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Stakeholder Perspectives in Men's Health August 2014
John A Welz, MPH

Collagenase clostridium histolyticum (CCH), a purified mixture of 2 microbial collagenases, is a minimally invasive intervention recently approved by the FDA for the treatment of PD, under the brand name XIAFLEX.1,2 XIAFLEX is indicated for the treatment of adult men with PD with a palpable plaque and curvature deformity of at least 30° at the start of therapy. To ensure that the benefits of the drug outweigh its risks, the FDA has required that XIAFLEX be made available for the treatment of PD only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX REMS Program.2

XIAFLEX is also approved by the FDA, Health Canada, and European Medicines Agency (as XIAPEX) for use in adults who have Dupuytren’s contracture with a palpable cord. In these patients, XIAFLEX/XIAPEX is injected into the Dupuytren cord, and a finger extension procedure is performed to further disrupt the cord, which may have been enzymatically weakened by the procedure.1

Injection of XIAFLEX into a Peyronie’s plaque, which is comprised mostly of collagen, may result in enzymatic disruption of the plaque, as shown in Figure 1. Following disruption of the plaque, penile curvature deformity and patient bother caused by PD are reduced.2

XIAFLEX injection requires a specific procedure, and should only be performed by a trained physician, who is experienced in the treatment of male urological diseases, and who has completed required training for use of XIAFLEX in the treatment of PD.2

XIAFLEX is injected into a PD plaque. If more than 1 plaque is present, injection should be administered into the plaque causing the curvature deformity. A XIAFLEX treatment course consists of a maximum of 4 treatment cycles. Each treatment cycle consists of 2 injection procedures and 1 penile modeling procedure. The interval between cycles is approximately 6 weeks. If the curvature deformity is less than 15° after the first, second, or third treatment cycle, or if the healthcare provider determines that further treatment is not clinically indicated, then the subsequent treatment cycles should not be administered.2

Efficacy data
The efficacy of XIAFLEX in subjects with PD was evaluated in 2 large double-blind, randomized, placebo- controlled phase 3 studies (IMPRESS [Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies] I and II). The objective of these studies was to evaluate the safety and effectiveness of CCH intralesional injections administered twice per treatment cycle for up to 4 treatment cycles in men with PD.1,2

The studies included patients with stable disease and curvature deformity of at least 30°. Conversely, patients with ventral curvature deformity, an isolated hourglass deformity, or a calcified plaque that could have interfered with the injection technique, were excluded from the studies. At baseline, penile pain was either not present or was mild in most (98%) patients.1,2

Patients were randomized 2:1 to receive either CCH (0.58 mg) or placebo injections plus penile remodeling. In addition, patients were stratified into 2 groups by degree of penile curvature: 30° to 60° and 61° to 90°. The duration of each study was 52 weeks.1,2

There were 2 coprimary end points, which measured the change from baseline to week 521-3:

  • Percentage change in penile curvature deformity
  • Change in Peyronie’s Disease Questionnaire (PDQ) bother domain score, whose components include concern about erection pain, erection appearance, impact of PD on intercourse, and impact of PD on frequency of intercourse.

Each treatment cycle included 2 injections of CCH or placebo, which were directly injected into the primary plaque at the point of maximal penile curvature abnormality at intervals of 24 to 72 hours between injections. Approximately 24 to 72 hours after the second injection of each treatment cycle, subjects underwent investigator penile plaque modeling.1,2

Baseline characteristics included mean age, mean duration of PD, history of ED, mean penile curvature deformity, and mean patient-reported PDQ bother domain score. These characteristics were similar across active treatment and control groups in both IMPRESS I and IMPRESS II studies.1,2

As shown in Figure 2, in both pivotal studies, XIAFLEX treatment significantly improved penile curvature deformity in patients with PD compared with placebo. Furthermore, the improvement in curvature deformity was numerically similar among subjects with baseline curvature deformity from 30° to 60° and those with curvature deformity from 61° to 90°.

Likewise, the mean change in the PDQ bother domain score was significantly improved in the XIAFLEX group versus the placebo group, as shown in Figure 3.1,2

All data for penile curvature deformity and patient-reported bother are from a modified intent-to-treat, last-observation-carried-forward (LOCF) analysis at week 52. P values are based on an LOCF analysis at week 52 and an analysis of variance with factors for drug, stratum of baseline penile curvature deformity, and their interaction.2,4

Safety and tolerability data
In pivotal studies, most patients completed all 4 cycles of treatment (8 injections total), including 434 of 551 XIAFLEX-treated men (78.8%) and 247 of 281 men who received placebo (87.9%). The majority of XIAFLEX-treated men and those who received placebo (92% and 61%, respectively) experienced at least 1 adverse reaction (AE).1,2

Most AEs were local events of the penis and groin and the majority were of mild or moderate severity. Of these events, 79% resolved without intervention within 14 days of the injection. The AE profile was similar after each injection; no cumulative effects were observed.2,4

In the XIAFLEX group, 30 patients did not receive all injections because of an AE and 44 patients did not receive all injections because their penile curvature deformity was less than 15° after one of the treatment cycles. Additional reasons patients did not receive all injections included inability to attend visits, treatment refusal, and consent withdrawal.5

