Options for the Medical Treatment of Peyronie’s Disease

KOL Interview

KOL Interview Options for the Medical Treatment of Peyronie’s Disease Laurence A. Levine, MD,1 Sanford J. Siegel, MD2 University Medical Center, Chicago, IL; 2Chesapeake Urology Associates, Owings Mills, MD 1Rush [Rev Urol. 2014;16(suppl 1):S1-S5 doi: 10.3909/riu16S1S001] ® © 2014 MedReviews , LLC I n this KOL (key opinion leader) interview, Laurence A. Levine, MD, Professor of Urology at Rush University Medical Center, and Sanford J. Siegel, MD, President and CEO of Chesapeake Urology Associates, discuss options for the medical treatment of Peyronie’s disease (PD). Disease State Dr Siegel: What is PD? Dr Levine: PD is currently recognized as a woundhealing disorder involving the tunica albuginea of the corpus cavernosum of the penis. The pathophysiology of PD is still not well understood; PD is thought to occur in genetically susceptible individuals as a result of trauma that leads to the production of a palpable scar in the tunica.1 In my practice, fewer than 80% of men recall a specific event that may be associated with activation of the Peyronie process. It is, therefore, more likely that the pressures that occur during intercourse may exceed the natural elasticity of the tunica albuginea, causing a microfracture that triggers the abnormal woundhealing response that results in the inelastic scar characteristic of PD known as a plaque. The scar prevents expansion in that area. As a result, the characteristic finding of PD is penile shaft curvature; it is frequently associated with erectile dysfunction (ED).1 Dr Siegel: What is the prevalence of the condition? Dr Levine: Multiple demographic studies indicate the prevalence of PD in adult men ranges from 3% to 9%.1 Comorbidities associated with PD include Dupuytren’s contracture, diabetes mellitus (DM), Vol. 16 Suppl. 1 • 2014 • Reviews in Urology • S1 4004170006_RIUS0001.indd 1 06/11/14 9:48 AM Options for the Medical Treatment of Peyronie’s Disease continued hypertension, dyslipidemia, and hypogonadism.2 Dr Siegel: You mentioned that one characteristic of PD is curvature deformity. Are there other aspects of the disease that should be considered? Dr Levine: It has been recognized that the most common reported deformity associated with PD is ­curvature, which is usually in the dorsal or dorsolateral direction.1 PD can impact the ability to engage in intercourse and the frequency of intercourse. These aspects associ- • Are you having intercourse LESS OFTEN than you used to due to your Peyronie’s Disease? • How bothered are YOU with having intercourse less often? Accurate and Differential Diagnoses Dr Siegel: Can you talk about a differential diagnosis among PD and ED? Dr Levine: PD has been associated with ED. In fact, men with PD have a higher prevalence of ED than men in the general population. It has Often, men with PD will have preexisting ED due to underlying vascular disorders such as DM, hypertension, and dyslipidemia, and ­are often smokers. ated with PD, as well as concern about erection pain and appearance, are examples of the considerable bother men with PD can have. Dr Siegel: How can a clinician measure the bother associated with PD? Dr Levine: The Peyronie’s Disease Questionnaire (PDQ) is a validated measure that was developed as a disease-specific, patient-reported measure to allow quantification of the symptom of bother. Questions on the PDQ include • Thinking about the LAST TIME you had an erection, how bothered were you by any pain or discomfort you may have felt in your erect penis? • Thinking about the LAST TIME you looked at your erect penis, how bothered were you by the way your penis looked? • Does your Peyronie’s Disease make having intercourse difficult or impossible? • Thinking of the LAST TIME you had or tried to have intercourse, how bothered were you by your Peyronie’s Disease? been estimated that the majority of men with PD have some degree of ED. Often, men with PD will have preexisting ED due to underlying vascular disorders such as DM, hypertension, and dyslipidemia, and are often smokers. Men who present with PD need to be asked about their erectile quality and whether they can engage in penetrative sex. It is my practice to assess penile vascular integrity, erectile response, and erect deformity with a duplex penile ultrasound using a vasoactive drug injection to induce erection. Previous Treatment Options Dr Siegel: How, and for how long, have you been treating PD? Dr Levine: My interest in PD began in the early 1990s, when I first began experimenting with intralesional