Isembyld: which tox species, and why?

“General toxicology studies were conducted in Sprague-Dawley rat (durations of up to 26 weeks) and cynomolgus monkey (4 weeks’ duration) using weekly IV administration.”

“showed binding to promyostatin from all five species with affinities between 2 and 8nM (Table 48). The sequence of myostatin is at least 96% conserved among these species, and the epitope for apitegromab within myostatin is 100% conserved among these species.”

“Inhibition of myostatin activation by muSRK-015P, the parenteral version of apitegromab on a mouse IgG1 backbone, in combination with a small molecule SMN splice modulator (SMN-C1), increased muscle size and function in a mouse model of SMA.”

“The HD was 100 mg/kg in the 4-week rat and monkey studies and 300 mg/kg in the 12- and 26-week rat studies.”

“Increased postimplantation loss was also seen in the embryo-fetal development (EFD) studies in rat and rabbit; however, variability and lack of dose-response in both species and confounding by possible drug contamination in the rabbit study made it difficult to reach definite conclusions. Effects on reproductive system development were also observed in the pre- and postnatal development (PPND) and juvenile animal (JAS) studies in rat.”

“Genetox and carcinogenicity studies were not conducted. The division waived the carcinogenicity study requirement after a review of the Sponsor’s Weight of Evidence justification (see review by Barbara Wilcox dated April 19, 2022).”

“Inhibition of myostatin activation by muSRK-015P, the parenteral version of apitegromab on a mouse IgG1 backbone, in combination with a small molecule SMN splice modulator (SMN-C1), increased muscle size and function in a mouse model of SMA.”