The efficacy of eculizumab in the treatment of AQP4-IgG-seropositive NMOSD has been evaluated in the phase III PREVENT study (Prevention of Relapses in Neuromyelitis Optica) . This pivotal, randomized, double-blind, placebo-controlled, multinational, time-to-event trial in 143 patients with AQP4-IgG-seropositive disease was conducted on the basis of encouraging findings from an earlier pilot study in 14 AQP4-IgG–seropositive patients . The PREVENT study enrolled individuals aged ≥ 18 years with NMOSD according to 2007 diagnostic criteria  (or neuromyelitis optica according to 2006 diagnostic criteria ) and confirmed AQP4-IgG seropositivity. They were also required to have a history of ≥ 2 relapses during the previous 12 months or 3 relapses during the previous 24 months (with ≥ 1 relapse in the previous 12 months) and an Expanded Disability Status Scale (EDSS) score of ≤ 7. Patients receiving immunosuppressive therapies (ISTs) for relapse prevention were eligible for inclusion, provided they were on stable-dose regimens . Key exclusion criteria included treatment with mitoxantrone or rituximab ≤ 3 months prior to screening, the use of IV immunoglobulin (IVIg) ≤ 3 weeks prior to screening, the receipt of prednisone doses > 20 mg/day (or equivalent) at screening, and the presence of a systemic bacterial or other infection that was considered to be clinically significant or inappropriately treated. Unresolved meningococcal disease was another exclusion criterion. Patients were vaccinated against Neisseria meningitidis in accordance with the then prevailing Advisory Committee on Immunization Practices (ACIP) recommendations prior to receiving a study medication, unless a previous vaccination provided adequate coverage; a 14-day course of antibiotics was administered if there were < 14 days between vaccination and starting trial treatment .
Participants were stratified by EDSS score and use of concomitant ISTs before being randomized to receive eculizumab (900 mg weekly for the first four doses then 1200 mg every 2 weeks from the following week; n = 96) or matching placebo (n = 47) administered via IV infusion over ≈ 35 (range 25–45) minutes. IVIg and PLEX were permitted as acute rescue therapies in the event of relapse .
The primary endpoint was (time to) the first adjudicated on-trial relapse. Briefly, treating physicians identified relapses on the basis of the following criteria: a new onset of neurological symptoms or worsening of existing neurological symptoms, with an objective change on neurological examination that persisted for > 24 h, signs and symptoms attributable to NMOSD rather than other causes, and onset preceded by ≥ 30 days of clinical stability. All physician-identified relapses were then adjudicated retrospectively using the same criteria by a blinded independent committee. Patients continued with their blinded treatment for 6 weeks following a relapse . The primary endpoint and six pre-specified secondary efficacy endpoints were tested in a hierarchical order. Regarding the latter, the adjudicated annualized relapse rate (ARR) was followed by two assessments of neurological disability [EDSS and Modified Rankin Scale (mRS) score], one of functional disability [Hauser Ambulation Index (HAI) score] and two of generic health-related quality of life [European Quality of Life 5-Dimension 3-Level (EQ-5D-3L) visual analogue scale and EQ-5D-3L summary index score] .
Patients who completed the core study could enter an open-label extension (OLE) of PREVENT (NCT02003144), where, following a 4-week, blinded induction phase, they received maintenance therapy with eculizumab 1200 mg every 2 weeks; their concomitant ISTs could be changed at the discretion of the treating physician . Some results of these trials are available from abstracts/posters [31,32,33,34,35,36,37].
At baseline in PREVENT, patients had a mean age of 44.3 years, a mean ARR during the previous 24 months of 1.99, and median scores on the EDSS, mRS and HAI that indicated moderate-to-severe disability. Overall, the vast majority (91%) were women, and three-quarters (76%) were receiving concomitant ISTs (glucocorticoids and/or another drug). Approximately one-third (32%) had received rituximab, albeit ≥ 3 months prior to screening. The two treatment groups were generally well balanced in terms of demographic and clinical characteristics .
Eculizumab significantly reduced the risk of the primary endpoint of adjudicated relapse relative to placebo in PREVENT. The trial was terminated after 23 of 24 pre-specified adjudicated relapses (there was uncertainty in estimating when the final event would occur); these relapses occurred in 3 (3%) of the 96 patients in the eculizumab group and 20 (43%) of the 47 patients in the placebo group [hazard ratio (HR) 0.06; 95% CI 0.02–0.20; p < 0.001] (Table 2) . The proportions of eculizumab- and placebo-treated patients who remained relapse-free were, respectively, 97.9% and 63.2% at week 48, 96.4% and 51.9% at week 96, and 96.4% and 45.4% at week 144 (Kaplan–Meier estimates) .
In post hoc analyses, the treatment effect of eculizumab on adjudicated relapse risk reduction was robust across all pre-specified subgroups analysed . These subgroups included those based on age (< 45 years; ≥ 45 years), sex, geographical region (Americas; Asia–Pacific; Europe) and ethnicity (Asian; Black or African American; White) . Among Asian patients, an estimated 97.3% of those treated with eculizumab (n = 37) versus 72.2% of those treated with placebo (n = 15) were free from relapse at week 48 (HR 0.054; 95% CI 0.007–0.453; p = 0.0002) . In terms of baseline demographics and concomitant IST use, the Asian subgroup was similar to the overall study population .
