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Pharmacotherapy in Peyronie’s disease: a state-of-the-art review on established contemporary and emerging drugs (2022)
Eric Chung & Faysal A. Yafi
ABSTRACT
Introduction: Current clinical guidelines on Peyronie’s disease (PD) advocate non-surgical treatment options as the first-line therapy despite inconsistent clinical outcomes when compared to definitive penile reconstructive surgery.
Areas covered: This article examines the current understanding of established contemporary and emerging pharmacotherapies for PD. Emphasis has been placed on published clinical studies on drugs in the last 10 years.
Expert opinion: Published studies have shown that combination therapy is likely more effective than monotherapy. Combined treatment modalities involving various oral and/or intralesional pharmacotherapies together with mechanical devices or clinical psychosexual therapy may provide additional or synergistic benefits for PD patients. A multidisciplinary approach coupled with more novel targets for pharmacological intervention could deliver a more effective treatment paradigm to prevent or at least delay the need for definitive penile reconstructive surgery. Drugs targeting the inhibition of TGF-β1 pathway and myofibroblast transformation are of great interest and studies into next-generation genetic sequencing and transcriptional biomarker regulatory pathways in PD will provide useful insights into the pathophysiology of PD, and assist the development of future regenerative technology including cellular-based therapies to target various anti-fibrotic molecular mechanisms and the potential to be integrated into existing treatment armamentarium for PD.
1. Introduction
Peyronie’s disease (PD) is often defined by the presence of penile plaque(s) and various penile complaints such as penile pain, curvature, and/or deformity [1–4]. While the basic pathophysiology is thought to arise from abnormal penile healing secondary to repetitive injury with ensuing extravasation and accumulation of various pro-fibrotic factors (especially transforming growth factor beta-1, TGFβ1), fibrin, and myofibroblast between the tunica layers following injury, the development of PD is more common in genetically susceptible individuals and in certain high-risk populations such as diabetic males or those with fibrotic disorders or post-prostate cancer treatment [5,6].
Current clinical guidelines on PD advocate non-surgical treatment options as the first-line therapy unless patients wish to undergo penile reconstructive surgery for the definitive solution and are willing to accept surgical risks [7,8]. Epidemiological studies have shown natural resolution is uncommon without intervention (12%) [9]. While the success rate of medical therapy for PD can be inconsistent when compared to penile reconstructive surgery, it is often prescribed in the early stage of PD to resolve or stabilize penile curvature, pain, and plaque size. However, most drugs to treat PD are used off-label apart from collagenase Clostridium histolyticum. The following article examines the current state-of-the-art understanding of established contemporary and emerging pharmacotherapies for PD
3. Oral and intralesional drugs for PD
3.1. Potaba
3.2. Estrogen receptor modulators
3.3. Colchicine
3.4. Phosphodiesterase inhibitors
3.5. Collagenase clostridium histolyticum
3.6. Hyaluronic acid
3.7. Verapamil
3.8. Interferon alpha 2B
3.9. Regenerative therapy: stem cells and platelet-rich plasma
3.10. Botulinum toxin (Botox)
4. Expert opinion
PD is an abnormal connective tissue disorder and is often characterized by the presence of (inflammatory) plaque within the bilaminar tunica albuginea [5] secondary to aberrant wound healing and erroneous genetic neurohumoral pathways [1,3]. Hence, the prescribed drug therapy will need to remodel the existing Peyronie’s plaque and address the underlying fibrotic process. Current clinical guidelines advocate the use of an oral drug as first-line treatment despite the relative sparse scientific evidence and the fact that published studies have significant heterogeneity in methodologies such as a small number of patients, mixed PD features, and limited objective outcome measures. The suboptimal efficacy of oral drug therapy relates to the lack of localized drug absorption and penetration to achieve sufficient drug concentration within the penile plaque. As expected, transdermal application of drugs with or without iontophoresis therapy is likely to be ineffective, and published guidelines do not recommend topical therapy in PD. Despite the relative paucity of high-quality evidence with the use of oral monotherapy, oral drugs may be useful in the early phase of PD with unstable or progressive penile curvature when the (inflammatory) plaque is not fully formed yet. Furthermore, for males who are not interested in surgical intervention, oral drugs can be used as an adjunct with other non-surgical therapy. Recent studies highlight a potential positive role of oral agents such as tamoxifen, pentoxifylline, and PDE5i in PD.
