What data exists on the use of collagenase clostridium histolyticum (CCH) for the treatment of Peyronie’s disease?

Introduction
Peyronie’s disease (PD) is an acquired, localized abnormality in which fibrous scar tissue, referred to as plaques, build up within the tunica albuginea of the penis.^1-3 The tunica albuginea, in those without PD, envelops penile erectile bodies and promotes penile rigidity and length.¹ Plaques occurring in PD can cause the penis to bend or become indented during erection and can occur anywhere along the penis. These plaques result in penile deformity, masses felt through the skin, pain, and erectile dysfunction (ED).^1-3 Based on population health studies, the rate of PD in men ranges from 3% to 16%, although the true prevalence may be underestimated as men may be reluctant to report their condition or accept PD as a consequence of aging.^4,5 Peyronie’s disease can have a detrimental impact on the quality of life in individuals with this disorder, and many men with PD may experience emotional distress, depression, and relationship difficulties.^2,3

Microvascular trauma to the penis secondary to sexual activity is typically the most common precipitating event, however, many individuals with PD may not know what event preceded symptoms.^1-3 In a minority of cases, PD can resolve spontaneously, while many require treatment to prevent worsening of curvature. Non-surgical treatment options for PD consist of oral or intralesional drug therapy. There are no US Food and Drug Administration (FDA) approved oral options to treat penile curvature.⁶ Oral therapy may consist of off-label use of colchicine, pentoxifylline, or potassium para-aminobenzoate to reduce plaque size and delay worsening of curvature, although oral therapy is not guideline-recommended.^2,3 Xiaflex (collagenase clostridium histolyticum [CCH]) is the only intralesional drug therapy approved by the FDA.^6,7 Intralesional verapamil is sometimes used off-label for treatment of PD.^2,3 Surgical management may be considered for individuals refractory to medical therapy with a penile deformity compromising sexual function or those with PD persisting for longer than 12 months. There are limited trials examining the efficacy of available treatments. This review provides a summary of currently available literature on the efficacy of CCH for intralesional treatment of PD (see Table).

Collagenase clostridium histolyticum
Collagenase clostridium histolyticum, FDA-approved in 2010, has demonstrated effectiveness in reducing plaque size in PD but does not change the curvature of the penis when used alone, so it should be followed with ‘modeling’, forcible bending of the penis in the direction opposite to the curve.^2,3,7 It is thought to contribute to lysis of collagen (plaque) deposits, allowing for manual reduction of curvature and deformity.⁷ The American Urological Association (AUA) published guidelines on PD in 2015.² These guidelines recommend administration of intralesional CCH in combination with modeling by the clinician and the patient for the reduction of penile curvature in stable PD (moderate recommendation, moderate certainty). The AUA recommends CCH over intralesional interferon α-2b (moderate recommendation, low certainty) or verapamil (conditional recommendation, low certainty). The International Society for Sexual Medicine (ISSM) (2016) similarly recommends CCH, as it has shown some outcome benefits in PD (grade B, level 2). Interferon α-2b (grade B, level 2) and verapamil (grade C, level 3) are also potential options for management.³

Intralesional CCH should be administered only by a urology healthcare professional and is indicated in men with PD with palpable plaques and curvature deformity of at least 30 degrees.⁷ It is available for PD through a restricted risk evaluation and mitigation strategy (REMS) program due to potential serious adverse effects. There is a boxed warning for corporal rupture, otherwise known as penile fracture, as this and penile hematoma have been reported in CCH-treated participants in clinical trials. A treatment course consists of a maximum of 4 treatment cycles and each cycle consists of 2 CCH injection procedures and 1 penile modeling procedure. The second injection is administered 1 to 3 days following the first and the modeling procedure is performed 1 to 3 days after the second injection. The interval between treatment cycles is about 6 weeks. Some patients may not require all treatment cycles. Contraindications include plaques involving the penile urethra and a history of hypersensitivity to CCH. Adverse reactions may include penile hematoma, swelling, and pain. There have been reports of post-injection back pain radiating to chest and limbs, triggering syncope and presyncope reactions.

Literature review
A recent meta-analysis has brought attention back to the lack of high-quality data supporting the use of non-surgical therapies for PD, including intralesional CCH.⁸ The Cochrane review by Rosenberg and colleagues evaluated 2 randomized controlled trials (RCTs) comparing the use of intralesional CCH to placebo. With very-low, low, or moderate certainty of evidence, the results demonstrated no evidence of patient-reported ability to have sexual intercourse in the short- (18 weeks post-treatment) and long-term (28 weeks post-treatment) and no short-term treatment-related adverse events after CCH compared to placebo injection. Injectional CCH may result in little to no difference in quality of life based on the Peyronie’s disease questionnaire and there may be little to no effect on the degree of penile curvature compared to placebo. Adverse effects were likely to increase with increased treatment cycles.

