Long-Term Safety and Curvature Deformity Characterization in Patients Previously Treated with Collagenase clostridium Histolyticum for Peyronie's Disease.

PURPOSE: We assessed the long-term safety and immunogenicity profile of collagenase clostridium histolyticum and characterized penile curvature deformity over time in patients previously treated for Peyronie's disease. MATERIALS AND METHODS: This phase 4 study included men who received collagenase clostridium histolyticum in either 12-month, double-blind, placebo controlled clinical trials (IMPRESS I/II), or one of two 9-month open label studies. Eligible patients received no additional collagenase clostridium histolyticum treatment and were followed once yearly for up to 5 years to assess Peyronie's disease clinical symptoms, patient reported outcomes and safety. RESULTS: Of 280 patients enrolled 204 (73%) completed the study. At baseline 247 patients had already experienced a mean±SD penile curvature decrease from 51.8±15.0 to 31.0±16.1 degrees (improvement of 20.9±16.2 degrees or 39.5%). At year 5 in 180 patients, despite no additional treatment, there was an additional 9.1% improvement in mean penile curvature compared with reference data (4.3±13.4 degrees, 95% CI 2.3-6.2, p <0.02). At baseline 183 patients experienced mean Peyronie's Disease Questionnaire bother domain score improvement from 6.5±3.5 to 3.4±3.3. At year 5 there was additional score improvement to 2.4±2.9 (p=0.0003). Adverse events were reported in 17.5% (49) of patients but no adverse events were considered treatment related. No long-term safety issues were identified up to 5 years after treatment. Long-term immunogenicity profiling showed a decreasing trend in the number of anti-AUX-I and anti-AUX-II seropositive cases at years 4 and 5 after collagenase clostridium histolyticum treatment. CONCLUSIONS: Most patients treated with collagenase clostridium histolyticum continued to have penile curvature and Peyronie's Disease Questionnaire domain score improvements through year 5 without additional collagenase clostridium histolyticum treatment, and no additional safety signals were identified.

Sixty years in the making: collagenase Clostridium histolyticum, from benchtop to FDA approval and beyond.

PURPOSE: The introduction of collagenase Clostridium histolyticum (CCH) as the first and only FDA-approved non-surgical treatment for Peyronie's disease (PD) has been an important step in its management. Our aim is to provide an overview of the historical origins of CCH and its development through FDA approval and beyond for the treatment of PD. METHODS: A PubMed search using the terms Peyronie OR Peyronie's AND collagenase and limited to clinical research studies resulted in 24 articles that were examined for the current review. RESULTS: PD is a connective tissue disorder of the penile tunica albuginea involving fibrotic penile plaques that cause abnormal curvature and, in many cases, erectile pain. Although the exact mechanism and underlying pathophysiology are not well characterized, the known lability of these plaques to exogenous bacterial collagenase combined with a lack of effective medical therapies led to the development of CCH as an evidence-based treatment of PD. The initial discovery of collagenase was followed by in vitro studies on PD plaque tissue and following the phase 3 IMPRESS trial culminated in FDA approval of CCH in 2013. Future directions in CCH therapy include improved patient selection, use in acute phase PD, adjuvant and combination therapies, and novel delivery mechanisms. CONCLUSION: CCH provides an effective non-surgical treatment option for men with PD. We have traced the development of CCH in the treatment of PD from the earliest in vitro investigations to comprehensive multi-study meta-analyses confirming its highly rated efficacy when compared to other historical non-surgical remedies.

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.

Intralesional Collagenase Clostridium histolyticum Causes Meaningful Improvement in Men with Peyronie's Disease: Results of a Multi-Institutional Analysis.