verapamil as a treatment for PD.3 Initial studies with intralesional verapamil demonstrated beneficial effects and, as a result, my interest in PD blossomed. Currently, I see up to 20 men per week with PD. For those men who are in the acute phase, nonsurgical treatment or observation have been the only options. Oral treatment with pentoxifylline and L-arginine has become popular as a result of elegant animal model studies that demonstrated their benefit as antifibrotic agents,4 but there is little evidence that these agents will actually reverse existing PD. Intralesional therapy with verapamil or interferon have been used, but, more recently, XIAFLEX® (collagenase clostridium histolyticum; Auxilium Pharmaceuticals, Inc., Chesterbrook, PA) became the first US Food and Drug Administration Important Safety Information About XIAFLEX • • XIAFLEX is contraindicated in the treatment of Peyronie’s plaques that involve the penile urethra due to potential risk to this structure and in patients with a history of hypersensitivity to XIAFLEX or to collagenase used in any other therapeutic application or application method Injection of XIAFLEX into collagen-containing structures such as the corpora cavernosa of the penis may result in damage to those structures and possible injury such as corporal rupture (penile fracture). Therefore, XIAFLEX should be injected only into the Peyronie’s plaque and care should be taken to avoid injecting into the urethra, nerves, blood vessels, corpora cavernosa or other collagen-containing structures of the penis Please see full Prescribing Information, including Boxed Warning, and Medication Guide on the inside back cover. S2 • Vol. 16 Suppl. 1 • 2014 • Reviews in Urology 4004170006_RIUS0001.indd 2 06/11/14 9:48 AM Options for the Medical Treatment of Peyronie’s Disease (FDA)–approved treatment for PD in adult men with a curvature of at least 30° at the start of therapy.5 For men who have stable disease and whose deformity makes intercourse impossible or compromised, then XIAFLEX (collagenase clostridium histolyticum) or surgical options are available, including pli- other hand, is a clostridial collagenase that may enzymatically break down the primary component of a PD plaque, collagen, as demonstrated in clinical trials. the stable phase of PD with lateral, dorsolateral, or dorsal curvature deformities with a palpable plaque and a curve of at least 30° at the start of treatment. Dr Siegel: What do you think XIAFLEX offers to PD patients? Dr Levine: This drug offers a sen- Dr Siegel: For which patients do you feel this is an appropriate treatment option? Dr Levine: XIAFLEX was approved for patients who have a palpable plaque and a dorsal or dorsolateral curvature of at least 30° at the start of therapy, which includes the majority of men presenting with PD.7 Patients in the XIAFLEX trials were excluded if they had a ventral curvature deformity, an isolated hourglass deformity, or a calcified plaque that could have interfered with the injection technique. Patients who had acute onset disease associated with significant pain to palpation, stretch, or erection were not included in the registration studies for XIAFLEX. XIAFLEX, on the other hand, is a clostridial collagenase that may enzymatically break down the primary component of a PD plaque, collagen, as demonstrated in clinical trials. cation techniques and grafting for the more severe deformity.6 Men who have PD without a significant deformity and obtain satisfactory erections should be reassured that no treatment is necessary if they are functional, but if there is exacerbation of their scar and/or deformity, follow-up is indicated. Treatment With XIAFLEX Dr Siegel: How do you feel about the fact that there is now an ­FDA-approved treatment option for PD? Dr Levine: That there is, at last, an FDA-approved treatment does many things to help men affected by PD. First, it demonstrates that there is an agent that has met the rigorous criteria established by the FDA to determine its efficacy and safety profile, which I expect will encourage more physicians to offer it as a treatment for PD in appropriate patients. Second, it provides a useful treatment for men who have been struggling with this disorder and looking for an effective treatment that may also be covered by their health insurance policies. Often, men have sought remedies on the Internet that have been touted as being “the cure” for this disorder. Virtually all of these Web-reported treatments are unproven and have little evidence to suggest that their mechanism of action works. XIAFLEX, on the