1. Intralesional Treatment: Is there a real
breakthrough?
Ege Can Serefoglu, MD, FECSM
Bagcilar Training & Research Hospital, Istanbul, Turkey

2. NO…!!!

3. Financial and Other Disclosures
Off-label use of drugs, devices, or other agents: None or FILL IN HERE; including your local
regulatory agency, such as FDA, EMA, etc.
Data from IRB-approved human research is presented [or state: “is not”]
3
I have the following financial interests or
relationships to disclose:
Disclosure code
No financial relationships N

4. Intralesional Treatment in PD
Definition & Epidemiology
Pathophysiology
Treatment
Intralesional Treatment

5. Intralesional Treatment in PD
Definition & Epidemiology
Pathophysiology
Treatment
Intralesional Treatment

6. Definition & Epidemiology of PD
Peyronie's disease (PD) is a fibrotic disorder of the tunica
albuginea of the penis.
Naming has been attributed to François Gigot de la Peyronie
(surgeon to king Louis XIV of France)
Memoire sur quelques obstacles qui s'opposent d l'Ejaculation
naturelle de la semence (Memoires de l'Academie royale de chirurgie - 1743)

7. Definition & Epidemiology of PD
Scarring/plaque of the tunica albuginea with excessive abnormal
collagen deposition
Potential symptoms:
• Curvature – 80-91%
• Nodule – 15%
• Pain – 3-22%
• ED – 15-28%
• Penile shortening – 14%
8-9% report preceding trauma
More common in white males (OR 8.47)
15-58% of patients are unaware of disease (incidental discovery)
Bella A. J Sex Med 2007; Kadioglu A, et al. J Uro 2002; Rhoden EL, et al. J Sex Med 2010; Kadioglu A, et al. IJIR 2004; Chung E, et al. BJUI 2012.

8. Definition & Epidemiology of PD
Prevalence varies:
In the general population: 0.4-13%
Among patients:
ED 7.9%
DM 8.1%
ED + DM 20.3%
Post-RP 15.9%
4 – Rhoden EL, et al: 2001 IJIR.
5– La Pera G, et al: 2001 Eur Urol.
6 – Mulhall JP, et al: 2004 J Urol.
1 – Lindsay MB, et al: 1991 J Urol.
2 – DiBenedetti DB, et al: 2011 Adv Urol.
3 - Schwarzer U, et al: 2001 BJU Int.

9. Intralesional Treatment in PD
Definition & Epidemiology
Pathophysiology
Treatment
Intralesional Treatment

10. Pathophysiology: What Is Collagen?
• Primary extracellular structural component
• All collagens contain a triple helix:
• Composed of three polypeptide chains
• Contains Gly-X-Y motifs (X and Y normally proline or
hydroxyproline)
• The triple helix
• Requires extensive post-translational modification (“hard to
make”)
• Is extremely stable (“hard to break”)

11. Intralesional Treatment in PD
Definition & Epidemiology
Pathophysiology
Treatment
Intralesional Treatment

12. Treatment
• Spontaneous resolution
• Oral therapy: Vitamin E, POTABA, Colchicine, Tamoxifen…
• Intralesional injection therapy
• Calcium channel blockers (Verapamil)
• Interferon (IFN)
• Collagenase (Xiaflex) – FDA approval Dec 6, 2013
• Surgical options
• Plication of contralateral corpora (Nesbit principle)
• Incision & grafting (I & G) procedures
• Prosthesis option with modeling or ancillary procedures

13. Treatment

14. • Clinicians should NOT offer:
• Vitamin E, tamoxifen, procarbazine, omega-3
fatty acids, or Vit E w/ L-carnitine
• Electromotive therapy w/ verapamil
• Shock wave therapy for curvature or plaque
size (may offer for pain)
• Radiotherapy
Treatment
AUA Guidellines on PD 2015

15. Clinicians may administer collagenase w/ modeling
for pts with:
• Stable disease
• 30-90°
• Intact erectile function w/ or w/o meds
Clinicians may offer intralesional interferon or
verapamil
Treatment
AUA Guidellines on PD 2015