While intralesional drugs appear more effective than oral drugs since they are injected directly into the Peyronie’s plaque, published clinical outcomes are mixed and this reflects the heterogeneous nature of PD with various presentations of atypical disease, at times the absence of a palpable plaque for injection, level of clinical experience in delivering intralesional therapy and optimal intralesional treatment protocols [53]. Placebo-controlled trials showed that injection of saline and the amount volume of injection can improve penile curvature and plaque size [1,4]. Furthermore, penile remodeling was not commonly administered at the time of intralesional therapy before the publication of the IMPRESS trials [48] and the lack of manual remodeling may play a factor in the suboptimal outcomes observed with other intralesional drugs therapy. To date, CCH remains the only licensed drug in PD. Nonetheless, CCH is an expensive, likely not cost-effective therapy when compared to definitive penile reconstructive surgery, and its availability is largely limited to the North American market only.
Published studies have shown that combination therapy is likely more effective than monotherapy. Combined treatment modality involving various oral and/or intralesional pharmacotherapies together with mechanical devices or clinical psychosexual therapy may provide additional or synergistic benefits for PD patients. A multidisciplinary approach coupled with more novel targets for pharmacological intervention could deliver a more effective treatment paradigm to prevent or at least delay the need for definitive penile reconstructive surgery. Larger, multicenter clinical trials with uniform research methodology and treatment protocols, with a greater emphasis on patient-reported outcomes and cost-effectiveness analysis, as well as utilizing generated proteomic, genomic, and metabolomic data will be useful to direct future PD management.
Current in vivo PD models have highlighted that TGFβ1-mediated activation of myofibroblasts appears to be the common denominator to PD [5], and hence, drugs targeting the inhibition of the TGF-β1 pathway and myofibroblast transformation are of great interest and likely form the new frontier in PD therapy. Drugs that enhance the expression of tissue inhibitors of metalloproteinases and/or inhibit the function of matrix metalloproteinases will provide a new avenue to redress the balance between pro-fibrotic and antifibrotic roles. Studies into next-generation genetic sequencing and transcriptional biomarker regulatory pathways in PD will provide useful insights into the pathophysiology of PD, and assist the development of future regenerative technology including cellular-based therapies to target various anti-fibrotic molecular mechanisms and the potential to be integrated into existing treatment armamentarium for PD. Further research is needed to develop and testing of these novel pathways and this needs to be matched with greater public awareness and patient education on PD to streamline the clinical care pathway for this debilitating heterogeneous and complex psychosexual condition.
Eric Chung & Faysal A. Yafi
ABSTRACT
Introduction: Current clinical guidelines on Peyronie’s disease (PD) advocate non-surgical treatment options as the first-line therapy despite inconsistent clinical outcomes when compared to definitive penile reconstructive surgery.
Areas covered: This article examines the current understanding of established contemporary and emerging pharmacotherapies for PD. Emphasis has been placed on published clinical studies on drugs in the last 10 years.
Expert opinion: Published studies have shown that combination therapy is likely more effective than monotherapy. Combined treatment modalities involving various oral and/or intralesional pharmacotherapies together with mechanical devices or clinical psychosexual therapy may provide additional or synergistic benefits for PD patients. A multidisciplinary approach coupled with more novel targets for pharmacological intervention could deliver a more effective treatment paradigm to prevent or at least delay the need for definitive penile reconstructive surgery. Drugs targeting the inhibition of TGF-β1 pathway and myofibroblast transformation are of great interest and studies into next-generation genetic sequencing and transcriptional biomarker regulatory pathways in PD will provide useful insights into the pathophysiology of PD, and assist the development of future regenerative technology including cellular-based therapies to target various anti-fibrotic molecular mechanisms and the potential to be integrated into existing treatment armamentarium for PD.
1. Introduction
Peyronie’s disease (PD) is often defined by the presence of penile plaque(s) and various penile complaints such as penile pain, curvature, and/or deformity [1–4]. While the basic pathophysiology is thought to arise from abnormal penile healing secondary to repetitive injury with ensuing extravasation and accumulation of various pro-fibrotic factors (especially transforming growth factor beta-1, TGFβ1), fibrin, and myofibroblast between the tunica layers following injury, the development of PD is more common in genetically susceptible individuals and in certain high-risk populations such as diabetic males or those with fibrotic disorders or post-prostate cancer treatment [5,6].