PURPOSE: In a multi-institutional setting we studied the efficacy and safety outcomes at multiple high volume centers where collagenase Clostridium histolyticum is used to treat Peyronie's disease. MATERIALS AND METHODS: We collected retrospective data on consecutive patients with Peyronie's disease who underwent treatment with collagenase C. histolyticum between April 2014 and March 2018 at a total of 5 institutions. Included in the study were 918 patients. Main outcomes of interest included the change in curvature after receiving collagenase C. histolyticum therapy and the frequency of serious treatment related adverse events. The 2-tailed paired Student t-test was used to compare continuous variables. Univariate and multivariate regression analyses were performed to assess predictors of the success of collagenase C. histolyticum therapy to improve curvature. RESULTS: In the cohort of 918 patients curvature improved from a mean of 48.2 degrees before treatment to 32.9 degrees after treatment, a 30.1% improvement from baseline (p <0.0001). Of the men 68.7% had a 20% or greater improvement in curvature. In the 502 patients who completed 4 or more cycles curvature improved from a mean of 49.7 degrees before to 32.7 degrees after treatment, a 33% improvement from baseline (p <0.0001). Of these men 74.4% experienced a 20% or greater improvement in curvature. A complication of treatment developed in 9% of patients. The number of cycles of collagenase C. histolyticum received was predictive of curvature improvement (p <0.0001). CONCLUSIONS: This large multi-institutional analysis confirms the safety and efficacy of collagenase C. histolyticum therapy in men with Peyronie's disease. Intralesional collagenase C. histolyticum for Peyronie's disease according to the IMPRESS (Investigation of Maximal Peyronie's Reduction Efficacy and Safety Studies) trial protocol produced an improvement in penile curvature in men with Peyronie's disease with a low rate of complications.

Collagenase Clostridium histolyticum for the Treatment of Peyronie's Disease: The Development of This Novel Pharmacologic Approach.

INTRODUCTION: The conception of collagenase Clostridium histolyticum (CCH) as treatment for Peyronie's disease (PD) was a vital first step in providing a nonsurgical, minimally invasive FDA-approved treatment for men with PD. AIM: To review the origins, clinical research history, and ultimately FDA approval of collagenase as PD treatment. METHODS: A PubMed search using (Peyronie's or Peyronie) AND collagenase, and limited to clinical research studies, returned nine papers that were examined in the current review. RESULTS: Collagenase as a PD treatment arose in response to a lack of effective nonsurgical treatments and the incomplete understanding of underlying PD etiology. Awareness of dense collagen in PD scarring and parallel initial exploration of collagenase to treat herniated lumbar discs coincided with and inspired laboratory-based investigation of collagenase effects on excised PD plaque tissue. The foundational conceptual work and the critical development of purified injectable collagenase allowed the pursuit of clinical studies. Progression of clinical studies into large-scale robust trials culminated in two important outcomes: development of the first validated, PD-specific measure of psychosexual function, the Peyronie's Disease Questionnaire, and the first FDA-approved treatment for PD. CONCLUSIONS: Collagenase therapy began as an attempt to modify the structure of PD-related tunica albuginea scarring, despite the lack of a fundamental understanding of the scar's origin. If we wish to advance PD treatment beyond this first effective step, the future needs to bring us full circle to the starting point: We need a greater understanding of the control of collagen deposition and wound healing in men with 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.

Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies.

PURPOSE: IMPRESS (Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies) I and II examined the clinical efficacy and safety of collagenase Clostridium histolyticum intralesional injections in subjects with Peyronie disease. Co-primary outcomes in these identical phase 3 randomized, double-blind, placebo controlled studies included the percent change in the penile curvature abnormality and the change in the Peyronie disease questionnaire symptom bother score from baseline to 52 weeks. MATERIALS AND METHODS: IMPRESS I and II examined collagenase C. histolyticum intralesional injections in 417 and 415 subjects, respectively, through a maximum of 4 treatment cycles, each separated by 6 weeks. Men received up to 8 injections of 0.58 mg collagenase C. histolyticum, that is 2 injections per cycle separated by approximately 24 to 72 hours with the second injection of each followed 24 to 72 hours later by penile plaque modeling. Men were stratified by baseline penile curvature (30 to 60 vs 61 to 90 degrees) and randomized to collagenase C. histolyticum or placebo 2:1 in favor of the former. RESULTS: Post hoc meta-analysis of IMPRESS I and II data revealed that men treated with collagenase C. histolyticum showed a mean 34% improvement in penile curvature, representing a mean ± SD -17.0 ± 14.8 degree change per subject, compared with a mean 18.2% improvement in placebo treated men, representing a mean -9.3 ± 13.6 degree change per subject (p <0.0001). The mean change in Peyronie disease symptom bother score was significantly improved in treated men vs men on placebo (-2.8 ± 3.8 vs -1.8 ± 3.5, p = 0.0037). Three serious adverse events (corporeal rupture) were surgically repaired. CONCLUSIONS: IMPRESS I and II support the clinical efficacy and safety of collagenase C. histolyticum for the physical and psychological aspects of Peyronie disease.