16. Intralesional Treatment in PD
Definition & Epidemiology
Pathophysiology
Treatment
Intralesional Treatment

17. Intralesional Treatment
• Interferon (IFN)
• Calcium channel blockers (Verapamil)
• Collagenase (Xiaflex)

18. Intralesional Interferon Alpha-2b
1 RCT, 1 randomized study (w/o placebo), 8
observational studies
Single-blind, multicenter, placebo controlled, parallel arm
N=103, age 55, PD >12 mo, curvature > 30°
Bi-weekly x 12 injections
Curvature reduction: 13.5° (IFN) vs 4.5°
Plaque size reduction: 2.6 cm2 (IFN) vs 0.9 cm2
Pain improvement: 67.7% (IFN) vs 28.1%
Hellstrom WJ, et al: 2006 J Urol.

19. Intralesional Interferon Alpha-2b
Role in men w/
Stable disease
Curvature >30°
Non-calcified plaque
ventral curvatures, penile pain
Pts should be informed regarding expected average curvature
reduction of 13.5 degrees (only 9 degrees different than
placebo)
Clinicians should counsel pts prior to tx about potential
adverse events
sinusitis, flu-like symptoms, and minor penile swelling.
AUA Guidellines on PD 2015

20. Intralesional Verapamil
2 RCTs, 8 observational studies
1. 10 – 27 mg intralesional verapamil weekly for 6 months1
N=14
Randomized, single-blind, placebo controlled
significant decrease in plaque length, width, and volume in the
verapamil group (but not in the placebo group)
2. 10 mg verapamil, twice weekly for 12 weeks2
N=80,
Randomized, single-blind, placebo controlled
No significant differences in curvature, pain, plaque size, or sexual
function
1- Rehman J et al. Urology 1998
2 – Shirazi M, et al. Int Urol Nephrol. 2009

21. Intralesional Verapamil
Clinicians who consider the use of intralesional
verapamil as a treatment for symptoms of PD should
fully consider the weakness of the evidence
demonstrating its efficacy.
Clinicians should counsel pts prior to tx about potential
adverse events,
penile bruising, dizziness, nausea, and pain at the injection site.
AUA Guidellines on PD 2015

22. 2014 – The Year of Collagenase
Clostridium Histolyticum

23.  Surgical specimens of excised plaque & normal tunica
 Injection into dorsal tunica (400 U clostridial collagenase in 0.2 mL)
 Incubation for 24 h before tissue processing
 Localized complete lysis of collagen (note sharp demarcation from normal tissue)
Gelbard MK, et al. Urol Res 1982
Hematoxylin & eosin stain
(collagen = dense pink stain)
Van Gieson’s stain
(collagen = dark red stain)
CCH injection into the Plaque

24. Amino acid release to buffer (ninhydrin) after CCH
injection into the plaque
Gelbard MK, et al. Urol Res 1982

25. Complete disruption of plaque collagen
• Surgically excised plaque bisected:
• Half was treated with collagenase (400 U in 0.1 mL)
• Half was injected with saline (0.1 mL)
• Incubation for 24 h before tissue processing
• Note difference in size & morphology (both are same magnification)
Saline Collagenase
Gelbard MK, et al. Urol Res 1982

26. Dupuytren’s Contracture
Starkweather KD, et al. J
Hand Surg Am. 1996.
Peyronie’s Disease
Gelbart M, et al. J Urol. 1993

27. CCH in PD
Investigation for Maximal Peyronie’s Reduction Efficacy
and Safety Studies (IMPRESS I + II)
2 large double-blind, randomized, placebo controlled phase 3
studies
Conducted at 64 sites in the U.S. and Australia
417 + 415 subjects with penile curvature deformity from 20 to
90o
Randomized to receive up to 8 injections of XIAFLEX 0.58
mg or placebo in 2:1 ratio
maximum of 4 treatment cycles, each separated by 6 weeks
Gelbart M, et al. J Urol. 2013

29. CCH Improved Penile Curvature Deformity
over 52 Weeks
20
25
30
35
40
45
50
55
XIAFLEX Placebo XIAFLEX Placebo
Baseline
EOS
37.6%
21.3%
15.2%
30.5%
DegreesofCurvatureDeformity
P=0.0005 P=0.0059
IMPRESS I IMPRESS II
N=199 N=104 N=202 N=107

