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Treatment for adult men with Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy

The efficacy and safety of XIAFLEX® were studied in more than 500 men from 2 large multicenter studies. The co-primary endpoints were the percentage change from baseline to Week 52 in erectile (penile) curvature deformity and the change from baseline to Week 52 in the Bother domain score of the PDQ.1

Efficacy proven in 2 large multicenter studies with XIAFLEX®1

Studies 1 and 2* were randomized, double-blind, placebo-controlled, multicenter studies1,2

  • Studies 1 and 2 were published in J Urol. as IMPRESS I and II (The Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies).
  • 551 received XIAFLEX®, 281 received placebo.1
  • All Intent-to-treat (ITT)=randomized men who received at least 1 dose of study drug.3,4
  • Modified intent-to-treat (mITT) population=patients with curvature deformity measurement and PDQ assessment at baseline, and at one or more subsequent time points, and who had engaged in vaginal intercourse within 3 months prior to each PDQ assessment.1

Study design

The efficacy of XIAFLEX® was evaluated in 2 randomized, double-blind, placebo-controlled, multicenter trials in 832 adult males with Peyronie’s disease (Studies 1 and 2). In these trials, patients were given up to 4 treatment cycles of XIAFLEX® or placebo (Weeks 0, 6, 12, 18), and were followed in a nontreatment follow-up period (Weeks 24–52). In each treatment cycle, 2 injections of XIAFLEX® or 2 injections of placebo were administered 1 to 3 days apart. A penile modeling procedure was performed 1 to 3 days after the second injection. The treatment cycle was repeated at ~6 week intervals for a maximum of 8 total injection procedures and 4 total modeling procedures. Patients also performed at-home penile modeling for 6 weeks. Before the first dose of study drug was administered, eligible patients were stratified by the degree of curvature deformity (30°–60°, and 61°–90°) and then randomized into 2 treatment groups to receive either XIAFLEX® or placebo in a 2:1 ratio.1

Study entry

  • In Studies 1 and 2, the co-primary endpoints were1:
    • The percentage change from baseline to Week 52 in erectile curvature deformity
    • The change from baseline to Week 52 in the Bother domain score of the PDQ
  • Patients must have had erectile curvature deformity of ≥30° in the stable phase of Peyronie’s disease1
  • Patients were excluded if they had a ventral curvature deformity, an isolated hourglass deformity, or a calcified plaque that could have interfered with the injection technique1
  • At baseline, penile pain was either not present or was mild in most (98%) patients1
  • At baseline, approximately 50% of patients in the XIAFLEX® clinical trials had a history of erectile dysfunction1

Co-primary endpoint result
Significant improvement in erectile curvature compared with placebo1

Mean percentage change in erectile curvature deformity from baseline to Week 521||¶

  • Last observation carried forward (LOCF).1
  • Patients were given up to 4 treatment cycles of XIAFLEX® or placebo at Weeks 0, 6, 12, 18.1
  • Study 1 Treatment Difference (95% CI): –17.2% (–26.7%, –7.6%). Study 2 Treatment Difference (95% CI): –11.4% (–19.5%, –3.3%).1
  • Mean percentage change, treatment difference, 95% CI, and P value were based on an analysis of variance (ANOVA) model with factors for treatment, stratum of baseline erectile curvature, and their interaction and using LOCF in the mITT population. The mITT population was defined as all randomized patients who had both an erectile curvature deformity measurement and a PDQ assessment at baseline and at one or more subsequent time points.1
  • Mean baseline measurements of erectile curvature deformity were1:
    • Study 1: 48.8° for XIAFLEX®; 49.0° for placebo
    • Study 2: 51.3° for XIAFLEX®; 49.6° for placebo
  • Change in erectile curvature deformity was similar when stratified by degree of baseline curvature deformity (30º–60º or 61º–90º)1

After up to 4 cycles of XIAFLEX®, improvement in erectile curvature from
baseline to Week 521

Mean percentage change in erectile curvature deformity from baseline1

  • Mean percentage change, treatment difference, 95% CI, and P value were based on an ANOVA model with factors for treatment, stratum of baseline erectile curvature, and their interaction and using LOCF in the mITT population. The mITT population was defined as all randomized patients who had both an erectile curvature deformity measurement and a PDQ assessment at baseline and at one or more subsequent time points.1
  • Study 1 Treatment Difference: –17.2% (–26.7%, –7.6%)1
  • Study 2 Treatment Difference: –11.4% (–19.5%, –3.3%)1

Co-primary endpoint result
Demonstrated erectile curvature improvement from baseline to Week 521

Images represent a 33% change from baseline

If the curvature deformity is <15° after the first, second, or third treatment cycle, or if the HCP determines that further treatment is not clinically indicated, then subsequent treatment cycles should not be administered.1

XIAFLEX® pivotal studies evaluated more than just erectile curvature1

What is Patient-Reported Bother domain score?

