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.

Background

Pathogenic autoantibodies against aquaporin 4 (AQP4) in neuromyelitis optica spectrum disorder (NMOSD) cause central nervous system injury, with subsequent release of astroglial and neuronal proteins such as glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) and Tau into the circulation. N-MOmentum is a randomized, placebo-controlled, double-masked trial of inebilizumab, a B-cell-depleting monoclonal antibody (NCT02200770).

Objectives

Investigate relationships of NfL, UCH-L1, Tau and serum (s)GFAP to disease activity and Expanded Disability Status Scale (EDSS) disability in N-MOmentum trial participants with either AQP4-immunoglobulin G (IgG) seropositive or seronegative NMOSD.

Methods

Serum biomarkers NfL, UCH-L1, Tau and sGFAP were measured using the single molecular array (SIMOA; Quanterix) in 1260 serial and attack-related samples from N-MOmentum participants (n=215) and healthy controls (HC; n=25).

Results

At baseline, biomarkers were elevated in subsets of patients with NMOSD (NfL, 16%; UCH-L1, 6%; Tau, 12%; sGFAP, 29%); NfL and UCH-L1 levels correlated with sGFAP (r=0.53 [p<0.001] and 0.18 [p=0.007]). Baseline elevations were significantly associated with increased attack risk (NfL, hazard ratio [HR] 2.5, p=0.01; UCH-L1, HR 2.8, p=0.039; Tau, HR 2.6, p=0.01; sGFAP, HR 3.03, p<0.001). After controlling for baseline sGFAP in Cox regressions, the other markers were not independently associated with attack risk (all HR <2; p>0.05). In the total cohort, a greater proportion of patients had an attack with placebo than inebilizumab (39% vs 12%). All biomarker levels increased after attacks and median-fold increases from baseline (95% confidence interval) trended higher with placebo than inebilizumab, reaching significance with sGFAP (NfL, 1.49 [0.93–3.37] vs 1.30 [0.84–2.14], p=0.4; UCH-L1, 6.70 [1.59–52.4] vs 1.85 [0.89–23], p=0.12; Tau, 2.19 [0.96–9.46] vs 1.09 [0.40–3.7], p=0.23; sGFAP, 20.2 [4.4–98] vs 1.11 [0.75–24.6], p=0.037). Following attacks, NfL correlated with EDSS score at attack assessments (R=0.55; p<0.001); other biomarkers did not correlate with EDSS score after controlling for NfL levels.

Conclusions

In NMOSD, serum NfL, UCH-L1 and Tau levels were higher than in HC; increased baseline sGFAP levels were associated with greater attack risk. Although sGFAP levels showed the greatest increase following attacks, NfL correlated with attack-related disability.

Background

The N-MOmentum trial of inebilizumab included patients with aquaporin 4-IgG seropositive (AQP4+) or seronegative (AQP4−) neuromyelitis optica spectrum disorder (NMOSD).

Objectives

To report AQP4− participant outcomes in N-MOmentum. .......................................................

Methods

Medical histories and screening data for AQP4− patients were assessed independently by 3 clinical experts before enrollment. Majority decision confirmed diagnoses using the 2006 criteria. Myelin oligodendrocyte glycoprotein-IgG (MOG) serology and annualized attack rates (AARs) were tested post hoc. These observations do not account for bias in estimates of effects on the AAR caused by regression to the mean, introduced by inclusion criteria requiring attacks during the 1 to 2 years before study entry.

Results

Only 18/50 AQP4− patients (36%) were eligible for randomization; 17 were randomized, 4 to placebo (1 MOG+) and 13 to inebilizumab (6 MOG+). Reasons for not enrolling prospective AQP4− NMOSD participants were mainly related to lack of fulfillment of MRI findings required by the 2006 criteria.

Owing to limited patient numbers, we compared the on-study to the pre-study AAR for treated participants to assess treatment effects.

