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Collagenase is no longer available. What now?

Javier Romero Otero
Andrology and Reconstructive Urology Unit
Department of Urology
Hospital Universitario 12 de Octubre, Madrid, Spain
Hospital Universitario HM Montepríncipe

Borja García Gómez
Andrology and Reconstructive Urology Unit, Department of Urology
Hospital Universitario 12 de Octubre, Madrid, Spain
Hospital Universitario HM Montepríncipe

About Peyronie’s disease

Peyronie´s disease (PD) is condition that results from fibrotic plaque formation of the tunica albuginea and that can develop to a number of penile deformities including cuvature, shortening, narrowing, hour-glass deformity and/or hinge deffect. PD usually affects men over their 50s and the estimated incidence varies from 3% to 9% (1). The etilogy of PD remains unknown, but the most accepted hyphotesis is that vascular microtrauma during sexual intercourse releases an uncontrolled inflammatory reaction in genetically susceptible men (2).

PD is usually divided in two well-defined phases: acute and chronic. During the acute inflammatory phase the plaque begins to form and the deformities progressively become apparent. Patients tipically present pain during this phase. In the chronic or stable phase the pain usually disappears and curvature (or any other malformation) stabilizes. The plaque begins to harden and, although described, curvature rarely resolves spontaneously (3). Depending on the severity of the curvature, men with PD may find penetrative sexual intercourse difficult or impossible, causing psychological or emotional distress, and relationship problems (4).

Many conservative treatments have been postulated, including shockwave therapy, iontophoresis and intralesional, topical and oral drugs. None of this treatments have demonstrated its efficacy and safety in large, well designed clinical trials (5). Surgical correction is indicated in men with estable disease unable to have penetrative sexual intercourse. Although the results of surgery in centers with experience correcting the curvature or penile deformity is usually excellent, the different procedures may have undesirable collateral effects: penile shortening, erectile dysfunction, penile numbness, recurrence of curvature, possible palpable stitches under the skin, and potential need of circumcision at the time of surgery (6).

The role of collogenase for the treatment of PD

After some previous studies regarding the efficacy and safety of the collagenase for PD (7), in 2013 the results from the “The Maximal Peyronie’s Reduction Efficacy and Safety Studies I and II” (IMPRESS I & II) lead to the approval of the collagenase of the Clostridium Histolyticum (CCH) as the first conservative treatment for PD by the Food and Drug Administration (8). Since then, many other trials and office based studies have demonstrated a reduction in curvature that varies between 28-34.4% (9,10), with a good safety profile, being the most common adverse effects ecchymosis, numbness and hematoma.
Other groups have published their results with CCH following the classic treatment scheme. Levine et al (11) reported in 2015 an improvement in curvature from an initial mean of 53º to 34.7º after treatment (-34.4% at 36 weeks). In 2016, Ziegelmann et al (12), published the results of their prospective study in 69 patients, in whom an improvement of 14% after the first cycle, 28% after the second, 30% after the third and 37% after completing treatment with a fourth cycle were observed. In 2017 Anaissie et al (13) found that there was no significant improvement in the curvature after the administration of a fourth cycle, with the best response seen after the first cycle. Patients with a response ≥20% after finishing the treatment have had a more intense response after the first injection (-16.2º vs -5.8º, p<0.001). This data introduced the possibility of not completing the classic four cycle scheme to achieve good results.

Since the approval of CCH, some groups have investigated modifications of the original protocol or inclusion criteria in order to achieve similar results reducing the cost of the treatment. Ralph et al (14) published in 2017 the results of a prospective study involving 53 patients with PD and treated with CCH using a new shortened protocol. Most of the participants had an improvement in the angle of curvature by a mean (range) of 17.36º (0º-40º) or 31.4% (0%-57%) from baseline after three CCH injections. There was an improvement in each of the IIEF questionnaire domains, all three PDQ domains and the GAPD. They concluded that the results of using just three CCH injections according to this modified protocol are comparable to those of the clinical trials that used eight CCH injections, reducing the duration and the cost of the treatment.

