The study is a Phase 1, single-center, randomized, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study to assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ART5803 compared with placebo in healthy adult participants
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis. The disease is caused by the development of autoantibodies against the amino (N)-terminal domain (NTD) of the NMDAR subunit 1 (NR1) that bind and cross link the receptors, leading to receptor internalization and loss of function. Arialys has developed a monovalent (one-armed) antibody, ART5803, that binds to the NTD of the NMDAR NR1 subunit without causing NMDAR inhibition, activation, or receptor internalization, while simultaneously blocking the ability of the pathogenic anti-NMDAR autoantibodies to bind to the receptor. This first-in-human (FIH) study will assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ART5803 compared with placebo in healthy participants.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
QUADRUPLE
Enrollment
64
A monovalent (one-armed) antibody, that binds to the NTD of the NMDAR NR1 subunit without causing NMDAR inhibition, activation, or receptor internalization, while simultaneously blocking the ability of the pathogenic anti-NMDAR autoantibodies to bind to the receptor.
Nucleus Network Pty Ltd
Melbourne, Victoria, Australia
Safety will be assessed by the incidence and severity of treatment-emergent adverse events (TEAEs)
ART5803 safety, as measured by the number of treatment emergent adverse events compared with placebo.
Time frame: 12 weeks
Safety will be assessed by clinically significant changes in physical and neurological examination findings
ART5803 safety, will be assessed by clinically significant changes in physical and neurological examination findings compared with placebo.
Time frame: 12 weeks
Safety by assessed by clinically significant changes in vital signs
ART5803 safety, will be assessed by clinically significant changes in vital signs including systolic and diastolic blood pressure, pulse rate, respiration rate, and body temperature as compared to placebo.
Time frame: 12 weeks
Safety by assessed by clinically significant changes in clinical laboratory outcomes
ART5803 safety, will be assessed by clinically significant changes in clinical laboratory outcomes including clinical chemistry, hematology, coagulation, and urinalysis as compared to placebo.
Time frame: 12 weeks
Safety by assessed by clinically significant changes in 12-lead ECG findings
ART5803 safety, will be assessed by clinically significant changes 12-lead ECG findings as compared to placebo.
Time frame: 12 weeks
Safety by assessed by clinically significant changes in concomitant medications
ART5803 safety, will be assessed by clinically significant changes in concomitant medications as compared to placebo.
Time frame: 12 weeks
Safety by assessed by clinically significant changes in presence of anti-drug antibodies (ADAs)
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ART5803 safety, will be assessed by clinically significant changes in presence of anti-drug antibodies (ADAs) as compared to placebo.
Time frame: 12 weeks
Safety will be assessed by incidence of dose-limiting toxicity (DLTs)
ART5803 safety, will be assessed by incidence of dose-limiting toxicity (DLTs) as compared to placebo.
Time frame: 12 weeks
Safety will be assessed by change in suicidal tendency measured by Columbia-Suicide Severity Rating Scale (C-SSRS)
ART5803 safety, will be assessed by change in suicidal tendency as measured by the incidence of positive responses (Yes) to Item 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) as compared to placebo.
Time frame: 12 weeks
To assess the pharmacokinetics (PK) of single ascending IV doses and multiple ascending IV doses of ART5803 compared with placebo
To characterize and compare the PK profile of single ascending IV doses and multiple ascending IV doses of ART5803 as measured by maximum concentration (Cmax) as compared with placebo.
Time frame: Serum collected over 96 hours after administration, Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, and Day 85; CSF collected 48 hours after administration, Day 29 and Day 43
To assess the pharmacokinetics (PK) of single ascending IV doses and multiple ascending IV doses of ART5803 compared with placebo
To characterize and compare the PK profile of single ascending IV doses and multiple ascending IV doses of ART5803 as measured by minimum concentration (Cmin) as compared with placebo.
Time frame: Serum collected over 96 hours after administration, Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, and Day 85; CSF collected 48 hours after administration, Day 29 and Day 43
To assess the pharmacokinetics (PK) of single ascending IV doses and multiple ascending IV doses of ART5803 compared with placebo
To characterize and compare the PK profile of single ascending IV doses and multiple ascending IV doses of ART5803 as measured by time at which Cmax is observed (tmax) as compared with placebo.
Time frame: Serum collected over 96 hours after administration, Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, and Day 85; CSF collected 48 hours after administration, Day 29 and Day 43
To assess the pharmacokinetics (PK) of single ascending IV doses and multiple ascending IV doses of ART5803 compared with placebo
To characterize and compare the PK profile of single ascending IV doses and multiple ascending IV doses of ART5803 as measured by area under the curve from time 0 to the last measurable concentration (AUC0-t) as compared with placebo.
Time frame: Serum collected over 96 hours after administration, Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, and Day 85; CSF collected 48 hours after administration, Day 29 and Day 43
To assess the pharmacokinetics (PK) of single ascending IV doses and multiple ascending IV doses of ART5803 compared with placebo
To characterize and compare the PK profile of single ascending IV doses and multiple ascending IV doses of ART5803 as measured by area under the curve from time 0 extrapolated to infinity (AUC0-∞) as compared with placebo.
Time frame: Serum collected over 96 hours after administration, Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, and Day 85; CSF collected 48 hours after administration, Day 29 and Day 43
To assess the pharmacokinetics (PK) of single ascending IV doses and multiple ascending IV doses of ART5803 compared with placebo
To characterize and compare the PK profile of single ascending IV doses and multiple ascending IV doses of ART5803 as measured by the half-life (t½) as compared with placebo.
Time frame: Serum collected over 96 hours after administration, Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, and Day 85; CSF collected 48 hours after administration, Day 29 and Day 43
To assess the pharmacokinetics (PK) of single ascending IV doses and multiple ascending IV doses of ART5803 compared with placebo
To characterize and compare the PK profile of single ascending IV doses and multiple ascending IV doses of ART5803 as measured by the volume of distribution (Vd) as compared with placebo.
Time frame: Serum collected over 96 hours after administration, Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, and Day 85; CSF collected 48 hours after administration, Day 29 and Day 43
To assess the pharmacokinetics (PK) of single ascending IV doses and multiple ascending IV doses of ART5803 compared with placebo
To characterize and compare the PK profile of single ascending IV doses and multiple ascending IV doses of ART5803 as measured by clearance (CL) as compared with placebo.
Time frame: Serum collected over 96 hours after administration, Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, and Day 85; CSF collected 48 hours after administration, Day 29 and Day 43
To assess the pharmacokinetics (PK) of single ascending IV doses and multiple ascending IV doses of ART5803 compared with placebo
To asses the CSF/serum ratio of ART5803 at multiple time points.
Time frame: Serum collected over 96 hours after administration, Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, and Day 85; CSF collected 48 hours after administration, Day 29 and Day 43