For AQP4− participants (n=17), 40 attacks occurred in 23 patient-years of pre-study follow-up with mean AAR (95% confidence interval) of 1.72 (1.23–2.33). For MOG+ participants (n=7), 16 attacks occurred in 8.3 patient-years of pre-study follow-up with an AAR of 1.93 (1.11–3.14). For double-seronegative participants (n=10), 24 attacks occurred in 15 patient-years of pre-study follow-up with an AAR of 1.60 (1.02–2.38).

After receiving inebilizumab, AARs declined in all groups by the end of the randomized controlled period: AQP4− participants (n=13), 0.09 (0.02–0.26), or 3 attacks in 34.2 patient-years; MOG+ participants (n=6), 0.08 (0.002–0.464), or 1 attack in 12 patient-years; double-seronegative participants (n=7), 0.09 (0.011–0.326), or 2 attacks in 22 patient-years.

The benefit was sustained with longer-term inebilizumab exposure. At 120 days into the open-label period (OLP), during which all participants received inebilizumab, the AAR in AQP4− participants (n=17) remained low (0.069 [0.014–0.202]). No attacks were seen in any AQP4−, MOG+ or double seronegative patient during the OLP.

Conclusions

The N-MOmentum trial provides clinically important insight on the difficulty of correctly diagnosing AQP4− NMOSD and suggests that inebilizumab may have a benefit on AAR in these patients.

Background

Magnetic resonance imaging (MRI) findings in patients with neuromyelitis optica spectrum disorder (NMOSD) have not previously been studied with data from a prospective, randomized controlled study. During N-MOmentum, longitudinal MRIs were performed systematically.

Objectives

To characterize MRI findings in patients with NMOSD in the N-MOmentum study of inebilizumab. .....................

Methods

MRIs of the spinal cord, optic nerve and brain were performed at baseline, within 8 days of an NMOSD attack and at the end of the randomized controlled period (RCP; month 6.5). MRIs were read centrally by two independent, blinded-to-treatment neuroradiologists for new gadolinium-enhancing (Gd)-T1 enhancement events. Attacks were adjudicated by an expert committee.

Results

Complete MRI data were available for 192 (83%) of 230 participants, 42 of whom had an adjudicated attack (22 myelitis, 14 optic neuritis, 6 multi-domain). The remaining 38 patients did not have valid post-baseline MRI scans available for analysis. Inter-rater agreement between the two neuroradiologists for gadolinium-enhancing lesions was 98% for brain, 95% for spinal cord and 90% for optic nerve.

At the time of acute adjudicated NMOSD attacks, new Gd-T1 MRI enhancement corresponding to the affected clinical domain was present in 19/22 myelitis attacks (86%) and 11/14 optic neuritis attacks (79%). At the time of acute optic neuritis attacks, asymptomatic, new Gd-T1 enhancement was simultaneously observed in 4/14 spinal cord MRIs (29%) and 1/14 brain MRIs (7%). At the time of acute myelitis attacks, asymptomatic, new Gd-T1 enhancement was simultaneously observed in 6/22 optic nerve MRIs (27%) and 3/22 brain MRIs (14%).

In the 150 participants without an adjudicated attack, new Gd-T1 MRI enhancements compared with baseline readings were observed in the brain, spinal cord and optic nerve in 3%, 18% and 51% of patients at the end of the RCP, respectively.

Conclusions

At the time of attack, MRI enhancements were highly correlated to the clinical presentations. However, asymptomatic Gd-T1 enhancements were detected outside the symptomatic attack domain in about one-third of cases. Furthermore, subclinical Gd-T1 enhancements were observed in many patients who did not experience clinically overt attacks. Subclinical blood–brain barrier breakdown, particularly in the optic nerve, may be a frequent phenomenon in patients with active NMOSD.

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.

Background

Brainstem and cerebellar involvement are recognized to occur in myelin-oligodendrocyte-glycoprotein-antibody-associated-disorder (MOGAD) and the clinical syndrome can be severe. However, data on brainstem and cerebellar involvement in MOGAD is limited.