Baseline characteristics from an ongoing phase 3 study of collagenase clostridium histolyticum in patients with Peyronie's disease.

INTRODUCTION: Peyronie's disease (PD) is a localized penile collagen disorder of the tunica albuginea associated with significant physical deformity and psychological impairment. Current understanding of pretreatment characteristics in patients with chronic PD is limited by small samples, varied quality of assessments, and the lack of a PD-specific, validated measure of the psychosexual impact of PD. AIMS: Reporting baseline demographic and disease characteristics of the large multinational cohort of subjects with chronic PD who participated in the collagenase clostridium histolyticum (CCH, an investigational intralesional injection and minimally invasive intervention) phase 3 clinical study program. Findings from well-defined assessments, including the Peyronie's Disease Questionnaire (PDQ), the first validated PD-specific patient-reported measure of psychosexual impact, are reported. METHODS: Subjects included men≥18 years old with PD symptoms≥12 months and penile deformity between 30° and 90°. Analysis data included demographics, disease history, and psychosexual impact. MAIN OUTCOME MEASURES: Penile deformity, disease symptoms, the International Index of Erectile Function, and the PDQ were assessed. RESULTS: Eight hundred thirty-two subjects were enrolled from 64 sites across the United States and Australia. The mean age was 57.7 years; mean PD duration was 4.1 years. The majority of subjects had penile deformity≤60° (77.3%); mean penile deformity was 50.5°. Subjects reported having intercourse a mean of 10.2 times in the previous 3 months, 70.8% reported difficulty in performing vaginal intercourse, and 80.4% reported less frequent vaginal intercourse. Approximately 71.5% of subjects with severe (>60°) and 58.1% of subjects with mild/moderate (≤60°) penile deformity were "very bothered" or "extremely bothered" upon last look at their erect penis (P=0.0041), as measured by the PDQ. CONCLUSIONS: These data add to the body of knowledge regarding the clinical impact of chronic phase PD, including the PD-specific patient-reported psychosexual symptoms, using a large multinational chronic PD cohort in the CCH phase 3 clinical program.

Phase 2b study of the clinical efficacy and safety of collagenase Clostridium histolyticum in patients with Peyronie disease.

PURPOSE: Collagenase Clostridium histolyticum is an investigational nonsurgical treatment for Peyronie disease. In this phase 2b, double-blind, randomized, placebo controlled study we determined the safety and efficacy of collagenase C. histolyticum and assessed a patient reported outcome questionnaire. MATERIALS AND METHODS: A total of 147 subjects were randomized into 4 groups to receive collagenase C. histolyticum or placebo (3:1) with or without penile plaque modeling (1:1). Per treatment cycle 2 injections of collagenase C. histolyticum (0.58 mg) were given 24 to 72 hours apart. Subjects received up to 3 cycles at 6-week intervals. When designated, investigator modeling was done 24 to 72 hours after the second injection of each cycle. We evaluated penile curvature by goniometer measurement, patient reported outcomes and adverse event profiles. RESULTS: After collagenase C. histolyticum treatment significant improvements in penile curvature (29.7% vs 11.0%, p=0.001) and patient reported outcome symptom bother scores (p=0.05) were observed compared to placebo. In modeled subjects 32.4% improvement in penile curvature was observed in those on collagenase C. histolyticum compared to 2.5% worsening of curvature in those on placebo (p<0.001). Those treated with collagenase C. histolyticum who underwent modeling also showed improved Peyronie disease symptom bother scores (p=0.004). In subjects without modeling there were minimal differences between the active and placebo cohorts. Most adverse events in the collagenase C. histolyticum group occurred at the injection site and were mild or moderate in severity. No treatment related serious adverse events were reported. CONCLUSIONS: Collagenase C. histolyticum treatment was well tolerated. We noted significant improvement in penile curvature and patient reported outcome symptom bother scores, suggesting that this may be a safe, nonsurgical alternative for Peyronie disease.

