) and upper respiratory tract infection (27.7%). Common SAEs, excluding NMOSD relapses, were pneumonia (3.6%), urinary tract infection (2.9%) and acute cholecystitis (2.9%). One patient died during PREVENT (pulmonary empyema) and one patient developed a disseminated Neisseria gonorrhoeae infection. In all, 25/137 patients (18.2%) developed a serious infection vs 6/47 (12.8%) receiving placebo in PREVENT. No patient had a meningococcal infection. During the OLE, 50/119 patients (42%) changed concomitant IST; most patients (44/50) stopped or decreased concomitant IST dose.
Conclusions
During PREVENT and its OLE, the percentage of relapse-free patients remained high (94%) through 192 weeks. Eculizumab was well tolerated and AEs were consistent with the safety profile established in other indications. ARRHR was low and many patients were able to reduce or stop concomitant IST.