Objectives

To determine the frequency and characteristics of brainstem/cerebellar involvement in MOGAD versus aquaporin-4-IgG-seropositive-neuromyelitis-spectrum-disorder (AQP4-IgG-NMOSD) and multiple sclerosis (MS).

Methods

In this observational study, we retrospectively identified 185 Mayo Clinic MOGAD patients and included those with: 1) characteristic MOGAD phenotype; 2) MOG-IgG seropositivity by live-cell-based-assay; 3) brainstem/cerebellar MRI lesion(s). We compared clinical, MRI and cerebrospinal fluid (CSF) characteristics of symptomatic brainstem/cerebellar attacks in MOGAD to AQP4-IgG-NMOSD (n=30) and MS (n=30).

Results

Brainstem/cerebellum involvement occurred in 62/185 (34%) MOGAD patients of which 39/62 (63%) had accompanying brainstem/cerebellum symptoms/signs. Ataxia (45%) and diplopia (26%) were common manifestations. The median age in years (range) in MOGAD of 24 (2–65) was younger than MS at 36 (19–65) and AQP4-IgG-NMOSD at 45 (6–72)(P<.05). Isolated brainstem/cerebellar attacks in MOGAD (9/39[23%]) were less frequent than MS (22/30[73%]; p<0.05) but not significantly different from AQP4-IgG-NMOSD (14/30[47%]; p=0.07). Diffuse middle cerebellar peduncle MRI-lesions favored MOGAD (17/37[46%]) over MS (3/30[10%]; P<0.05) and AQP4-IgG-NMOSD (3/30[10%]; p<0.05), while diffuse medulla, pons or midbrain MRI-lesions occasionally occurred in MOGAD and AQP4-IgG-NMOSD but never in MS. CSF oligoclonal bands were similarly rare in MOGAD (2/30[7%]) and AQP4-IgG-NMOSD (1/22[5%]; p>0.99) but common in MS (17/22[77%]; p<0.05). Expanded-disability-status-scale-score (EDSS) and brainstem/cerebellar functional-system-scores (FSS) at nadir and recovery did not significantly differ between the groups.

Conclusions

Brainstem/cerebellar involvement is common in MOGAD but usually occurs as a component of a multifocal CNS attack rather than in isolation. We identified clinical, CSF, and MRI attributes that can help discriminate MOGAD from AQP4-IgG-NMOSD and MS.

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.

Background

Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) are a biomarker of MOG-IgG associated disorder (MOGAD), a CNS demyelinating disease that disproportionately affects the optic nerves as optic neuritis (ON). MOG-IgG ON is usually associated with pain and is often steroid responsive, but details of this in a large cohort are lacking.

Objectives

To investigate whether timing of steroid treatment affects the rate and extent of visual recovery in a large cohort of MOGAD patients and examine the temporal relation of eye pain to visual loss.

Methods

We included consecutive patients evaluated by the neuro-ophthalmology departments at 5 centers from January 2017 to April 2020. Patients fulfilling the following criteria were included: (1) clinically documented history of ON; (2) serum positivity for MOG-IgG by live cell-based-assay. The details of each ON attack was recorded, including presence of eye pain, days of eye pain prior to the onset of vision loss, nadir of visual acuity loss, type of acute treatment, time to treatment, time to recovery, and final visual acuity after each attack.

Results

A total of 221 ON attacks in 115 patients with one or more episodes of MOG-IgG ON were included. The average age at the initial ON onset was 36.8 (SD 19.3); 71 (62%) were female. Eye pain was present in 171/193 (89%) of attacks with data collected on eye pain. Among 98 attacks with available temporal data, the pain began a mean of 4.2 (SD 4.2) days prior to the vision loss. Early steroid therapy administered to 9 patients (6 with MRI optic nerve enhancement; 3 had clinical ON but no MRI) with eye pain but lacking vision loss had resolution of eye pain and never developed vision loss.

