Human Pharmacokinetics and Safety of Subcutaneous Collagenase Clostridium Histolyticum in Women

September 2020 | Volume 19 | Issue 9 | Original Article | 852 | Copyright © September 2020


Published online August 24, 2020

Ashish C. Bhatia MDa, Michael P. McLane PhDb, Tony Priestley PhDb, Saji Vljyan MBBSb, Martin K. Gelbard MDc

aDepartment of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL; Dermatologic, Laser, & Cosmetic Surgery at Oak Dermatology, Naperville, IL bEndo Pharmaceuticals Inc., Malvern, PA cUCLA School of Medicine, Los Angeles, CA *At the time the studies were conducted.

hemorrhage/hematoma, fibrosis, bile duct hyperplasia, and/ or hepatocellular necrosis were not completely resolved (data not shown). Plasma concentrations of AUX-I were generally measurable for up to 30 minutes post-IV dose of CCH and AUXII, up to 1 and 2 hours post-dose. There was no accumulation of plasma AUX-I or AUX-II observed during repeat dosing.

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proposed therapeutic human dose (0.52 mg/kg) had no effect on early embryonic development and did not harm the fetus (unpublished data).8

DISCUSSION

CCH has been shown to be safe and generally well tolerated for the treatment of PD and DC. The current studies were conducted to assess the PK and safety of a different presentation of CCH, which is being investigated as a treatment for cellulite in women. No quantifiable circulating CCH levels were observed in healthy women after a single SC dose up to 3.36 mg (0.84 mg CCH administered per treatment area [thigh or buttock] containing cellulite). The most common AEs reported with CCH administration were injection-site bruising, pain, and edema; events were mild or moderate in intensity and transient. Data are consistent with a phase 2, randomized, double-blind, placebo-controlled study in 375 women with moderate to severe cellulite on the buttocks and/or posterolateral thighs, in which the most common AEs reported in the CCH treatment group were injection-site bruising (75.1%) or injection-site pain (59.3%), 92.3% of which were mild or moderate in intensity.13 Similarly, most women treated with CCH reported injectionsite bruising or injection-site pain (RELEASE-1, 76.7% and 36.2%; RELEASE-2, 92.1% and 59.3%, respectively) as the most common AEs, AEs that were mild and/or moderate (RELEASE-1, 73.5%; RELEASE-2, 86.3%) and transient (≤2 weeks) in two phase 3, randomized, double-blind, placebo-controlled studies in 843 women.14 Furthermore, <5% of women discontinued due to AEs in the phase 2 and phase 3 studies.13,14 Therefore, the AE profile observed across the phase 1, 2, and 3 studies has been consistent.

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