Human Pharmacokinetics and Safety of Subcutaneous Collagenase Clostridium Histolyticum in Women.

BACKGROUND: Clostridium collagenase histolyticum (CCH) is being evaluated in women as a cellulite treatment. OBJECTIVE: To report preclinical safety and human pharmacokinetics (PK) and safety data for CCH. METHODS: Across 3 PK studies, 41 women received 12 subcutaneous injections per thigh/buttock in 1 session (up to 3.36 mg/dose). Blood samples were taken at baseline; at 5, 10, 20, and 30 minutes postdose; and at 1, 2, 4, 8, 12, 24, 48, 168, and 504 hours postdose. In a preclinical study, rats received 0, 0.029, 0.13, or 0.29 mg/dose of CCH intravenously (IV) every other day (QOD) for 16 days (total, 8 doses) and were evaluated for histopathologic changes. RESULTS: In human PK studies, no quantifiable plasma concentrations of AUX-I or AUX-II were observed postdose (n= 39 evaluable). Adverse events were injection site–related (bruising [97.6%], pain [87.8%], and edema/swelling [46.3%]). Antidrug antibodies were seen in most women at 504 hours postdose. In rats, plasma concentrations of AUX-I and AUX-II (CCH components) were measurable for 30 minutes and 1-2 hours, respectively, after IV administration. At ≥43× proposed human therapeutic dose on a mg/kg basis, rats experienced elevated liver enzyme levels, increased liver weights, and histologic changes that were mostly reversed during a 14-day recovery period. CONCLUSIONS: In human studies, no quantifiable circulating CCH levels were observed after a single subcutaneous dose of CCH up to 3.36 mg. Preclinical data indicated that repeat IV dosing (QOD; 8 doses) at ≥43× proposed human dose on a mg/kg basis for CCH was generally well tolerated.J Drugs Dermatol. 2020;19(9):852-856. doi:10.36849/JDD.2020.5048THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Collagenase Clostridium histolyticum for the pharmacological management of Peyronie's disease.

Peyronie's disease (PD) is defined as the abnormal accumulation of connective tissue in the tunica albuginea of the penis, and is an ongoing physical and psychological challenge for thousands of Americans. In vitro studies in the 1950s uncovered the potential of collagenase Clostridium histolyticum (CCH) to disrupt the collagen-containing plaques in PD, and opened the door to more in-depth clinical trials. Results indicated that with multiple dosage cycles followed by plaque modeling, penile curvature can be corrected, on average, in up to 35% of cases, with the majority of patients achieving ≥ 25% improvement in penile curvature. Most studies also indicated an improvement in patient-reported symptoms from the Peyronie's Disease Questionnaire. Adverse events from treatment with CCH included penile bruising, pain and edema, but most were mild to moderate in severity and usually resolved without intervention, suggesting that CCH is an effective and safe treatment for PD.

Clinical safety and effectiveness of collagenase clostridium histolyticum injection in patients with Peyronie's disease: a phase 3 open-label study.

INTRODUCTION: Collagenase clostridium histolyticum (CCH; Xiaflex, Auxilium Pharmaceuticals, Inc., Chesterbrook, PA, USA) is a Food and Drug Administration-approved, intralesional treatment for Peyronie's disease (PD). AIM: The aim of this study was to assess the safety and effectiveness of CCH in the treatment of PD. METHODS: This phase 3, open-label study enrolled subjects who were CCH-naïve, were enrolled in a previous pharmacokinetic study, or had received placebo in an earlier phase 2 CCH study. Each treatment cycle included two intralesional injections of CCH 0.58 mg, approximately 24-72 hours apart, and plaque modeling 24-72 hours after the second injection of each cycle. The treatment cycle was repeated after 6 weeks for ≤4 treatment cycles. MAIN OUTCOME MEASURES: The co-primary end points were the mean percent change in penile curvature deformity and the mean improvement in PD bother score (range 0-16) from baseline to week 36. RESULTS: Of the 347 subjects treated with ≥1 injection, 238 had both a penile curvature measurement and a Peyronie's Disease Questionnaire response at baseline and ≥1 subsequent time point. Mean baseline penile curvature deformity was 53.0° and mean PD symptom bother was 7.3. Statistically significant mean improvements from baseline to week 36 were observed in both penile curvature deformity (34.4% [95% confidence interval {CI}, 31.2%, 37.6%]) and PD symptom bother score (3.3 [95% CI, 2.8, 3.7]). Most adverse events (AEs) were mild or moderate in severity and local to the penis. There were three serious treatment-related AEs, two penile hematomas and one corporal rupture; all resolved with treatment. CONCLUSIONS: Potentially clinically meaningful and statistically significant improvements in penile curvature deformity and PD symptom bother scores were observed with intralesional injection of CCH compared with baseline in men with PD. CCH was generally well tolerated, with AEs primarily transient and local to injection site. In conjunction with previous studies, the results of this open-label study support the use of CCH in the treatment of PD.