Clinical Significance of Shortened Penile Length and Alterations in Penile Length Following Treatment for Peyronie's Disease.

INTRODUCTION: Across many cultures, penis size has been associated with virility, and concerns about penile length are commonplace. Peyronie's disease (PD) is a known acquired cause of penile shortening. OBJECTIVES: This paper describes the psychosocial impacts of penile length on men and their partners, both generally and in men with PD, and evaluates the effect of PD treatments (eg, collagenase clostridium histolyticum , surgery, mechanical therapy) on this outcome measure. METHODS: A PubMed database search was performed for English language articles through July 2021. Main outcome measures were association of penile length with emotional well-being, selfesteem, and relationship satisfaction in men with PD, and change from baseline penile length after treatment. RESULTS: Shortened penile length caused by PD can negatively impact patient and partner quality of life, including effects on body image, emotional well-being, sexual function, and interpersonal relationships. In men with PD, studies have demonstrated an association between loss of penile length and emotional problems, reduced satisfaction with sexual performance, poor self-esteem, depression, and relationship difficulties. Loss of penile length can frequently occur after surgery for PD (including plication, plaque incision/excision with grafting, and penile implant). Advanced surgical techniques may preserve/increase penile length, but the increased risks associated with these complex procedures must be carefully considered. Treatment with collagenase clostridium histolyticum does not appear to negatively impact penile length, and 5-year follow-up data suggest potential longterm posttreatment improvements in this outcome measure. Penile traction therapy, either alone or as adjunctive therapy, may increase penile length in men with PD, but nonadherence may limit improvement. CONCLUSION: Changes in penile length are important to many men, particularly those with PD, and should be considered during PD treatment selection. Penile length should be measured objectively before and after treatment for PD and should be included as an outcome measure in future studies on treatment effectiveness. Goldstein I, Gelbard MK, Lipshultz LI. Clinical Significance of Shortened Penile Length and Alterations in Penile Length Following Treatment for Peyronie's Disease. Sex Med Rev 2022;10:409-420.

Fibroproliferative disorders and diabetes: Understanding the pathophysiologic relationship between Peyronie's disease, Dupuytren disease and diabetes.

Introduction: Fibrosis is characterized by dysregulation and accumulation of extracellular matrix. Peyronie's disease and Dupuytren disease are fibroproliferative disorders of the tunica albuginea of the penis and fascia of the hand, respectively. Chronic hyperglycaemia due to diabetes mellitus can also lead to tissue injury and fibrosis. A meta-analysis has shown a relationship between Dupuytren disease and diabetes (overall odds ratio, 3.1; 95% confidence interval, 2.7-3.5). This review explores commonalities in the pathogenesis of Peyronie's disease, Dupuytren disease and diabetes. Methods: A search of the PubMed database was conducted using the search terms "diabetes" AND "Peyronie's disease"; and "diabetes" AND "Dupuytren." Results: Genome-wide association and gene expression studies conducted with tissue from people with Peyronie's disease or Dupuytren disease identified signalling pathways associated with wingless-type mammary-tumour virus integration site signalling, extracellular matrix modulation and inflammation. Biochemical studies confirmed the importance of these pathways in the pathogenesis of fibrosis with Peyronie's disease and Dupuytren disease. Dysregulation of matrix metalloproteinase activity associated with extracellular matrix breakdown was implicated in fibroproliferative complications of diabetes and in the aetiology of Peyronie's disease and Dupuytren disease. A notable percentage of people with diabetes have comorbid Peyronie's disease and/or Dupuytren disease. Conclusions: Studies have not been performed to identify fibroproliferative pathways that all 3 conditions might have in common, but data suggest that common pathways are involved in the fibroproliferative processes of Peyronie's disease, Dupuytren disease, and diabetes.

