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.

Development of neural repair therapy for chronic spinal cord trauma: soluble nogo receptor decoy from discovery to clinical trial

“…AXER-204 was safe, well tolerated, and achieved desired CSF levels. The safety and tolerability of AXER-204 match that of other neural repair-targeted approaches that have advanced to clinical trials in the acute or subacute stage for SCI and related indications [56][57][58][59]. Upper extremity strength was not improved by AXER-204, but posthoc analyses indicate that AXER-204 may be efficacious in treatment-na€ ıve individuals with incomplete SCI.…”

Comparability of Elezanumab Safety, Tolerability, and Pharmacokinetics in Healthy Japanese, Chinese, and White Participants

“…The t 1/2 at lower doses (150 and 450 mg) were shorter compared to higher doses (1600 and 3600 mg) in this study. 26 This could be due to nonlinear PK of elezanumab at lower dose ranges as observed in other Phase 1 studies (SAD in healthy participants and multiple-ascending-dose study in patients with relapsing forms of multiple sclerosis). 26 The higher estimates for t 1/2 (48.2-72.5 days) at higher doses (1600 and 3600 mg) were also within the same t 1/2 range observed at higher exposure (higher doses in the SAD study or at steady state in the multiple-ascending-dose study) in other Phase 1 studies.…”

“…26 This could be due to nonlinear PK of elezanumab at lower dose ranges as observed in other Phase 1 studies (SAD in healthy participants and multiple-ascending-dose study in patients with relapsing forms of multiple sclerosis). 26 The higher estimates for t 1/2 (48.2-72.5 days) at higher doses (1600 and 3600 mg) were also within the same t 1/2 range observed at higher exposure (higher doses in the SAD study or at steady state in the multiple-ascending-dose study) in other Phase 1 studies. Although the White/Western participants showed relatively lower variability in t 1/2 estimates (17-50 days) across lower and higher doses, the 3600-mg group had the estimated pseudo-standard deviation of 88.5 relative to a harmonic mean t 1/2 of 48.2 days, which explains the difference in the estimated t 1/2 range.…”

“…The safety, tolerability, pharmacokinetics (PK), and immunogenicity of elezanumab was assessed in 2 Phase 1 clinical studies to date, in which 35 healthy participants and 15 patients with multiple sclerosis were exposed to elezanumab. 26 The first-in-human study was a single-ascending-dose (SAD) study in healthy participants. In this study, elezanumab exhibited a mean time to the maximum observed serum concentration (t max ) of approximately 4 hours, and harmonic mean terminal phase elimination half-life (t 1/2 ) that ranged from 19 to 50 days.…”

“…Elezanumab is a fully human monoclonal antibody that is directed against RGMa. The safety, tolerability, pharmacokinetics (PK), and immunogenicity of elezanumab was assessed in 2 Phase 1 clinical studies to date, in which 35 healthy participants and 15 patients with multiple sclerosis were exposed to elezanumab 26 . The first‐in‐human study was a single‐ascending‐dose (SAD) study in healthy participants.…”