dose of IV CCH (0.52 mg/kg [43-fold higher than proposed human therapeutic dose]) QOD starting before cohabitation (males, 28 days; females, 15 days); during cohabitation (maximum of 21 days for both); and on gestation days 0, 3, 5, and 7 (females) or continuing through 1 to 2 days before euthanasia (males). Viability and other clinical observations (eg, abortion, premature delivery) during the fertility and embryo-fetal development studies were made twice and three times daily, respectively, for the study duration and once daily during the postdose period for female rats. After euthanasia (dosing days 64–67 [males] or gestation day 13 [females]), histopathologic evaluation of reproductive organs was performed.
An embryo-fetal reproductive toxicology study evaluated embryo-fetal development; presumed pregnant female Sprague-Dawley rats (25 per dose) received 0, 0.0145, 0.0435, or 0.13 mg/dose of IV CCH (0.52 mg/kg [43-fold higher than proposed human therapeutic dose]) once daily during presumed gestation, days 7 through 17. Viability and other clinical observations (eg, abortion, premature delivery) were made twice daily for the study duration and once daily during the postdose period. Rats were euthanized on gestation day 21, and histopathologic evaluation of reproductive organs and fetuses was performed.
RESULTS
Human Pharmacokinetics and Safety'
A total of 41 women were included in the safety and PK populations from the 3 studies (Table 1). There were no quantifiable plasma concentrations of AUX-I or AUX-II at any time point postdose for 39 evaluable women (2 individuals were excluded because of potential serum component interference with the enzyme-linked immunosorbent assay used). The most common treatment-emergent AEs were injection-site related (Table 2) and were mild or moderate in intensity. The majority of all treatment-related AEs resolved within 14 to 30 days. The 2 most common treatment-related AEs were injectionsite bruising (93 AEs) and injection-site pain (90 AEs), and overall these AEs resolved in approximately 21 and 14 days, respectively. No serious AEs were reported and no AEs resulted in discontinuation from any study.
At day 22, more than half of 41 women had antibodies to AUX-I (68.3%) or AUX-II (56.1%). In Study 1, 1 of 6 women who tested positive for anti—AUX-I or anti—AUX-II antibodies developed neutralizing antibodies, and 0 of 14 patients had neutralizing antibodies in Study 2. In Study 3, 5 of 8 women developed neutralizing antibodies for AUX-II, one of whom also developed neutralizing antibodies to AUX-I. One woman who was seropositive for anti—AUX-II antibodies was not tested for neutralizing antibodies.
Preclinical Safety
A repeat IV dose general toxicity rat study (QOD; 8 doses over 16 days) was undertaken with high concentrations of CCH being injected systemically to address concerns about potential inadvertent IV dosing in humans. Due to dose-limiting signs at the injection site, euthanasia was performed on 4 rats (male, 1; female, 3) at 97× the proposed therapeutic human dose (1.16 mg/kg); at the same dose, 2 male and 4 female rats died between days 9 and 11 with no adverse clinical signs apparent before their deaths. At doses ≥43× the proposed therapeutic human dose on a mg/kg basis (0.52 mg/kg CCH), rats experienced elevated liver enzyme levels (aspartate aminotransferase and alanine aminotransferase), increased liver weights, and histologic changes (chronic inflammation and/or bile duct hyperplasia). Liver findings were mostly reversed during the 14-day recovery period, although liver findings of chronic active inflammation,
A total of 41 women were included in the safety and PK populations from the 3 studies (Table 1). There were no quantifiable plasma concentrations of AUX-I or AUX-II at any time point postdose for 39 evaluable women (2 individuals were excluded because of potential serum component interference with the enzyme-linked immunosorbent assay used). The most common treatment-emergent AEs were injection-site related (Table 2) and were mild or moderate in intensity. The majority of all treatment-related AEs resolved within 14 to 30 days. The 2 most common treatment-related AEs were injectionsite bruising (93 AEs) and injection-site pain (90 AEs), and overall these AEs resolved in approximately 21 and 14 days, respectively. No serious AEs were reported and no AEs resulted in discontinuation from any study.
At day 22, more than half of 41 women had antibodies to AUX-I (68.3%) or AUX-II (56.1%). In Study 1, 1 of 6 women who tested positive for anti—AUX-I or anti—AUX-II antibodies developed neutralizing antibodies, and 0 of 14 patients had neutralizing antibodies in Study 2. In Study 3, 5 of 8 women developed neutralizing antibodies for AUX-II, one of whom also developed neutralizing antibodies to AUX-I. One woman who was seropositive for anti—AUX-II antibodies was not tested for neutralizing antibodies.
Preclinical Safety
A repeat IV dose general toxicity rat study (QOD; 8 doses over 16 days) was undertaken with high concentrations of CCH being injected systemically to address concerns about potential inadvertent IV dosing in humans. Due to dose-limiting signs at the injection site, euthanasia was performed on 4 rats (male, 1; female, 3) at 97× the proposed therapeutic human dose (1.16 mg/kg); at the same dose, 2 male and 4 female rats died between days 9 and 11 with no adverse clinical signs apparent before their deaths. At doses ≥43× the proposed therapeutic human dose on a mg/kg basis (0.52 mg/kg CCH), rats experienced elevated liver enzyme levels (aspartate aminotransferase and alanine aminotransferase), increased liver weights, and histologic changes (chronic inflammation and/or bile duct hyperplasia). Liver findings were mostly reversed during the 14-day recovery period, although liver findings of chronic active inflammation,
