Translational Pharmacokinetic/Pharmacodynamic Analysis of MYO-029 Antibody for Muscular Dystrophy.

Suppression of the myostatin (GDF-8) pathway has emerged as an important therapeutic paradigm for muscle-wasting disorders. In this study, we conducted a translational pharmacokinetic/pharmacodynamic (PK/PD) analysis of MYO-029, an anti-myostatin monoclonal antibody, using PK data in mice, rats, monkeys, humans, mouse tissue distribution data with 125 I-labeled MYO-029, muscle weight increase in SCID mice, and muscle circumference changes in monkeys. This analysis revealed significant in vivo potency shift between mice and monkeys (72 nM vs. 1.3 μM for 50% effect on quadriceps). Estimated central clearance of MYO-029 (0.38 mL/h/kg) in humans was greater than twofold higher than typical IgG mAbs. Peak and trough steady-state exposures of MYO-029 in patients at biweekly intravenous doses of 10 mg/kg MYO-029 are predicted to achieve only 50% and 10% of the maximum effect seen in monkeys, respectively. These retrospective analyses results suggest that the MYO-029 exposures in this trial had a low probability of producing robust efficacy.