Collagenase Clostridium histolyticum (CCH; Xiaflex®) is an injectable therapeutic agent that enzymatically degrades collagen, suppresses fibroblast adhesion and proliferation, and decreases the expression of structural proteins (fig. 1). CCH was first utilized to achieve enzymatic fasciotomy in the treatment of Dupuytren’s contracture, a condition of disordered fibrotic connective tissue that causes progressive deformity of the hand.¹ CCH was first applied for the treatment of Peyronie’s disease (PD) in a clinical trial in 1982.² In 2013, the U.S. Food and Drug Administration approved the use of CCH in the nonsurgical treatment of PD in men with dorsal or lateral penile curvature >30 degrees and/or with a tangible penile scar tissue plaque (fig. 2).

Figure 1. The mechanism of action of CCH involves enzymatic digestion of type I and III collagens, suppression of fibroblast adhesion and proliferation, and decreased expression of transforming growth factor-β1 (TGF-β1), smooth muscle actin and fibronectin. CCH class (AUX) I enzymes preferentially cleave fragments from end regions of intact collagen, and AUX II enzymes preferentially cleave fragments from central collagenous domains. Adapted from Sexual Medicine Reviews.¹

Figure 2. Timeline of points of interest in development of collagenase CCH for clinical treatment.

The safety and efficacy of CCH for the treatment of PD was documented in the IMPRESS (Investigation of Maximal Peyronie’s Reduction Efficacy and Safety Studies) trials, 2 double-blinded, placebo-controlled phase 3 studies which included 836 patients at 64 sites in the United States and Australia.³ Enrolled subjects had penile curvature deformities of between 30 and 90 degrees and received either up to 8 injections of 0.58 mg Xiaflex or placebo in a 2:1 ratio. Patients in the treatment group showed an average of 34% improvement at 52 weeks (compared to 18% for placebo). Treatment-related adverse events were generally mild and included penile hematoma, ecchymosis, penile pain and injection site edema. Six patients experienced serious adverse events, including 3 corporal ruptures and 3 penile hematomas. The “Real-World Trial,” which is the largest multi-institutional analysis of CCH efficacy, retrospectively reviewed data from 5 institutions where IMPRESS protocol was implemented for routine treatment of PD.⁴ This study found similar results to the IMPRESS trials, including a 33% improvement in penile curvature after 4 cycles of treatment and low rates of serious adverse events: 5.1% large penile hematoma, 0.8% corporal rupture, 0.9% severe penile swelling, 0.1% hematuria, 1.9% other.

Figure 3. Histology of rat urethral tissue sections (top-H&E stain-Bottom, ×400) demonstrating normal urethral lumen surrounded by normal distribution of collagen bundles and smooth muscle cells without fibrosis in the sham group, moderate fibrosis with densely packed collagenous stroma involving submucosal tissue in urethral fibrosis group, mild submucosal fibrosis in vehicle group, mild submucosal fibrosis in low dose CCH group and minimal fibrosis in high dose CCH group. CSP, Corpus spongiosum; FB, fibrosis; L, lumen; U, urothelium. Adapted from Urology.⁷

Current AUA guidelines limit recommendations for treatment of PD to those patients with stable phase disease, and the IMPRESS trials precluded patients with acute phase disease or atypical curvature. However, future clinical practice could include patients with a wider spectrum of clinical presentations. The Real-World Trial, whose sample included 17% of subjects with acute phase disease, and 2 small, retrospective studies have shown similar or greater efficacy with regards to reduction in penile curvature for patients treated for acute phase PD compared to those treated with stable phase disease without significant differences in adverse events.^4,5 Similarly, although ventral curvature was excluded from the IMPRESS trials for fear of urethral injury during penile modelling, recent literature suggests similar safety and efficacy in CCH treatment for ventral curvature compared to other plaque locations. A prospective study that included 228 patients, including 83%, 50% and 11% with dorsal, lateral and ventral curvature, respectively, found average curvature improvement to be 25%, 38% and 49% for the groups, respectively.⁶ Although this study was limited by small, atypical curvature groups, results pointing to greater improvement in atypical curvature groups and lack of higher rates of complications in these groups indicate potential for treatment in the future.

Urethral stricture disease (USD) is a progressive condition of tissue proliferation and scarring that narrows the lumen of the urethra, leading to urinary obstruction. Current therapeutic options for USD include urethral dilation, direct visual internal urethrotomy, urinary diversion such as through a suprapubic tube and surgical reconstruction. Similarities between the likely pathogenesis of trauma-induced fibroproliferation behind PD and USD led to the hypothesis that CCH may be useful as an adjunctive therapy for USD. CCH may also represent a safer alternative to mitomycin C injection after internal urethrotomy in anterior urethral stricture patients as the chemotherapeutic agent represents potential for toxicity to local tissues. A rat model study conducted by Sangkum et al observed 30 rats injected with TGF-β1, a profibrotic cytokine, to produce a urethral fibrosis-like condition with type I and III collagen.⁷ The effect of CCH was investigated using H&E stain, MT stain, and Western blot analysis (fig. 3). Results demonstrated dose dependent decreases in type I and III collagen. Both the low and high dose treatment groups revealed decreased type I and III collagen expression compared to the control group, with the high dose CCH treatment group showing greater decreases in collagen expression. A prospective, open-label phase 2 clinical trial of CCH in the treatment of USD was recently scheduled to have been completed in December 2020. Results of this study may provide further guidance toward implementing CCH for clinical treatment of USD.

Endo Pharmaceuticals, the makers of Xiaflex, are currently developing products involving CCH for the treatment of adhesive capsulitis and cellulite. Adhesive capsulitis is a musculoskeletal condition of the shoulder characterized by stiffness, pain and loss of motion that is likely caused by inflammation followed by reactive fibrosis and adhesions at the synovial linings of the joint. Fitzpatrick et al recently reported the single-center results from a randomized, double-blinded, placebo-controlled study for the use of CCH in the treatment of adhesive capsulitis.⁸ Patients with at least 60 degrees of restricted active range of motion (AROM) compared to the contralateral shoulder were randomized in a 3:1 fashion to receive 0.58 mg CCH or placebo. Both the treatment (9) and control (2) groups exhibited improvement in AROM at day 95 without a statistically significant difference at day 95 between the treatment and control groups. Cellulite is a condition of skin dimpling and nodularity in women that is associated with thickening of collagen in the subdermal layers. A randomized, double-blinded study of 375 women with moderate or severe cellulite demonstrated that patients treated with up to 3 treatment sessions with 0.84 mg CCH were more likely than placebo to experience improvement from baseline according to standardized screening tools.⁹ Results from phase 3 trials have been similarly positive.

Although currently available data have yet to prove effectiveness of these experimental treatments, future results will serve to better characterize the efficacy of treatments in these special conditions. Considering that Endo Pharmaceuticals products for adhesive capsulitis and cellulite are in phase 2 and phase 3 of development, respectively, it is likely that CCH will gain popularity in treatment of these and other fibroproliferative conditions.