Gregory J. Kaufman

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 Peyronies 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.

Dupuytren Contracture Recurrence Following Treatment with Collagenase Clostridium Histolyticum (CORDLESS Study): 3-Year Data

PURPOSE To evaluate long-term efficacy and safety of collagenase clostridium histolyticum (CCH) after the third year of a 5-year nontreatment follow-up study, Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study. METHODS This study enrolled Dupuytren contracture patients from 5 previous clinical studies. Beginning 2 years after their first CCH injection, we re-evaluated patients annually for joint contracture and safety. Recurrence in a previously successfully treated joint (success = 0° to 5° contracture after CCH administration) was defined as 20° or greater worsening in contracture in the presence of a palpable cord or medical/surgical intervention to correct new or worsening contracture. We assessed partially corrected joints (joints reduced 20° or more from baseline contracture but not to 0° to 5°) for nondurable response, also defined as 20° or greater worsening of contracture or medical/surgical intervention. RESULTS Of 1,080 CCH-treated joints (648 metacarpophalangeal [MCP]; 432 proximal interphalangeal [PIP]; n = 643 patients), 623 (451 MCP, 172 PIP) had achieved 0° to 5° contracture in the original study. Of these joints, 35% (217 of 623) recurred (MCP 27%; PIP 56%). Of these recurrences, an intervention was performed in 7%. Of the 1,080 CCH-treated joints, 301 were partially corrected in the original study. Of these, 50% (150 of 301; MCP: 38% [57 of 152]; PIP: 62% [93 of 149]) had nondurable response. We identified no new long-term or serious adverse events attributed to CCH during follow-up. Anti-clostridial type I collagenase and/or anti-clostridial type II collagenase antibodies were reported for 96% or more of patients who received 2 or more CCH injections and 82% who received 1 injection. CONCLUSIONS The recurrence rate, which is comparable to other standard treatments, and the absence of long-term adverse events 3 years after initial treatment indicate that CCH is an effective and safe treatment for Dupuytren contracture. Most successfully treated joints had a contracture well below the threshold for surgical intervention 3 years after treatment. Recurrence rates among successfully treated joints were lower than nondurable response rates among partially corrected joints. TYPE OF STUDY/LEVEL OF EVIDENCE Therapeutic IV.

Bother and Distress Associated with Peyronie's Disease: Validation of the Peyronie’s Disease Questionnaire

PURPOSE We validated the Peyronies Disease Questionnaire (http://www.auxilium.com/PDQ), a 15-question self-reported survey that measures the impact and severity of Peyronies disease symptoms in 3 domains, including 1) psychological and physical symptoms, 2) penile pain and 3) symptom bother. MATERIALS AND METHODS We used baseline data from 2 phase 3 clinical trials (334 and 345 patients, respectively) of collagenase clostridium histolyticum treatment for Peyronies disease associated penile curvature and bother. Collected data included PDQ domain scores, International Index of Erectile Function scores, objective penile curvature measures and patient reported Peyronies disease symptom severity. Psychometric analyses included confirmatory factor analysis, inter-item reliability, and tests of convergent and discriminant validity, all related to the overall construct validity of the scale. RESULTS Confirmatory factor analysis supported the conceptual framework of the PDQ with 3 confirmed subdomains. Each scale showed good consistency, ie internal reliability (each Cronbach α >0.70). Convergent and discriminant validity were noted in the pattern of associations between PDQ domains and other Peyronies disease measures. PDQ domain scores significantly differed between patients with vs without erectile dysfunction and between patients with vs without Peyronies disease related symptom distress, further supporting PDQ construct validity. CONCLUSIONS This study confirms the conceptual framework, factor structure, and convergent and discriminant validity of the PDQ psychological and physical symptoms, penile pain, and symptom bother domains. Used in conjunction with objective penile curvature measurements, the PDQ can serve as a valuable diagnostic tool or outcome measure to assess treatment related improvements in Peyronies disease symptoms.

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 Peyronies 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 Peyronies 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 of collagenase Clostridium histolyticum in the treatment of Peyronie's disease by subgroup: results from two large, double-blind, randomized, placebo-controlled, phase III studies

To examine the efficacy of intralesional collagenase Clostridium histolyticum (CCH) in defined subgroups of patients with Peyronies disease (PD).