sible approach for treatment of this disorder, as it is an enzyme that breaks down the primary components of a PD plaque, type I and III collagen. As a result of collagen lysis, there can be remodeling of the scar with subsequent reduction of curvature.7 Although other deformities occur with PD, including indentation and shortening, these have not yet been studied for treatment with XIAFLEX. Therefore, further evaluation is necessary to address the effect of XIAFLEX on other penile deformities. In the meantime, XIAFLEX provides a nonsurgical treatment option that can be employed in patients during Dr Siegel: What common side effects do you see with XIAFLEX (collagenase clostridium histolyticum)? Important Safety Information About XIAFLEX • In the double-blind, placebo-controlled portions of the clinical trials in Peyronie’s disease, a greater proportion of XIAFLEX-treated patients (4%) compared to placebo-treated patients (1%) had localized pruritus after up to 4 treatment cycles (involving up to 8 XIAFLEX injection procedures). The incidence of XIAFLEX-associated pruritus was similar after each injection regardless of the number of injections administered • Because XIAFLEX contains foreign proteins, severe allergic reactions to XIAFLEX can occur. Anaphylaxis was reported in a post-marketing clinical trial in one patient who had previous exposure to XIAFLEX for the treatment of Dupuytren’s contracture. Healthcare providers should be prepared to address severe allergic reactions following XIAFLEX injections. The safety of more than one treatment course of XIAFLEX is not known Please see full Prescribing Information, including Boxed Warning, and Medication Guide on the inside back cover. Vol. 16 Suppl. 1 • 2014 • Reviews in Urology • S3 4004170006_RIUS0001.indd 3 06/11/14 9:48 AM Options for the Medical Treatment of Peyronie’s Disease continued Dr Levine: Common side effects that I see with XIAFLEX include penile hematoma, swelling, and pain. I discuss these with my patients in advance so they are prepared and know to call me if they have severe pain or swelling following treatment. Incorporating XIAFLEX Into Clinical Practice Dr Siegel: How has XIAFLEX been have acute disease with significant pain, extensive plaque calcification in the area of maximum curvature that would interfere with the injection, ventral curvature, an hourglass deformity, those with Peyronie’s plaques that involve the penile urethra, and those with a history of hypersensitivity to XIAFLEX or to collagenase used in other therapeutic applications. The XIAFLEX manufacturer, through The PCP can ask men if their erect penises curve or if there is a bump on their penises. The PCP should also be aware of the bother that this disorder can cause the patient. incorporated into your practice? How do you see this treatment option being incorporated into a mid-sized or large group practice? Dr Levine: Once the practice and the interested physician have completed the training and enrollment requirements of the XIAFLEX Risk Evaluation and Mitigation Strategy (REMS) program, they may offer this treatment option to appropriate men who present with PD. Examples of individuals who are not offered this drug are those who Auxilium AdvantageTM, offers assistance with insurance coverage/benefits research and a generous copay assistance program to help patients and healthcare practitioners access XIAFLEX. The XIAFLEX protocol involves four 6-week cycles. The first week of each cycle involves two separate visits for injections and a third visit for manual penile modeling.7 My practice is fortunate to have a skilled physician’s assistant who assists with the XIAFLEX Important Safety Information About XIAFLEX • • In the XIAFLEX controlled trials in Peyronie’s disease, 65.5% of XIAFLEX-treated patients developed penile hematoma, and 14.5% developed penile ecchymosis. Patients with abnormal coagulation (except for patients taking low-dose aspirin, eg, up to 150 mg per day) were excluded from participating in these studies. Therefore, the efficacy and safety of XIAFLEX in patients receiving anticoagulant medications (other than low-dose aspirin, eg, up to 150 mg per day) within 7 days prior to XIAFLEX administration is not known. In addition, it is recommended to avoid use of XIAFLEX in patients with coagulation disorders, including patients receiving concomitant anticoagulants (except for low-dose aspirin) In the XIAFLEX clinical trials for Peyronie’s disease, the most frequently reported adverse drug reactions ($ 25%) and at an incidence greater than placebo included: penile hematoma, penile