Likewise, the treatment effect of eculizumab on adjudicated relapse risk reduction was robust across pre-specified subgroups based on prior rituximab use (yes; no) and baseline IST use [corticosteroids alone; azathioprine (with or without corticosteroids); mycophenolate mofetil (with or without corticosteroids); other] . Among patients not receiving concomitant ISTs at baseline, adjudicated relapses occurred in none (0%) of 21 eculizumab recipients versus 7 (54%) of 13 placebo recipients (p < 0.0001) . Similar results were seen in a post hoc analysis of all patients receiving concomitant ISTs at baseline (albeit not a pre-defined subgroup), with adjudicated relapses occurring in 3 (4%) of 75 eculizumab recipients versus 13 (38%) of 34 placebo recipients (between-group statistical comparison not reported) .
Regarding the six pre-specified secondary endpoints, the adjudicated ARR significantly favoured eculizumab over placebo (rate ratio 0.04; 95% CI 0.01–0.15; p < 0.001) (Table 2) . However, the mean change from baseline in EDSS score, the next pre-specified secondary endpoint to be tested hierarchically, did not differ significantly between the two groups; hence, no statistical inferences based on p-values could be made for the remaining pre-specified assessments of disability and quality of life in the sequence (Table 2) . The observed lack of improvement in the EDSS score with eculizumab could have reflected, in part, the short (6-week) period of post-relapse follow-up prior to entering the OLE, as per the trial design.
The results of the hierarchical testing strategy notwithstanding, improvements in disability and quality of life endpoints assessed as secondary or tertiary outcomes consistently favoured eculizumab over placebo (Table 2) [27, 32, 33]. In post hoc analyses of disability worsening, significantly fewer eculizumab than placebo recipients experienced a protocol-defined increase in EDSS score (11.5 vs. 23.4%; p < 0.05) or HAI score (8.3 vs. 23.4%; p < 0.01) between baseline and study end . Also in post hoc analyses, changes from baseline to study end in the proportions of patients reporting problems significantly (p < 0.05) favoured eculizumab over placebo for 3 of the 5 EQ-5D-3L dimension scores, namely self-care, pain/discomfort and usual activities . Generic health-related quality of life was further assessed using the 36-item Short-Form Health Survey (SF-36); improvements between baseline and study end were significantly (p < 0.05) greater with eculizumab than placebo for the physical component score (PCS) and 2 of the 8 scales, namely physical functioning and role limitations due to physical health . Based on a categorical analysis of clinically meaningful changes in SF-36 score, eculizumab, compared with placebo, significantly (p < 0.05) decreased the probability of PCS deterioration and increased the probability of PCS improvement .
Interestingly, in terms of the impact on healthcare resource utilization, eculizumab relative to placebo significantly reduced the annualized rate of adjudicated relapse-related hospitalization (0.012 vs. 0.267; p < 0.0001), as well as the annualized rates of use of IV methylprednisolone (0.012 vs. 0.286; p < 0.0001), high-dose oral corticosteroids (0.012 vs. 0.114; p = 0.0021) and PLEX (0.012 vs. 0.134; p = 0.0006) in relation to the acute treatment of such relapses .
The observed durable efficacy of eculizumab in the core study has been supported by findings from the ongoing OLE. According to the most recent interim analysis (database cut-off date of 31 October 2018), 119 patients had been enrolled and treated in the OLE (78 and 41 who had previously received eculizumab and placebo, respectively, in PREVENT); the median duration on treatment during the study was 20 (range 0.1–198) weeks. Relative to the historical ARR (i.e. based on the 24 months prior to screening in PREVENT; mean value: 2.013), the median reduction in the primary efficacy endpoint of the on-trial, physician-determined ARR [− 1.829 (minimum, maximum: − 6.38, 1.63)] represented a statistically significant (p < 0.0001) and clinically meaningful effect of eculizumab . The majority (95.8%) of patients in the OLE did not experience an on-trial, adjudicated relapse, with an estimated 94.6%, 91.1% and 91.1% of patients being free from adjudicated relapses at weeks 48, 96 and 144, respectively .
Combined data from patients receiving at least one dose of eculizumab in PREVENT or the OLE (based on the same database cut-off date of 31 October 2018) are also available [35, 37]. According to this pooled analysis, only 8 (5.8%) out of a total of 137 patients who were treated with eculizumab and followed for a median of 107.8 (range 5.1–237.9) weeks experienced an on-trial, adjudicated relapse [three in PREVENT and five in the OLE (one patient had two relapses)]. An estimated 96.8%, 93.9%, 93.9% and 93.9% of patients were relapse-free at weeks 48, 96, 144 and 192, respectively, and the adjudicated ARR was 0.032 (95% CI 0.017–0.062) . On-trial, adjudicated relapse findings for the Asian subgroup (n = 50) were consistent with those for the overall study population, with an estimated 95.2% of Asian patients being free from relapse at week 192 .