The Efficacy and Safety of Concurrent Collagenase Clostridium Histolyticum Injections for 2 Dupuytren Contractures in the Same Hand: A Prospective, Multicenter Study

PURPOSE To evaluate efficacy and safety of concurrent administration of 2 collagenase clostridium histolyticum (CCH) injections to treat 2 joints in the same hand with Dupuytren fixed flexion contractures (FFCs). METHODS Patients with 2 or more contractures in the same hand caused by palpable cords participated in a 60-day, multicenter, open-label, phase 3b study. Two 0.58 mg CCH doses were injected into 1 or 2 cords in the same hand (1 injection per affected joint) during the same visit. Finger extension was performed approximately 24, 48, or 72 or more hours later. Changes in FFC and range of motion, incidence of clinical success (FFC ≤ 5°), and adverse events (AEs) were summarized. RESULTS The study enrolled 715 patients (725 treated joint pairs), and 714 patients (724 joint pairs) were analyzed for efficacy. At day 31, mean total FFC (sum of 2 treated joints) decreased 74%, from 98° to 27°. Mean total range of motion increased from 90° to 156°. The incidence of clinical success was 65% in metacarpophalangeal joints and 29% in proximal interphalangeal joints. Most treatment-related AEs were mild to moderate, resolving without intervention; the most common were swelling of treated extremity, contusion, and pain in extremity. The incidence of skin lacerations was 22% (160 of 715). Efficacy and safety were similar regardless of time to finger extension. CONCLUSIONS Collagenase clostridium histolyticum can be used to effectively treat 2 affected joints concurrently without a greater risk of AEs than treatment of a single joint, with the exception of skin laceration. The incidence of clinical success in this study after 1 injection per joint was comparable to phase 3 study results after 3 or more injections per joint. Two concurrent CCH injections may allow more rapid overall treatment of multiple affected joints, and the ability to vary the time between CCH injection and finger extension may allow physicians and patients greater flexibility with scheduling treatment.

Analysis of the clinical safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for adults with Peyronie's disease (PD)

To examine the safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for the treatment of Peyronies disease (PD), using a pooled safety analysis of patients who received at least one dose of CCH in any of six clinical studies.

Treatment of Recurrent Dupuytren Contracture in Joints Previously Effectively Treated With Collagenase Clostridium histolyticum

PURPOSE Collagenase Clostridium histolyticum (CCH) is approved for the treatment of adults with Dupuytren contracture with a palpable cord. This open-label, phase 4 study evaluated the safety and efficacy of CCH for the retreatment of recurrent contractures in joints that were previously effectively treated with CCH. METHODS Patients participating in a long-term follow-up study who had contracture recurrence (increased ≥ 20° with a palpable cord) after successful treatment in the previous study were eligible. Recurrent joint contractures were treated with up to 3 CCH injections (∼ 1 month apart). Patients were followed for 1 year to evaluate safety. Assessments included change in joint contracture, range of motion, and the percentage of joints that achieved contracture of 5° or less at day 30 after the last injection. RESULTS The efficacy analysis included 51 patients with 1 treated joint per patient (31 metacarpophalangeal, 20 proximal interphalangeal). A total of 35 joints (69%) received 1 injection, 12 (24%) received 2 injections, and 4 (8%) received 3 injections. Fifty-seven percent of joints achieved contracture of 5° or less (29 of 51). Overall, 86% (43 of 50) patients had a 20° or greater increase in range of motion. The adverse event profile was consistent with previous studies. One ligament injury was reported. CONCLUSIONS At a short-term follow-up of 1 year, recurrent contracture in joints previously successfully treated with CCH may be effectively retreated with up to 3 injections of CCH. TYPE OF STUDY/LEVEL OF EVIDENCE Therapeutic IV.

Factors Associated With Erectile Dysfunction and the Peyronie's Disease Questionnaire in Patients With Peyronie Disease

OBJECTIVE To elucidate patient characteristics that impact symptom-related bother and erectile function in patients with Peyronie disease (PD). METHODS A post hoc analysis used data from patients with PD (ie, had PD symptoms ≥12 months and penile curvature deformity of 30-90 degrees) who received ≥1 injection of study medication in 2 phase 3 trials of collagenase clostridium histolyticum (Investigation for Maximal Peyronies Reduction Efficacy and Safety Study I [n = 417] and Investigation for Maximal Peyronies Reduction Efficacy and Safety Study II [n = 415]). The Covariance Analysis of Linear Structural Equations procedure was used to estimate the potential relationship of specified variables on the level of distress and erectile dysfunction associated with PD as measured by the Peyronies Disease Questionnaire and the International Index of Erectile Function, erectile function domain. RESULTS Pain during intercourse (P = .02) and PD bother (P <.0001) had a significant impact on International Index of Erectile Function, erectile function scores. The Peyronies Disease Questionnaire bother domain score was significantly affected by penile curvature deformity, penile shortening, pain during intercourse, and the presence of plaques (P ≤.0005 for all), with pain during intercourse having the greatest impact (maximum likelihood estimation ± standard error = .496 ± .030; P <.0001). Erectile function did not appear to be directly influenced by the presence of plaques, penile curvature deformity, or penile shortening but was associated with PD bother and penile pain. CONCLUSION This post hoc analysis provides a conceptual framework through which disease characteristics may impact PD-related bother and erectile function in patients with PD.