Table 1 shows the treatment-related AEs that occurred in ≥1% of patients treated with XIAFLEX and occurred at a greater incidence in the treatment group than in the placebo group. The most frequently reported AEs (≥45.0%) in XIAFLEX-treated men included penile hematoma, penile swelling, and penile pain.2

In the controlled and uncontrolled clinical studies of XIAFLEX in PD, 1044 patients received a total of 7466 XIAFLEX injections. There were serious AEs. Five of 1044 (0.5%) patients reported corporal rupture as an AE after XIAFLEX injection. In other XIAFLEX-treated patients (9 of 1044; 0.9%), a combination of penile ecchymosis or hematoma, sudden penile detumescence, and/or a penile “popping” sound or sensation was reported, and, in these cases, a diagnosis of corporal rupture cannot be excluded. These patients were managed without surgical intervention, but the long-term consequences are unknown. Severe penile hematoma was reported as an AE in 39 of 1044 patients (3.7%) who were treated with XIAFLEX.2

Coding for Peyronie’s Disease
XIAFLEX should only be administered by a physician who is experienced in the treatment of male urological diseases and who has completed required training for use of XIAFLEX in the treatment of PD. A treatment course consists of a maximum of 4 treatment cycles; a treatment cycle consists of 2 injection procedures and a penile modeling procedure.2

The ICD-9 diagnosis code for PD is 607.85.6

The following CPT® codes are used to bill for the injection procedure7:

  • 54235: Injection of corpora cavernosa with pharmacologic agent(s) to induce erection (eg, papaverine, phentolamine). This is necessary to determine where to inject XIAFLEX
  • 54200: Initial injection procedure for PD in a treatment cycle
  • 54200-58: Second injection procedure for PD in a treatment cycle. Use of the -58 modifier indicates a staged or related procedure or service by the same physician during the postoperative period.

The correct drug code is J0775, which represents 0.01 mg of XIAFLEX.8 Because a single-use vial contains 0.90 mg,2 XIAFLEX is billed at 90 units.

Conclusion
PD is believed to be a wound-healing disorder that occurs in genetically susceptible men and results in penile curvature deformity.9,10 Typically, PD does not resolve without clinical intervention.11

Only a small percentage of men with PD seek treatment (approximately 118,000 in the United States). Within this population of men who seek treatment, 38,646 (32.7%) have moderate to severe curvature deformity of ≥30°.5

Effective treatment options for PD are limited. Most historically available, minimally invasive treatments have neither substantial data from controlled trials showing efficacy nor FDA approval as safe and effective for the treatment of PD. Surgical intervention may correct curvature deformity, but is associated with complications such as penile shortening, ED, neurovascular injury, infection, and decreased sexual sensation.9,10

XIAFLEX injection is FDA approved as effective for the treatment of PD in men with a palpable plaque and curvature deformity of at least 30° at the start of therapy, and represents an alternative to surgical intervention in appropriate patients.2

In today’s challenging healthcare environment for providers, treatment of PD with XIAFLEX promises to be an important therapeutic innovation for the practices of urologists and others who treat men’s urological conditions. Not only can XIAFLEX fulfill an unmet clinical need in treating appropriate patients with PD, but it also represents a potential business opportunity for urologists who are interested in expanding their service offerings to support the provision of comprehensive men’s healthcare.

References

  1. Gelbard M, Goldstein I, Hellstrom WJG, et al. Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of Peyronie’s disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J Urol. 2013;190: 199-207.
  2. XIAFLEX [prescribing information]. Chesterbrook, PA: Auxilium Pharmaceuticals, Inc; 2013.
  3. Auxilium Pharmaeuticals. Peyronie’s Disease Questionnaire (PDQ)—US Version. 2013.
  4. XIAFLEX website. https://peyronies-disease.xiaflex.com/hcp/how-xiaflex-works.php. Accessed May 16, 2014.
  5. Data on file. Auxilium Pharmaceuticals, Inc.
  6. Buck CJ. 2012 ICD-9-CM for Physicians, Volumes 1 & 2, Professional Edition. St. Louis, MO: Saunders, an imprint of Elsevier, Inc; 2012.
  7. American Urological Association. Coding for new medical treatment of Peyronie’s disease. Health Policy Brief. 2014;21. American Urological Association website. www.auanet.org/publications/hpbrief/view.cfm?i=2857&a=5645. Accessed May 19, 2014.
  8. Center for Medicare & Medicaid Services. Alpha-Numeric HCPCS codes: 2014 Table of Drugs. Center for Medicare & Medicaid Services website. http://www.cms.gov/Medicare/Coding/HCPCSReleaseCodeSets/Downloads/DRUG2014.pdf. Updated November 25, 2013. Accessed May 20, 2014.
  9. Ralph D, Gonzalez-Cavadid N, Mirone V, et al. The management of Peyronie’s disease: evidence-based 2010 guidelines. J Sex Med. 2010;7:2359-2374.
  10. Wespes E, Hatzimouratidis K, Eardley I, et al; European Association of Urology. Guidelines on penile curvature. European Association of Urology website. www.uroweb.org/gls/pdf/16%20Penile%20Curvature_LR.pdf. Published February 2012. Accessed May 9, 2014.
  11. Levine LA. The clinical and psychosocial impact of Peyronie’s disease. Am J Manag Care. 2013;19:S55-S61.
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