Multiple concurrent collagenase clostridium histolyticum injections to Dupuytren's cords: an exploratory study.

BACKGROUND: Dupuytren's contracture (DC) is a progressive fibroproliferative disorder characterized by development of nodules and collagen cords within the palmar fascia of the hand. Collagenase clostridium histolyticum (CCH) is currently approved in adults with DC for the nonsurgical treatment of a single palpable cord during a 30-day treatment cycle. This open-label pilot study was designed to examine the safety, efficacy, and multiple-dose pharmacokinetics of injecting two cords (affected joints) with multiple doses of CCH concurrently into the same hand in subjects with DC and multiple contractures. METHODS: Twelve subjects with DC were enrolled, each with ≥3 contractures caused by palpable cords. Efficacy assessments were taken 30 days after treatment and adverse events (AEs) were recorded throughout. In the first treatment period, all subjects were injected with a single dose of CCH (0.58 mg) into a single cord. The same subjects entered a second treatment period 30 days later, where two different cords (affected joints) were injected concurrently on the same hand. A finger extension procedure was performed 24 hours after each administration of CCH to disrupt the enzymatically weakened cord. RESULTS: For metacarpophalangeal (MP) joints, mean contracture reduction per joint treated was 29.0 ± 20.7 degrees following single injection vs 30.3 ± 10.9 degrees per treated joint following multiple injections. For proximal interphalangeal (PIP) joints, mean reduction in contracture was 30.7 ± 21.1 and 22.1 ± 4.9 degrees per treated joint, respectively, for the two periods. All patients (100%) were either "quite satisfied" or "very satisfied" following either treatment cycle. The most common treatment-related AEs were edema peripheral, contusion, and pain in the treated extremity; the differences in severity for local effects of the injections were minimal between treatment periods. No serious treatment-related AEs or systemic complications were reported. CONCLUSION: These results provide preliminary evidence that two cords (affected joints) can be treated concurrently with CCH with similar efficacy and safety as cords treated individually in a sequential fashion. Multiple concurrent injections would eliminate the 30-day wait between single treatments and allow for rapid and effective treatment of patients with multiple affected joints, a significant advantage for both patient and physician. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry #ACTRN12610001045000.

Collagenase clostridium histolyticum injection for the treatment of Dupuytren's contracture.

Collagenase clostridium histolyticum is a novel treatment for Dupuytren's contracture, approved by the U.S. Food and Drug Administration in February 2010. Prior to its availability, surgery was the only treatment for contracture related to this disorder. Dupuytren's disease is a benign, progressive fibroproliferative disorder affecting the palms of the hands. It is characterized by the formation of collagen- rich nodules and cords, which gradually shorten by the action of myofibroblasts, resulting in finger contractures. Intralesional use of clostridial collagenase has been evaluated in a total of 1,082 patients receiving 2,630 injections during its clinical development, including 2 large prospective, randomized, double-blind, placebo-controlled trials: Collagenase Option for Reduction of Dupuytren's I (CORD I) and CORD II. Both studies showed a statistically significant reduction in contracture compared to placebo and treatment was well-tolerated with the majority of adverse events self-limited. Serious adverse events related to collagenase activity were rare. Maximal improvement was seen in patients with less severe contractures and with contractures of the metacarpophalangeal joint. This first-in-class biologic, injectable clostridial collagenase histolyticum, provides a safe, effective alternative to surgery for patients with Dupuytren's contracture.

[Collagenase Clostridum histolyticum in the management of Dupuytren's contracture]. / Kollagenase Clostridium histolyticum im Management der Dupuytrenschen Kontraktur.

