Author Of 3 Presentations
LB1239 - Pharmacodynamic modeling and exposure-response assessment of inebilizumab in subjects with neuromyelitis optica spectrum disorders (ID 2124)
Abstract
Background
Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disease. Compared to CD20, CD19 is expressed on a wider range of the B cell lineage, from pro-B to plasmablasts and some plasma cells. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1κ monoclonal antibody that binds to CD19 resulting in effective depletion of B cells.
Objectives
To conduct population modeling of B cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome.
Methods
In a double-blind, placebo-controlled study (NCT02200770), adult NMOSD patients were randomized in a 3:1 ratio to receive intravenous infusions of either inebilizumab (300 mg) or placebo on Days 1 and 15 of a randomized-controlled period (RCP, 197 days) and every 6 months thereafter during the open label period. A hematopoietic transit model was developed to describe the depletion of circulating CD20+ B cell by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint (Adjudication Committee (AC)-determined NMOSD attack) and key secondary efficacy endpoints were evaluated.
Results
Treatment with inebilizumab led to rapid, profound, and sustained depletion of circulating B cells in NMOSD patients. The pharmacodynamic effect of inebilizumab was exerted by joint effects of reducing influx from pro-B cells and accelerating CD20+ B cell depletion in the blood. At the 300 mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and number of NMOSD-related in-patient hospitalizations) with PK exposure. Subjects with low, medium and high PK exposure had a similar hazard ratio of AC-determined NMOSD attack for inebilizumab.
Conclusions
The pharmacodynamic modeling and exposure-response analyses of primary and key secondary endpoints confirmed effective depletion of B cells is achieved with 300 mg dose administered as an IV infusion on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on the hazard ratio for NMOSD attack.
P0155 - Serum neurofilament light chain levels correlate with attack-related disability in neuromyelitis optica spectum disorder (ID 1291)
Abstract
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.
P0229 - Quiescent MRI activity in neuromyelitis optica spectrum disorder: results from the N-MOmentum randomized placebo-controlled trial (ID 1292)
Abstract
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.