Among 37 ON attacks treated with intravenous methylprednisolone (IVMP) within 2 days of onset of vision loss, the average time to recovery was 1.9 days (SD 3.1) compared to 12.1 days (SD 12.1) in 84 ON attacks treated later than 2 days (p<0.001). Those treated within 2 days had less severe visual acuity (VA) loss at time of treatment (mean LogMAR VA 0.62, SD .77) compared to those treated later than 2 days (mean LogMAR VA 1.6, SD 0.9), p<0.001, and also had a better final VA after IVMP (mean LogMAR VA 0.05, SD 0.11) compared to those treated later than 2 days (LogMAR VA 0.26, SD 0.57), p=0.034.

Conclusions

The observational findings that early IVMP leads to faster recovery and better outcomes and that pain precedes vision loss in the majority of MOG-IgG ON attacks suggests there may be a therapeutic window for steroid treatment that reduces the risk of permanent deficits.

Background

Aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD) and acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR+ gMG) are neurological disorders with complement involvement. Eculizumab (a terminal complement inhibitor) demonstrated efficacy in reducing relapse risk and in eliciting clinical improvements during the phase 3, randomized, double-blind PREVENT and REGAIN studies and their open-label extensions (OLEs) (NCT01892345/NCT02003144 [interim data, July 2019] and NCT01997229/NCT02301624) previously published.

Objectives

To compare infection rates in patients with AQP4+ NMOSD or AChR+ gMG receiving eculizumab or placebo with or without concomitant immunosuppressive therapy (IST) during PREVENT, REGAIN and their OLEs.

Methods

Patients were randomized to eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo. Concomitant ISTs, excluding rituximab, were permitted. Post hoc analysis was performed to examine rates of infections in these studies and for subgroups determined by number of ISTs received at baseline.

Results

Rates/100 patient-years (PY) and types of infection were similar in eculizumab and placebo groups. In patients with NMOSD, rates/100 PY and % (n/N), respectively, were: no IST: 176.1, 80.0% (28/35) vs 192.2, 61.5% (8/13); 1 IST: 171.5, 81.8% (45/55) vs 154.1, 63.6% (14/22); 2 ISTs: 186.7, 85.1% (40/47) vs 238.2, 83.3% (10/12). For patients with gMG, rates/100 PY and % (n/N), respectively, were: no IST: 236.8, 100.0% (2/2) vs 305.6, 50.0% (1/2); 1 IST: 228.8, 82.9% (34/41) vs 253.1, 50.0% (9/18); 2 ISTs: 170.5, 91.0% (71/78) vs 192.5, 58.5% (24/41); ≥ 3 ISTs: 97.5, 50.0% (1/2) vs 100.1, 50.0% (1/2). In patients with NMOSD or gMG receiving eculizumab vs placebo, serious infection rates/100 PY and % (n/N), respectively, were: no IST: 2.3, 5.7% (2/35) vs 8.0, 7.7% (1/13) and none observed (0/2 vs 0/2); 1 IST: 11.2, 16.4% (9/55) vs 7.0, 9.1% (2/22) and 16.2, 24.4% (10/41) vs 34.5, 5.6% (1/18); 2 ISTs, 14.8, 29.8% (14/47) vs 47.6, 25.0% (3/12) and 13.4, 21.8% (17/78) vs 24.1, 12.2% (5/41); ≥ 3 ISTs (gMG only), 13.9, 50.0% (1/2) vs 0.0, 0.0% (0/2). One patient with gMG (2 ISTs) had meningococcal meningitis that resolved with antibiotics and eculizumab was resumed.

Conclusions

In AQP4+ NMOSD and AChR+ gMG, infection rates/100 PY were similar in eculizumab and placebo groups, regardless of concomitant IST. Infection rates/100 PY were consistent with the established safety profile of eculizumab.