30. CCH Improved Penile Curvature Deformity
over 52 Weeks
Baseline curvature deformity – 48o
End of study curvature deformity – 28o (38% improvement)
Gelbart M, et al. J Urol. 2013

31. CCH Improved PDQ Bother
Domain Score over 52 Weeks
PDQBotherScale
P=0.0451 P=0.0496
IMPRESS I IMPRESS II
2.4
(32.4%)
1.6
(20.7%
)
N=199 N=104 N=202 N=107
Gelbart M, et al. J Urol. 2013

32. Most Common Adverse Events > 5%
ITT analysis/Preferred term listed
IMPRESS I IMPRESS II
XIAFLEX Placebo XIAFLEX Placebo
N = 277
n (%)
N = 140
n (%)
N = 274
n (%)
N = 141
n (%)
Any non-serious AE 256 (92.4) 81 (57.9) 252 (92.0) 88 (62.4)
Penile hematoma 171 (61.7) 19 (13.6) 165 (60.2) 22 (15.6)
Penile Pain 119 (41.2) 11 (7.9) 96 (35.0) 8 (5.7)
Penile swelling 114 (41.2) 1 (0.7) 95 (34.7) 2 (1.4)
Injection site pain 70 (25.3) 5 (3.6) 41 (15.0) 4 (2.8)
Penile hemorrhage 60 (21.7) 14 (10.0) 43 (15.7) 1 (0.7)
Injection site hematoma 45 (16.2) 14 (10.0) 61 (22.3) 16 (11.3)

33. Most Common Adverse Events > 5%
ITT analysis/Preferred term listed
IMPRESS I IMPRESS II
XIAFLEX Placebo XIAFLEX Placebo
N = 277
n (%)
N = 140
n (%)
N = 274
n (%)
N = 141
n (%)
Penile edema 45 (16.2) 1 (0.7) 40 (14.6) 0 (0.0)
Injection site swelling 30 (10.8) 0(0.0) 35 (12.8) 2 (1.4)
Contusion 28 (10.1) 0 (0.0) 27 (9.9) 1 (0.7)
Ecchymosis 26 (9.4) 0 (0.0) 12 (4.4) 0 (0.0)
Blood blister 9 (3.2) 0 (0.0) 17 (6.2) 0 (0.0)
Injection site hemorrhage 15 (5.4) 10 (7.1) 10 (3.6) 3 (2.1)

34. Serious Adverse Events
ITT analysis/Preferred term listed
IMPRESS I IMPRESS II
XIAFLEX Placebo XIAFLEX Placebo
N = 277
n (%)
N = 140
n (%)
N = 274
n (%)
N = 141
n (%)
Treatment emergent SAE 27 (9.7) 7 (5.0) 12 (4.4) 4 (2.8)
Treatment related SAE 3 (1.1) 0(0.0) 3 (1.1) 0 (0.0)
XIAFLEX Treatment Related SAEs
Hematoma 2 (0.7) 0 (0.0) 1 (0.4) 0 (0.0)
Corporal Rupture
(penile fracture)
1 (0.4) 0 (0.0) 2 (0.7) 0 (0.0)

35. Conclusions of IMPRESS trials
• CCH showed statistically significant improvements in
• penile curvature deformity (physical) [p-values of 0.0005 and
0.0059]
• PD bother (psychosocial) [p-values of 0.0451 and 0.0496]
• XIAFLEX is an effective FDA-approved biological therapy for the
treatment of PD
• How many pts drop out the study???
(pain, hematoma, swelling, 8 mo tx)
• Is a mean curvature reduction of 17° is “functionally” significant
for the patient?
• If the whole course of 8 injections is used, the cost would be >£8
000 (€11 200). (more than double compared with a tariff of £1
856 for a Nesbit procedure) (NHS England).

36. Conclusions
• PD is a common condition that can be both
physically and psychologically devastating for men
and their partners
• Intralesional interferon and verapamil treatment
may be effective.
• CCH showed statistically significant improvements
(17°) in penile curvature and PD bother
• It can be effective in PD patients with
• Dorsal curvature <50-60 degrees
• Without calcified plaque
• Reducing the number of treatment cycles needed
would make the treatment significantly more cost
effective.