Dupuytren's contracture is a fibroproliferate disease of the palmar aponeurosis with a formation of nodules and cords. Surgical treatment is the gold standard for Dupuytren's contracture at the moment. A short while ago Collagenase clostridium histolyticum was licensed as a non-surgical method to treat Dupuytren's contracture. Collagenase clostridium histolyticum is injected directly into the Dupuytren's cord and after 24 h the contracture is distended by manual rupturing. Collagenase clostridium histolyticum causes a depletion of collagen, however neurovascular structures are spared. 2 clinical phase III studies showed that contractures could be effectively reduced when using Collagenase clostridium histolyticum. However, there are no long-term results regarding effectiveness and side effects, or comparative studies using surgical methods. This paper presents a review of Collagenase clostridium histolyticum and its role in the management of Dupuytren's contracture. Indication, technical procedure, treatment results and complications are described.

Collagen as a clinical target: nonoperative treatment of Dupuytren's disease.

The cellular events leading to abnormal synthesis of collagen are important to our understanding of pathologic processes leading to impaired joint function. The contracture of Dupuytren's disease is a notable example. In a series of controlled phase-2 clinical trials, excessive collagen deposition in Dupuytren's disease has been targeted by a unique nonoperative method using enzyme (Clostridial collagenase) injection therapy to lyse and rupture finger cords causing metacarpophalangeal and/or proximal interphalangeal joint contractures. Forty-nine patients were treated in a random, placebo-controlled trial of one dose of collagenase versus placebo at one center. Subsequently 80 patients were treated in a random, placebo-controlled, dose-response study of collagenase at 2 test centers. The results of these studies indicate that nonoperative collagenase injection therapy for Dupuytren's disease is both a safe and effective method of treating this disorder in the majority of patients as an alternative to surgical fasciectomy. Phase-3 efficacy trials are now being planned to further develop and test this method under Food and Drug Administration regulatory guidelines. The findings of our study may lead to simpler and less invasive nonoperative treatments of joint limitation in which collagen plays a major pathologic role.

Fluorogenic bimane substrates with dabsyl group for endopeptidases; chymotrypsin, collagenase and thermolysin.

It was found that the fluorescence of 9,10-dioxa-syn-3,4,6,7-tetramethylbimane (bimane) can be quenched in the presence of dimethylaminoazobenzensulfonyl (Dabsyl) group. New combination of bimane (fluorophor) and dabsyl group (quencher) was applied to the syntheses of intramolecularly quenched fluorogenic substrates for hydrolytic enzymes. Bimane peptides containing dabsyl group were prepared, and were shown to be useful fluorogenic substrates for the assay of endopeptidases such as chymotrypsin, collagenase and thermolysin.

[The effect of procyanidolic oligomers on vascular permeability. A study using quantitative morphology]. / Action des oligomères procyanidoliques sur la perméabilité de la paroi vasculaire. Etude par morphologie quantitative.

In normal conditions vascular permeability is precisely regulated by mechanisms which involve among others the macromolecules of extracellular matrix of the vascular wall. Permeability for a given substance will vary according to the anatomical localisation of the vessel determining also its structure and composition. In some pathological conditions, such as inflammation or diabetes, permeability can be abnormally increased. Increased permeability can be reproduced by i.v. collagenase injection. This permeability increase can be quantified by image analysis using appropriate tracers such as FITC-dextrans or horse-radish peroxidase, on histological sections from control and collagenase treated rats, pretreated or not with procyanidolic oligomers (PCO). We studied cerebral capillaries, aorta and cardiac muscle capillaries. It could be shown that previous treatment of animals with procyanidolic oligomers prevented the permeability increase produced by collagenase injection.

[Comparative study of the properties of preparations of native and modified collagenase]. / Sravnitel'noe izuchenie svoistv preparatov nativnoi i modifitsirovannoi kollagenazy.

Collagenase was gradually modified by aldehyde dextran and hyaluronidase. The modification increased enzyme stability and widened pH-optimum of its activity against specific and biological substrates. The modified complex with collagenolytic and hyaluronidase activity accumulated in the lungs of mice after intravenous injection. These results demonstrate its possible use for the treatment of lung disorders.