A repeat IV dosing study of CCH evaluated fertility and reproductive toxicology in rats. Euthanasia was performed on day 1 in 1 male rat due to vocalization, forelimb swelling, and immobility of right forelimb (dose, 14× the proposed therapeutic human dose [0.17 mg/kg]); there were also 2 male rat deaths on day 15 related to restraint-associated trauma during injection procedure. None of the events were considered related to CCH treatment by the study director.
In both sexes, fertility was 96.0% for placebo and ranged from 88.0% to 92.0% for the 3 CCH doses (0.0145, 0.0435, and 0.13 mg/kg [43× the proposed therapeutic human dose]). In a repeat IV dosing study of CCH to evaluate embryo-fetal development in rats, euthanasia was performed on presumed gestation day 8 in 1 female rat (0.52 mg/kg dose, 43× the proposed therapeutic human dose) because of dose-limiting clinical signs at the injection site. Overall, CCH at 43× the proposed therapeutic human dose (0.52 mg/kg) had no effect on early embryonic development and did not harm the fetus (unpublished data).8
The human PK results in the current manuscript demonstrate a lack of systemic exposure following administration of 1 SC dose of CCH (up to 3.36 mg) and are similar to the results following a single (0.58 mg) injection or 2 concurrent injections (1.16 mg) of CCH into DC cords in patients.8 The intensity, duration, and characteristics of injection-site AEs reported following CCH administration in the current human PK studies were similar to data reported when patients with DC or PD were injected with CCH.9-11
In a pooled safety analysis of 1082 patients with DC treated with CCH, most treatment-related AEs were injection-site related (peripheral edema [77.4%], bruising [54.5%], injection-site pain [40.6%]), were mostly mild to moderate in intensity, and most resolved within 7 to 10 days.10 In a 5-year CCH posttreatment follow-up study, a subgroup of 66 patients with DC had received repeat treatment with CCH.9 Patients (n=28) reported AEs, mostly mild to moderate in intensity, with the most common AEs being peripheral edema (12%) and bruising (11%). A pooled safety analysis of 1044 patients with PD indicated that the most frequently reported treatment-related AEs after CCH treatment were bruising (82.7%), hematoma (50.2%), pain (33.5%), and swelling (28.9%) of the penis; most AEs were mild or moderate in intensity and resolved without intervention.11
In other studies, <1% of patients with PD (9/1044) or DC (3/1082) reported serious AEs (PD: penile hematoma [n=5], corporal rupture [n=4]; DC: tendon rupture [n=3]) following treatment with CCH.10,11 A pooled analysis of patients with PD treated with CCH reported that 1.6% of patients (17/1044) from 6 clinical studies discontinued because of AEs11; however, no patients discontinued because of AEs during 5-year follow-up after injection.12 In 13 trials of CCH for the treatment of DC, 1.3% of patients discontinued because of AEs.
Immunogenicity profiling has shown that administration of CCH in patients with PD or DC9,12 or administration of CCH in women with cellulite typically results in seropositivity for anti—AUX-I and/or anti—AUX-II antibodies. In the current study, the majority of the women were seropositive for anti—AUX-I and anti—AUXII antibodies after CCH treatment, but only 6 women developed neutralizing antibodies. In the phase 2 and two phase 3 studies, all women treated with CCH and tested for immunogenicity were seropositive for anti—AUX-I and anti—AUX-II antibodies on day 71.13,14 Pooling data from 270 seropositive women in the 3 studies shows that 155 (57.4%) were positive for neutralizing antibodies (anti—AUX-I, 54.4%; anti—AUX-II, 60.4%). Even so, the presence of neutralizing antibodies did not impact safety and efficacy outcomes.13,14 In addition, no serious hypersensitivity reactions were observed in women treated with CCH in the