The usefulness the the CCH therapy in combination with other treatments for PD has also been explored. Ziegelmann et al (15) hypothesized that PTT in combination with CCH would result in greater improvements in penile curvature and lenght relative to CCH alone. They recruited a total of 51 patients who underwent a similar protocol to the described in the IMPRESS I and II, including manual modelling and stretching. The mean (SD) improvement in penile curvature was 20.9º (17.3º, p<0.0001), with no significant difference indentified in the degree of curve improvement based on frequency or duration of PTT. Nevertheless, Ralph et al (16) performed a recent study evaluating the efficacy and safety of CCH plus vacuum-pump therapy with and without penile modeling. They recluted 30 patients that were offered a standard CCH treatment of a maximun of 4 cycles 6-week apart with 2 injections for each cycle. The found no significant difference in the curvature improvemente between both groups, but the results seem to be slightly better than the previously reported in similar studies without using the vacuum therapy (mean change from baseline -23.7º [SD=10.9] for CCH+vacuum+modeling and -23.3º [SD=7.2] for CCH+vacuum; between-group difference=0.3º, 95% CI= -7.3 to 6.6). Also in a recent paper from the authors (17) with a series of 87 patients that followed a classic protocol of CCH but adding a PTT for at least 4 hours a day, we found a mean reduction in curvature of -23.29° (-41%) with a mean number of cycles of about two. so we concluded that the concomitant use of CCH and PTT may limit the number of treatment cycles necessary to optimize outcomes when compared with CCH alone.

To conclude, CCH has demonstrated to be a safe and effective treatment for PD. Even in those cases in which the response is not complete and there is still a need of surgery, it allows to approach it from a better baseline, potentially reducing the possibility of adverse effects (penile shortening, erectile dysfunction). The decision of the manufacturer (Endo Pharmaceuticals, Malvern, PA, USA) to withdraw CCH from the market out of the United Stated, has removed from our treatment armamentarium an option that was being stablished as a first line choice for this disease, in our opinion. This decision seems to respond exclusively to economic reasons, as long as no additional serious adverse event has been reported to our knowledge, and there has been no concern of the European Medicines Agency about its use in PD.

Which are the alternatives?

Once experienced the efficacy of the CCH for PD, it is our opinion that start offering again our patients surgery as the only and gold standard treatment is a step backwards for both the patients and their physicians. So, in this way, we need to review our armamentarium to think which could be the alternatives.

First, we need to focus on the diagnosis of PD during the early acute stage. When identifying in this moment, we can avoid or palliate the penile deformities that could appear in the future stablishing strategies like the use of a PTT in monotherapy. In this respect, Martínez Salamanca et al (18) published in 2004 their series with 55 patients with active phase PD treated with PTT 6-9 hours daily for 6 months, comparing them with a control group of 41 patients. An improvement in the curvature of 20º in patients treated with the PTT was observed, in contrast to a progression of 23º in the control group. If we success identifying the disease in the active phase, at least we will be able to try to reduce the potential development of curvature and penile shortening.

And second, there are still options for the treatment of the stable phase, although in our opinion there is still a lack of evidence about them. In this regard, the most recent EAU Guidelines on Sexual and Reproductive Health (18) introduce a ‘strong’ recommendation for the use of Interferon α-2b in PD. This drug has been shown to decrease fibroblast proliferation, extracellular matrix production and collagen production from fibroblasts and improve the wound healing process from PD plaques in vitro. Intralesional injections (5×10^6 units of IFN-α2b in 10 mL saline every two weeks over twelve weeks for a total of six injections) significantly improved penile curvature, plaque size and density, and pain compared to placebo. A study showed that regardless of plaque location, IFN-α2b is an effective treatment option. Treatment with IFN-α2b provided a greater than 20% reduction in curvature in the majority of men with PD, independent of plaque location. Given the mild side-effects, which include sinusitis and flu-like symptoms, which can be effectively treated with NSAIDs drugs before IFN-α2b injection, and the moderate strength of data available, IFN-α2b is currently recommended for treatment of stable-phase PD.

