First-in-Human Dose Selection and Safety, Tolerability, Pharmacokinetics, and Immunogenicity of the Muscle-Specific...

Adimanebart (ARGX-119), a first-in-class, humanized, agonistic monoclonal antibody, specifically targets and activates muscle-specific kinase, stabilizing the neuromuscular junction, increasing muscle strength, and decreasing muscle weakness and fatigability in nonclinical, proof-of-concept studies. Adimanebart may have broad therapeutic potential in neuromuscular junction disorders. This Phase I, first-in-human, double-blinded, placebo-controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of adimanebart in healthy participants. With no pharmacodynamic marker for muscle-specific kinase dimerization by adimanebart, human dose predictions were based on the minimum anticipated biological effect level in nonclinical studies. In this two-part study, 112 healthy participants were randomized to receive adimanebart or placebo in single ascending intravenous doses (0.005-15 mg/kg) or a single subcutaneous dose (5 mg/kg; Part A; n = 76), or weekly multiple ascending intravenous doses (0.3-5 mg/kg; Part B; n = 36). Adimanebart was well tolerated with a favorable safety profile. In single-ascending dose (SAD) cohorts, adimanebart demonstrated nonlinear pharmacokinetics at low concentrations, a dose-proportional increase in maximum concentration (mean range: 0.1-343 µg/mL), and a ≈6-fold increase in area under the concentration-time curve (0 to infinity) following a single intravenous dose, indicating target-mediated drug disposition. Incidence and prevalence of adimanebart anti-drug antibodies were comparable between treatment groups in SAD cohorts (adimanebart: 16.0% and 18.0%, placebo: 16.7% and 22.2%, respectively) and were not detected in multiple-ascending-dose cohorts. There was no apparent impact of anti-drug antibodies on adimanebart pharmacokinetics or safety. This study supports investigation of adimanebart as an agonistic muscle-specific kinase monoclonal antibody treatment for neuromuscular junction disorders.