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

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

NMOSD is a chronic, auto-immune disease characterized by acute relapses that lead to accumulating disability. Satralizumab, a humanized, monoclonal antibody that inhibits the interleukin-6 receptor, reduced relapse frequency and had a favourable safety profile in two randomized, phase 3 clinical trials: SAkuraSky (satralizumab in combination with baseline immunosuppressants; NCT02028884), and SAkuraStar (satralizumab monotherapy; NCT02073279).

Objectives

To assess the impact of satralizumab on infection risk in patients with NMOSD.

Methods

Infections and serious infections (those meeting serious adverse event [AE] criteria) in the double-blind (DB: satralizumab 120mg Q4W vs placebo) and open-label extension (OLE: satralizumab 120mg Q4W) periods of SAkuraSky and SAkuraStar were evaluated (data cut 7 Jun 2019). Exposure-adjusted rates (events per 100 patient-years [PY] of exposure) were assessed, as the total exposure time in the DB period was longer for satralizumab than placebo.

Results

Overall, 180 patients were included. In the DB period, infection rates [95% CI] were lower with satralizumab vs placebo in SAkuraStar (99.8 [82.4–119.8] vs 162.6 [125.8–206.9] events/100PY); there was no between-group difference in infection rates in SAkuraSky (satralizumab: 132.5 [108.2–160.5]; placebo: 149.6 [120.1–184.1] events/100PY). Serious infection rates were comparable between satralizumab and placebo in both studies (SAkuraSky: 2.6 [0.3–9.2] vs 5.0 [1.0–14.7] events/100PY, respectively; SAkuraStar: 5.2 [1.9–11.3] vs 9.9 [2.7–25.2] events/100PY, respectively). In both studies, the most common infections in both treatment groups were upper respiratory tract infections and urinary tract infections.

In the combined DB/OLE period (all patients receiving ≥1 dose of satralizumab; n=166; median [range] exposure: 184 [4–276] weeks in SAkuraSky; 122 [5–243] weeks in SAkuraStar), infection and serious infection rates were similar to the DB period (SAkuraSky: 134.5 [119.5–150.8] infections/100PY, 4.1 [1.9–7.8] serious infections/100PY; SAkuraStar: 90.6 [78.4–104.0] infections/100PY, 3.6 [1.6–7.2] serious infections/100PY). The rates of infections and serious infections did not increase over time. There were no cases of progressive multifocal leukoencephalopathy in either study.

Conclusions

There was no increased risk of infection or serious infection observed in patients treated with satralizumab vs placebo in the DB and OLE periods of the SAkura studies.

Background

NMOSD is a chronic, auto-immune disease characterized by acute relapses that lead to accumulating disability. Satralizumab, a humanized, monoclonal antibody that inhibits the interleukin-6 receptor, reduced relapse frequency and had a favourable safety profile in two randomized, phase 3 clinical trials: SAkuraSky (satralizumab in combination with baseline immunosuppressants; NCT02028884), and SAkuraStar (satralizumab monotherapy; NCT02073279).

Objectives

To assess the impact of satralizumab on infection risk in patients with NMOSD.

Methods

Infections and serious infections (those meeting serious adverse event [AE] criteria) in the double-blind (DB: satralizumab 120mg Q4W vs placebo) and open-label extension (OLE: satralizumab 120mg Q4W) periods of SAkuraSky and SAkuraStar were evaluated (data cut 7 Jun 2019). Exposure-adjusted rates (events per 100 patient-years [PY] of exposure) were assessed, as the total exposure time in the DB period was longer for satralizumab than placebo.

Results

Overall, 180 patients were included. In the DB period, infection rates [95% CI] were lower with satralizumab vs placebo in SAkuraStar (99.8 [82.4–119.8] vs 162.6 [125.8–206.9] events/100PY); there was no between-group difference in infection rates in SAkuraSky (satralizumab: 132.5 [108.2–160.5]; placebo: 149.6 [120.1–184.1] events/100PY). Serious infection rates were comparable between satralizumab and placebo in both studies (SAkuraSky: 2.6 [0.3–9.2] vs 5.0 [1.0–14.7] events/100PY, respectively; SAkuraStar: 5.2 [1.9–11.3] vs 9.9 [2.7–25.2] events/100PY, respectively). In both studies, the most common infections in both treatment groups were upper respiratory tract infections and urinary tract infections.

In the combined DB/OLE period (all patients receiving ≥1 dose of satralizumab; n=166; median [range] exposure: 184 [4–276] weeks in SAkuraSky; 122 [5–243] weeks in SAkuraStar), infection and serious infection rates were similar to the DB period (SAkuraSky: 134.5 [119.5–150.8] infections/100PY, 4.1 [1.9–7.8] serious infections/100PY; SAkuraStar: 90.6 [78.4–104.0] infections/100PY, 3.6 [1.6–7.2] serious infections/100PY). The rates of infections and serious infections did not increase over time. There were no cases of progressive multifocal leukoencephalopathy in either study.

Conclusions

There was no increased risk of infection or serious infection observed in patients treated with satralizumab vs placebo in the DB and OLE periods of the SAkura studies.