Role of Myostatin in Muscle Growth: Key Learnings From PK/PD Modeling Analysis

Suppression of the myostatin (GDF-8) pathway is considered an important therapeutic strategy for the treatment of muscle-wasting disorders, including muscular dystrophy, cachexia and sarcopenia. Myostatin is a member of TGF-β superfamily and negatively regulates skeletal muscle mass, muscle fiber size, and fiber count. Clinical trials targeting the myostatin pathways have produced mixed results. ACE-031, a Fc fusion of ActRIIB, is a decoy receptor for GDF-8. ACE-O31 was reported to increase muscle mass in Phase I/II trials with healthy post-menopausal women and in patients with Duchenne muscular dystrophy (DMD). In contrast, an antibody against myostatin, MYO-029, failed to achieve clinical efficacy in DMD patients. Given these contrasting results, it is critical to understand whether the clinical and preclinical data support GDF-8 as a novel paradigm for the treatment of muscular dystrophy disease. We performed a detailed pharmacokinetic-pharmacodynamic (PK/PD) analysis of preclinical and clinical data on MYO-029 to address animal model translation and predict the level of target inhibition at the clinical doses. A combination of mouse, non-human primates, and clinical data were analyzed, and exposure-response relationships were established for various pharmacodynamic endpoints. These included muscle weight increase in SCID mice efficacy studies, muscle circumference changes in a 39-week toxicology study in monkeys, and total myostatin levels observed in multiple-ascending dose (MAD) studies in Phase I/II trials. Our modeling analysis revealed a significant, in-vivo potency shift between mice and monkeys species. Further, our results showed that the exposures of Myo-029 in humans had low probability of success in modulating the target or in providing robust efficacy. The PK/PD analysis presented in this report supported the rationale for therapeutic strategies targeting the myostatin pathway