  • Patient-Reported Bother domain score of the PDQ from baseline to Week 52 was a co-primary endpoint in clinical trials1

In 2 clinical studies for XIAFLEX®, the Patient-Reported Bother domain score measured the impact of Peyronie’s disease on5:

INTERCOURSE

Q1: Does your Peyronie’s disease make having vaginal intercourse difficult or impossible?

Q2: Thinking of the last time you had or tried to have vaginal intercourse, how bothered were you by your Peyronie’s disease?

ERECTION PAIN

Q3: 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?

ERECTION APPEARANCE

Q4: Thinking about the last time you looked at your erect penis, how bothered were you by the way your penis looked?

INTERCOURSE FREQUENCY

Q5: Are you having vaginal intercourse less often than you used to due to your Peyronie’s disease?

Q6: How bothered are you with having vaginal intercourse less often?

In 2 large multicenter studies with XIAFLEX®, the co-primary endpoints were the percentage change from baseline to Week 52 in erectile curvature deformity and the change from baseline to Week 52 in the Bother domain score of the PDQ.

Men with lesser degrees of erectile deformity may have similar Bother domain scores as those with more severe curvature deformity6

Co-primary endpoint result
Significant reduction in Patient-Reported Bother1

Patient-Reported Bother domain score range: 0–16 (higher numbers represent greater Bother)1,6

Mean change in Patient-Reported Bother1††

Mean baseline Patient-Reported
Bother domain scores1

  • Study 1: XIAFLEX® 7.5; placebo 7.4
  • Study 2: XIAFLEX® 7.4; placebo 8.2
  • Mean change, treatment difference, 95% CI, and P value all based on an ANOVA model with factors for treatment, stratum of baseline erectile curvature, and their interaction and using LOCF in the mITT population. The mITT population was defined as all randomized patients who had both an erectile curvature deformity measurement and a PDQ assessment at baseline and at one or more subsequent time points.1
  • Study 1 Treatment Difference (95% CI): –1.2 (–2.4, –0.03).
    Study 2 Treatment Difference (95% CI): –1.1 (–2.1, –0.002).1

Adverse reactions in Studies 1 and Study 2 combined occurring in ≥1% of
patients treated with XIAFLEX® and also at a frequency greater than
placebo-treated patients after up to 4 treatment cycles1

  • Includes: injection-site hematoma and penile hematoma were reported with the verbatim term of penile bruising or injection-site bruising in 87% of patients.
  • Includes: injection-site swelling, penile edema, penile swelling, local swelling, scrotal swelling, and injection-site edema.
  • Includes: injection-site pain, penile pain, and injection-site discomfort.
  • Includes: contusion, ecchymoses, penile hemorrhage, and injection-site hemorrhage.
  • Most adverse reactions were local events of the penis and groin and the majority of these events were of mild or moderate severity, and most (79%) resolved within 14 days of the injection1
  • Severe penile hematoma or severe injection-site hematoma were reported in 33/551 (6.0%) of XIAFLEX®-treated patients and 0/281(0%) of placebo-treated patients, in Studies 1 and 2 combined1

Important Safety Information for XIAFLEX®

WARNING: CORPORAL RUPTURE (PENILE FRACTURE) OR OTHER SERIOUS PENILE INJURY IN THE TREATMENT OF PEYRONIE'S DISEASE

Corporal rupture (penile fracture) was reported as an adverse reaction in 5 of 1044 (0.5%) XIAFLEX®‑treated patients in clinical studies. In other XIAFLEX®‑treated patients (9 of 1044; 0.9%), a combination of penile ecchymoses 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. Severe penile hematoma was also reported as an adverse reaction in 39 of 1044 (3.7%) XIAFLEX®‑treated patients.

Signs or symptoms that may reflect serious penile injury should be promptly evaluated to assess for corporal rupture or severe penile hematoma which may require surgical intervention.

Because of the risks of corporal rupture or other serious penile injury, XIAFLEX® is available for the treatment of Peyronie's disease only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XIAFLEX® REMS Program.

  • 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
  • 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
  • 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, e.g., 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

INDICATION

XIAFLEX® is indicated for the treatment of adult men with Peyronie's disease with a palpable plaque and curvature deformity of at least 30 degrees at the start of therapy.

Please see the full Prescribing Information, including Boxed Warning and Medication Guide.

References:

1.  XIAFLEX® [package insert]. Malvern, PA: Endo Pharmaceuticals Inc.
2.  Gelbard M, Goldstein I, Hellstrom WJ, 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(1):199-207.
3.  Data on file. DOF-XPD-03. Endo Pharmaceuticals Inc; September 22, 2015.
4.  Data on file. DOF-XPD-04. Endo Pharmaceuticals Inc; September 22, 2015.
5.  Data on file. DOF-XPD-02. Endo Pharmaceuticals Inc; July 16, 2015.
6.  Hellstrom WJ, Feldman R, Rosen RC, Smith T, Kaufman G, Tursi J. Bother and distress associated with Peyronie’s disease: validation of the Peyronie’s disease questionnaire. J Urol. 2013;190(2):627-634.