Phase 1 Evaluation of Elezanumab (Anti-Repulsive Guidance Molecule A Monoclonal Antibody) in Healthy and Multiple Sclerosis Participants

Abstract

Objective: This study was undertaken to describe the safety, tolerability, pharmacokinetics, and immunogenicity of elezanumab (ABT-555), a fully human monoclonal antibody (mAb) directed against repulsive guidance molecule A (RGMa), in healthy and multiple sclerosis (MS) study participants.

Methods: The single-center, first-in-human, single ascending dose (SAD) study evaluated elezanumab (50-1,600mg intravenous [IV] and 150mg subcutaneous) in 47 healthy men and women. The multicenter multiple ascending dose (MAD; NCT02601885) study evaluated elezanumab (150mg, 600mg, and 1,800mg) in 20 adult men and women with MS, receiving either maintenance or no immunomodulatory treatment.

Results: No pattern of study drug-related adverse events was identified for either the SAD or MAD elezanumab regimens. Across both studies, the T_max occurred within 4 hours of elezanumab IV infusion, and the harmonic mean of t_1/2 ranged between 18.6 and 67.7 days. Following multiple dosing, elezanumab C_max , area under the curve, and C_trough increased dose-proportionally and resulted in dose-dependent increases in elezanumab cerebrospinal fluid (CSF) concentrations. Elezanumab CSF penetration was 0.1% to 0.4% across both studies, with CSF levels of free RGMa decreased by >40%. Changes in CSF interleukin-10 (IL-10) and free RGMa demonstrated dose/exposure-dependence.

Interpretation: The elezanumab pharmacokinetic profile supports monthly, or bimonthly, administration of up to 1,800mg with the option of a loading dose of 3,600mg. Elezanumab partitioning into CSF is within the range expected for mAbs. Reduced CSF levels of free RGMa demonstrate central nervous system target binding of elezanumab with an apparent maximal effect at 1,800mg IV. Exposure-associated increases in CSF IL-10, an anti-inflammatory cytokine with neuroprotective/neurorestorative properties, support potential pathway modulation in MS participants. ANN NEUROL 2023;93:285-296.

FIGURE 1

Study dose and group assignments for first‐in‐human single ascending dose (SAD) and multiple ascending dose (MAD) studies. SAD: Visits 168 and 196 are optional. Participants could return for a final follow‐up visit after day 196 at the investigator's discretion. MAD: Participants had the option of staying overnight at the study site or other local accommodation on days associated with the first dose (days 1–3); Group 3 loading dose of 3,600mg was given as 1,800mg on day 1 and 1,800mg on day 2. IV = intravenous; PK = pharmacokinetic.

FIGURE 2

Mean and standard deviation of elezanumab serum concentration versus time profiles for single doses in healthy participants from the single ascending dose (SAD) study and multiple doses in multiple sclerosis participants from the multiple ascending dose (MAD) study. IV = intravenous; Q = every; SC = subcutaneous.

FIGURE 3

Free repulsive guidance molecule A (RGMa) in cerebrospinal fluid (CSF) of multiple sclerosis participants (multiple ascending dose study) at day 113 by elezanumab dose levels (A) and elezanumab CSF levels (B). Estimates and tests were done in an analysis of covariance (4 groups) on log‐transformed data. Tests were 1‐sided for free RGMa, all t tests with 8 degrees of freedom. Estimated geometric mean value is the back transformation of the adjusted mean from the analysis of covariance for the transformed data. *p < .05, **p < .001, ***p < .0001. Conc = concentration; CV% = percent coefficient of variation; SE = standard error.

FIGURE 4

Percent change in cerebrospinal fluid (CSF) interleukin‐10 (IL‐10) and neurofilament light (NF‐L) levels by day 113 from baseline in multiple sclerosis participants (multiple ascending dose study) by elezanumab dose level.