Preclinical Safety Assessment and Toxicokinetics of Apitegromab, an Antibody Targeting Proforms of Myostatin for the Treatment of Muscle-Atrophying Disease

Abstract

Myostatin is a negative regulator of skeletal muscle and has become a therapeutic target for muscle atrophying disorders. Although previous inhibitors of myostatin offered promising preclinical data, these therapies demonstrated a lack of specificity toward myostatin signaling and have shown limited success in the clinic. Apitegromab is a fully human, monoclonal antibody that binds to human promyostatin and latent myostatin with a high degree of specificity, without binding mature myostatin and other closely related growth factors. To support the clinical development of apitegromab, we present data from a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies confirmed the ability of apitegromab to inhibit the activation of promyostatin. Toxicology studies in monkeys for 4 weeks and in adult rats for up to 26 weeks showed that weekly intravenous administration of apitegromab achieved sustained serum exposure and target engagement and was well-tolerated, with no treatment-related adverse findings at the highest doses tested of up to 100 mg/kg and 300 mg/kg in monkeys and rats, respectively. Additionally, results from an 8-week juvenile rat study showed no adverse effects on any endpoint, including neurodevelopmental, motor, and reproductive outcomes at 300 mg/kg administered weekly IV. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that apitegromab is a selective inhibitor of proforms of myostatin that does not exhibit toxicities observed with other myostatin pathway inhibitors. These data support the conduct of ongoing clinical studies of apitegromab in adult and pediatric patients with spinal muscular atrophy (SMA).

Inhibition of myostatin and related signaling pathways for the treatment of muscle atrophy in motor neuron diseases

“…A clinical trial on RO7204239 (GYM329) is about to start, while a clinical trial on apitegromab (SRK-015) is ongoing. Apitegromab is a fully human, monoclonal antibody that binds to human promyostatin and latent myostatin with a high degree of specificity, without binding mature myostatin and other closely related growth factors [ 142 ]. As discussed in the preceding section on preclinical studies, apitegromab in combination with an SMN upregulator was able to increase muscle mass and strength in SMA mice [ 97 ].…”

“…Before translating apitegromab into clinic, a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species was performed. Safety studies conducted on monkeys and rats showed that weekly intravenous administration of apitegromab at high doses achieved sustained serum concentration and target engagement, in absence of tolerability issues and treatment-related adverse events [ 142 ]. No detrimental effects were observed on neurodevelopmental, motor, and reproductive outcomes in juvenile rats.…”

Advances and limitations for the treatment of spinal muscular atrophy

“…Administration of eight weekly doses of apitegromab to cynomolgus monkeys also resulted in a dose-dependent (but not dose-proportional) response in accumulated latent myostatin. These apitegromab-induced increases in serum latent myostatin which were observed in animals [ 90 ], healthy volunteers [ 91 ] and patients with SMA (see below), are considered indicative of target (latent myostatin) engagement with apitegromab and complex formation of latent myostatin with apitegromab in the muscle that is ultimately reaching systemic circulation and measured in the serum [ 92 ].…”