The dose of CCH used in the studies was the dose that led to FDA-approval, 0.58 mg CCH each injection, with 2 injections per cycle followed by a modeling procedure.^8-10 Exclusion criteria in the 2 RCTs included in the Cochrane review included men with penile curvature of less than 30 or greater than 90 degrees, severe pain during penile palpation, ED unresponsive to phosphodiesterase type 5 inhibitors, and previous PD treatment.⁸ Limitations included the inclusion of only heterosexual men, unclear risk of bias (Gelbard 2013 only), and lack of standardized clinical relevance of outcomes. Additionally, the only 2 identified RCTs, Gelbard 2012 and Gelbard 2013, were conducted by the same study group, making it difficult to know if reproducibility is possible.^9,10

 A 2022 RCT by Chung and colleagues conducted an open-label study comparing intralesional CCH to verapamil in 50 men with PD.¹¹ They found that 24 months after therapy, CCH was more effective than verapamil to decrease penile curvature and improve quality of life scores. CCH was associated with a higher rate of penile bruising, swelling, and pain. The results are limited by the small sample size, variation in dosing compared to FDA-approved dose of CCH, and open-label design.

Conclusion
Little evidence exists on the use of CCH or other non-surgical therapies in the treatment of PD. A recent meta-analysis including the 2 RCTs leading to FDA-approval of CCH has demonstrated little to no improvement in quality of life and penile curvature for PD up to 28-weeks after CCH injection compared to placebo, with an increased risk of adverse events with increased injection cycles.^8-10 Based on this data, intralesional CCH has recommendations (of differing strengths) as a non-surgical treatment of stable PD from AUA and ISSM guidelines.^2,3 An even more recent RCT compared intralesional CCH to verapamil and found that CCH was more effective in decreasing penile curvature and improving quality of life, but the doses used differed from the FDA-approved dose of CCH.¹¹ Replicated RCTs or additional studies comparing CCH to active comparators will help further establish the role of CCH and other non-surgical treatments in PD. Associated risks with CCH use should be discussed with patients prior to injection, including the boxed warning for corporal rupture and hematoma, back pain, syncope and pre-syncope, and other possible adverse effects.⁷

References

1. Penile curvature (Peyronie’s disease). National Institutes of Health. Updated August 2019. Accessed September 21, 2023. https://www.niddk.nih.gov/health-information/urologic-diseases/penile-curvature-peyronies-disease
2. Nehra A, Alterowitz R, Culkin DJ, et al. Peyronie’s disease: AUA guideline. J Urol. 2015;194(3):745-753. doi: 10.1016/j.juro.2015.05.098
3. Chung E, Ralph D, Kagioglu A, et al. Evidence-based management guidelines on Peyroni’s disease. J Sex Med. 2016;13(6):905-923. doi: 10.1016/j.jsxm.2016.04.062
4. Schwarzer U, Sommer F, Klotz T, Braun M, Reifenrath B, Engelmann U. The prevalence of Peyronie’s disease: results of a large survey. BJU Int. 2001;88(7):727-730. doi: 10.1046/j.1464-4096.2001.02436.x
5. Kadioglu A, Oktar T, Kandirali E, Kendirci M, Sanli O, Ozsoy C. Incidentally diagnosed Peyronie’s disease in men presenting with erectile dysfunction. Int J Impot Res. 2004;16(6):540-543. doi: 10.1038/sj.ijir.3901247
6. Drugs@FDA: FDA-approved drugs. US Food and Drug Administration. 2023. Accessed September 21, 2023. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
7. Xiaflex. Package insert. Endo Pharmaceuticals, Inc.; 2023.
8. Rosenberg JE, Ergun O, Hwang EC, et al. Non-surgical therapies for Peyronie’s disease. Cochrane Database Syst Rev. 2023;7(7):CD012206. doi: 10.1002/14651858.CD0112206.pub2
9. Gelbard M, Lipshultz LI, Tursi J, Smith T, Kaufman G, Levine LA. Phase 2b study of the clinical efficacy and safety of collagenase clostridium histolyticum in patients with Peyronie disease. J Urol. 2012;187(6):2268-2274. doi: 10.1016/j.juro.2012.01.032
10. Gelbard M, Goldstein I, Hellstrom WJG, et al. 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. J Urol. 2013;190(1):199-207. doi: 10.1016/j.juro.2013.01.087
11. Chung E, Wang J. Intralesional collagenase clostridium histolyticum vs. verapamil injections in males with Peyronie’s disease: a prospective, matched-pair, non-blinded, randomized clinical study comparing clinical outcomes and patient satisfaction rates. Investig Clin Urol. 2022;63(5):563-568. doi: 10.4111/icu.20220145

Prepared by:
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2023

The information presented is current as of September 21, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.