References

1. Pryor JP, Ralph DJ. Clinical presentations of Peyronie’s disease. Int J Impot Res 2002;14:414-417.
2. Herati AS, Pastuszak AW. The genetic basis of Peyronie’s disease: a review. Sex Med Rev 2016;4:85-94.
3. Kadioglu A, Tefekli A, Erol B, et al. A retrospective review of 307 men with Peyronie’s disease; results of a large survey. BJU Int 2001;88:727-730.
4. Goldstein I, Hartzell R, Shabsigh R. The impact of Peyronie’s disease on the patient: gaps in our current understanding. J Sex Marital Ther 2016;42:178-190.
5. Levine LA. Seeking answers on the quest for effective nonsurgical treatment of Peyronie’s disease. Eur Urol 2007; 51:601-604.
6. Kendirci M, Hellstrom WJ. Critical analysis of surgery for Peyronie’s disease. Curr Opin Urol 2004;14:381-388.
7. 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 [published correction appears in J Urol. 2012 Aug;188(2):678]. J Urol. 2012;187(6):2268–2274.
8. 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; 190:199-207.
9. Ziegelmann MJ, Viers BR, McAlvany KL, Bailey GC, Savage JB, Trost LW. Restoration of Penile Function and Patient Satisfaction with Intralesional Collagenase Clostridium Histolyticum Injection for Peyronie’s Disease. J Urol. 2016 Apr;195(4):1051–6.
10. Yafi FA, Diao L, DeLay KJ, et al. Multi-institutional Prospective Analysis of Intralesional Injection of Collagenase Clostridium Histolyticum, Tunical Plication, and Partial Plaque Excision and Grafting for the Management of Peyronie’s Disease. Urology. 2018;120:138–142.
11. Levine LA, Cuzin B, Mark S, Gelbard MK, Jones NA, Liu G, et al. Clinical safety and effectiveness of collagenase clostridium histolyticum injection in patients with Peyronie’s disease: a phase 3 open-label study. J Sex Med. enero de 2015;12(1):248-58.
12. Ziegelmann MJ, Viers BR, McAlvany KL, Bailey GC, Savage JB, Trost LW. Restoration of Penile Function and Patient Satisfaction with Intralesional Collagenase Clostridium Histolyticum Injection for Peyronie’s Disease. J Urol. abril de 2016;195(4 Pt 1):1051-6.
13. Anaissie J, Yafi FA, DeLay KJ, Traore EJ, Sikka SC, Hellstrom WJG. Impact of Number of Cycles of Collagenase Clostridium Histolyticum on Outcomes in Patients With Peyronie’s Disease. Urology. febrero de 2017;100:125-30.
14. Abdel Raheem A, Capece M, Kalejaiye O, et al. Safety and effectiveness of collagenase clostridium histolyticum in the treatment of Peyronie’s disease using a new modified shortened protocol. BJU Int. 2017;120(5):717–723.
15. Ziegelmann MJ, Viers BR, Montgomery BD, Avant RA, Savage JB, Trost LW. Clinical Experience With Penile Traction Therapy Among Men Undergoing Collagenase Clostridium histolyticum for Peyronie Disease. Urology. 2017 Jun;104:102-109.
16. Ralph DJ, Abdel Raheem A, Liu G. Treatment of Peyronie’s Disease With Collagenase Clostridium histolyticum and Vacuum Therapy: A Randomized, Open-Label Pilot Study. J Sex Med 2017; 14:1430-1437.
17. García-Gómez B, García-Rojo E, Alonso-Isa M, et al. Treatment of peyronie’s disease with combination of clostridium histolyticum collagenase and penile traction therapy: a prospective, multicenter, single-arm study [published online ahead of print, 2020 May 4]. Int J Impot Res. 2020;10.1038/s41443-020-0292-y. doi:10.1038/s41443-020-0292-y
18. Salonia A et al. EAU Guidelines on Sexual and Reproductive Health. Available at https://uroweb.org/wp-content/uploads/EAU-Guidelines-on-Sexual-and-Reproductive-Health-2020.pdf

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