swelling, and penile pain Please see full Prescribing Information, including Boxed Warning, and Medication Guide on the inside back cover. injections and modeling. This increases the efficiency of the practice, allowing patients to come in during off hours when there may be more time to attend to their concerns and to observe them following injection. It is important to ensure that any allied health individual administering the drug has completed REMS training for the administration of the product and is familiar and comfortable with the injection technique and performs it according to protocol. Dr Siegel: Tell us more about the REMS program for this product. Dr Levine: Because there is a risk for corporal rupture and other serious penile injuries, XIAFLEX is only available through the XIAFLEX REMS Program. Prescribers are certified by completing training in the administration of XIAFLEX for PD, and healthcare sites are also certified to ensure that XIAFLEX is only dispensed for use by certified prescribers. Dr Siegel: Please describe the continuum of care among the primary care physician (PCP) and the urologist for the PD patient. Dr Levine: Many men with PD will present to their PCP with a complaint of a palpable lump in the penis and/or with a deformity during erection. These men should undergo a physical examination to determine if they have PD. If it is determined that they have PD, they should be referred to a urologist who can treat this problem. The key is responding to the concern expressed by the patient and performing a physical examination to find PD. In addition, more men will be identified by asking them questions in the review of systems about sexual function and whether they are having any issues with their erections, including deformity. S4 • Vol. 16 Suppl. 1 • 2014 • Reviews in Urology 4004170006_RIUS0001.indd 4 06/11/14 9:48 AM Options for the Medical Treatment of Peyronie’s Disease Dr Siegel: What are some questions a PCP may want to ask patients if they suspect that the patient may have PD? Dr Levine: The PCP can ask a patient if his erect penis curves or if there is a bump on his penis. The PCP should also be aware of the bother that this disorder can cause the patient. They certainly should be asking a man with erectile function issues if his erect penis curves or if there is a bump on his penis and whether he would like to have further assessment by a specialist who is able to offer treatment. We now know from ­natural history studies that no more than 12% to 13% of patients will have some improvement without treatment, but complete resolution is rare.8 On the other hand, there is almost a 50% chance of having deformity progression when PD is left untreated in the first year from onset of symptoms.8 If the patient answers affirmatively regarding having a curved penis or a bump, then he should be referred to a ­urologist experienced in the treatment of PD. Publication of this article was made possible via sponsorship from Auxilium Pharmaceuticals, Inc. (Chesterbrook, PA). Editorial assistance was provided by MedReviews®, LLC. Auxilium had the opportunity to review this work for scientific accuracy. Dr Levine is a paid consultant for Auxilium. Drs Levine and Siegel received honoraria for their contributions. 2. 3. 4. 5. 6. 7. 8. Levine LA, Burnett AL. Standard operating procedures for Peyronie’s disease. J Sex Med. 2013;10: 230-244. Levine LA, Merrick PF, Lee RC. Intralesional verapamil injection for the treatment of Peyronie’s disease. J Urol. 1994;151:1522-1524. Valente EG, Vernet D, Ferrini MG, et al. L-arginine and phosphodiesterase (PDE) inhibitors counteract fibrosis in the Peyronie’s fibrotic plaque and related fibroblast cultures. Nitric Oxide. 2003;9:229-244. FDA approves first drug treatment for Peyronle’s disease [press release]. Silver Spring, MD: US Food and Drug Administration; December 6, 2013. Hatzimouratidis K, Eardley I, Giuliano F, et al; European Association of Urology. EAU guidelines on penile curvature. Eur Urol. 2012;62:543-552. XIAFLEX® (collagenase clostridium histolyticum) for injection, for intralesional use [prescribing information]. Chesterbrook, PA: Auxilium Pharmaceuticals, Inc.; December 2013. Mulhall JP, Schiff J, Guhring P. An analysis of the natural history of Peyronie’s disease. J Urol. 2006; 175:2115-2118. References 1. Ralph D, Gonzalez-Cadavid N, Mirone V, et al. The management of Peyronie’s disease: evidence-based 2010 guidelines. J Sex Med. 2010;7:2359-2374. XPD-00616 Vol. 16 Suppl. 1 • 2014 • Reviews in Urology • S5 4004170006_RIUS0001.indd 5 17/11/14 2:23 PM