First-in-Human Dose Selection and Pharmacokinetics, Safety, Tolerability, and Immunogenicity of ARGX-119, an Agonist Antibody for Human Muscle-Specific Kinase
Tonke van Bragt1, Christa Kneip2, Sofie Priem2, Xinghong Leng2, Rachelle Mutch3, Sonya K. Patel2, Peter Vanhoenacker2, Cristina Vaghi2, Rebecca Shilling2, Roeland Vanhauwaert2
1Curare Consulting B.V., 2argenx, 3argenx and Thermo Fisher Scientific
Objective:
To present the approach for selection of first-in-human (FIH) doses and the results of a phase 1, FIH, double-blinded, placebo-controlled study (NCT05670704) of single ascending doses (SAD) and multiple ascending doses (MAD) of ARGX-119 in healthy participants.
Background:
ARGX-119 is the first agonist antibody for human muscle-specific kinase (MuSK). Upon activation of MuSK, ARGX-119 may stabilize the neuromuscular junction (NMJ) in patients with neuromuscular diseases such as congenital myasthenic syndrome (CMS) and amyotrophic lateral sclerosis (ALS). Nonclinical, proof-of-concept (PoC) studies of ARGX-119 showed restoration of NMJ signaling in mouse models of Docking Protein 7 (DOK7)-CMS and MuSK-myasthenia gravis. Results from nonclinical, repeated dose toxicity studies supported initiation of this FIH study with ARGX-119.
Design/Methods:
Dose selection was based on the determination of the (minimally) active dose in nonclinical PoC studies and human pharmacokinetic (PK) predictions based on a non-human primate PK model. This FIH study evaluated the safety, tolerability, PK, and immunogenicity of ARGX-119 versus placebo, administered as intravenous SAD (9 cohorts), subcutaneous SAD, and intravenous MAD (4 once-weekly intravenous doses in 4 cohorts) in healthy participants.
Results:
Preliminary results from the FIH study suggest that ARGX-119 has a favorable safety profile in healthy participants at the doses investigated. There were no changes in the original design of single and multiple doses as decided by the Data Review Team evaluating accumulating PK and safety data. PK data in humans showed nonlinear elimination, suggesting target-mediated elimination as the relevant elimination pathway at low ARGX-119 concentrations, as observed in nonclinical studies.
Conclusions:
ARGX-119 was well tolerated and has a favorable safety profile in healthy participants at the doses investigated in single- and multiple-dose cohorts in this FIH study. ARGX-119 is currently being evaluated in a phase 1b study in adult participants with DOK7-CMS (NCT06436742) and a phase 2a study in adult participants with ALS (NCT06441682).
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