Long-term Curvature Deformity Characterization in Men Previously Treated With Collagenase Clostridium Histolyticum for Peyronie's Disease, Subgrouped by Penile Plaque Calcification.

OBJECTIVE: To examine the long-term (5-year) efficacy and safety of collagenase clostridium histolyticum (CCH) therapy in men with Peyronie's disease and varying degrees of plaque calcification. MATERIALS AND METHODS: CCH-treated adult men from the 12-month Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies I/II or 9-month open-label studies were eligible. Degree of plaque calcification (no calcification, noncontiguous stippled calcification, or calcification that did not interfere with CCH injection) was determined by penile x-ray or ultrasound. Penile curvature deformity and Peyronie's Disease Questionnaire responses were assessed annually for up to 5 years, with ≥6 months between consecutive visits. RESULTS: For no calcification group, from baseline to last (Reference) visit during the prior studies (n = 160), mean penile curvature improved by 20.9° ± 16.3° (39.3%) with CCH. Similar improvements with CCH from baseline to Reference were observed in stippled calcification (n = 27; improvement of 24.1° ± 20.2° [42.7%]) and calcification (n = 27; improvement of 21.7° ± 14.8° [43.3%]) subgroups. At Year 5 follow-up in no calcification group (n = 119), an additional 10.0% improvement in mean penile curvature vs Reference (4.3°) occurred. Penile curvature improvements seen at Reference in stippled calcification and calcification groups were maintained through Year 5. Additional numeric improvements in 3 Peyronie's Disease Questionnaire domains were observed at Year 5 visit vs baseline scores. No long-term safety issues were identified. CONCLUSION: This first report of long-term (5-year) CCH clinical trial outcomes in a population with penile plaque calcification demonstrates that nonsurgical intralesional CCH therapy is an appropriate Peyronie's disease treatment in men with penile plaque calcification that is stippled or does not impede CCH injection.

Safety and Efficacy of Collagenase Clostridium histolyticum in the Treatment of Acute Phase Peyronie's Disease: A Multi-institutional Analysis.

OBJECTIVE: To study, in a multi-institutional setting, the efficacy/safety outcomes in acute phase Peyronie's disease (PD) of multiple high-volume centers employing CCH to treat PD, which is defined as the abnormal formation of fibrous plaque(s) in the tunica albuginea of the penis. It is a chronic condition that afflicts 3%-13% of the US male population. There is no current multi-institutional research on the efficacy and safety of collagenase Clostridium histolyticum (CCH) in the treatment of acute phase PD. METHODS: Retrospective data were collected for consecutive patients with PD who underwent treatment with CCH between April 2014 and March 2018 at 5 institutions. 918 patients were included. Patients with duration of PD no longer than 6 months at presentation qualified as being in the acute phase of PD. Main outcomes of interest include the change in curvature after receiving CCH therapy, and frequency of serious treatment-related adverse events. Successful improvement in curvature is defined as an at least 20% decrease in penile curvature from baseline after CCH therapy. RESULTS: A total of 918 patients were included in the analysis, of which 134 (14.6%) qualified as acute phase PD (group 1) and the remaining 784 (85.4%) qualified as stable phase (group 2). Mean duration of PD was 4.44 ± 1.68 months for group 1, and 40.8 ± 61.2 months for group 2. There was no significant difference in final change in curvature between acute and stable phase of PD (13.5° vs 15.6°, P = .09). There was no statistically significant difference in frequency of treatment-related adverse events between the acute phase (16 patients, 11.9%) and the stable phase (77 patients, 9.8%; P = .44). In our multivariate analysis, only number of CCH cycles received was predictive of improvement of curvature. CONCLUSION: This large multi-institutional analysis confirms that CCH therapy is as safe and efficacious in acute phase PD as it is in stable phase PD.