Current clinical guidelines on PD advocate non-surgical treatment options as the first-line therapy unless patients wish to undergo penile reconstructive surgery for the definitive solution and are willing to accept surgical risks [7,8]. Epidemiological studies have shown natural resolution is uncommon without intervention (12%) [9]. While the success rate of medical therapy for PD can be inconsistent when compared to penile reconstructive surgery, it is often prescribed in the early stage of PD to resolve or stabilize penile curvature, pain, and plaque size. However, most drugs to treat PD are used off-label apart from collagenase Clostridium histolyticum. The following article examines the current state-of-the-art understanding of established contemporary and emerging pharmacotherapies for PD
3. Oral and intralesional drugs for PD
3.1. Potaba
3.2. Estrogen receptor modulators
3.3. Colchicine
3.4. Phosphodiesterase inhibitors
3.5. Collagenase clostridium histolyticum
3.6. Hyaluronic acid
3.7. Verapamil
3.8. Interferon alpha 2B
3.9. Regenerative therapy: stem cells and platelet-rich plasma
3.10. Botulinum toxin (Botox)
4. Expert opinion
PD is an abnormal connective tissue disorder and is often characterized by the presence of (inflammatory) plaque within the bilaminar tunica albuginea [5] secondary to aberrant wound healing and erroneous genetic neurohumoral pathways [1,3]. Hence, the prescribed drug therapy will need to remodel the existing Peyronie’s plaque and address the underlying fibrotic process. Current clinical guidelines advocate the use of an oral drug as first-line treatment despite the relative sparse scientific evidence and the fact that published studies have significant heterogeneity in methodologies such as a small number of patients, mixed PD features, and limited objective outcome measures. The suboptimal efficacy of oral drug therapy relates to the lack of localized drug absorption and penetration to achieve sufficient drug concentration within the penile plaque. As expected, transdermal application of drugs with or without iontophoresis therapy is likely to be ineffective, and published guidelines do not recommend topical therapy in PD. Despite the relative paucity of high-quality evidence with the use of oral monotherapy, oral drugs may be useful in the early phase of PD with unstable or progressive penile curvature when the (inflammatory) plaque is not fully formed yet. Furthermore, for males who are not interested in surgical intervention, oral drugs can be used as an adjunct with other non-surgical therapy. Recent studies highlight a potential positive role of oral agents such as tamoxifen, pentoxifylline, and PDE5i in PD.
While intralesional drugs appear more effective than oral drugs since they are injected directly into the Peyronie’s plaque, published clinical outcomes are mixed and this reflects the heterogeneous nature of PD with various presentations of atypical disease, at times the absence of a palpable plaque for injection, level of clinical experience in delivering intralesional therapy and optimal intralesional treatment protocols [53]. Placebo-controlled trials showed that injection of saline and the amount volume of injection can improve penile curvature and plaque size [1,4]. Furthermore, penile remodeling was not commonly administered at the time of intralesional therapy before the publication of the IMPRESS trials [48] and the lack of manual remodeling may play a factor in the suboptimal outcomes observed with other intralesional drugs therapy. To date, CCH remains the only licensed drug in PD. Nonetheless, CCH is an expensive, likely not cost-effective therapy when compared to definitive penile reconstructive surgery, and its availability is largely limited to the North American market only.
Published studies have shown that combination therapy is likely more effective than monotherapy. Combined treatment modality involving various oral and/or intralesional pharmacotherapies together with mechanical devices or clinical psychosexual therapy may provide additional or synergistic benefits for PD patients. A multidisciplinary approach coupled with more novel targets for pharmacological intervention could deliver a more effective treatment paradigm to prevent or at least delay the need for definitive penile reconstructive surgery. Larger, multicenter clinical trials with uniform research methodology and treatment protocols, with a greater emphasis on patient-reported outcomes and cost-effectiveness analysis, as well as utilizing generated proteomic, genomic, and metabolomic data will be useful to direct future PD management.
Current in vivo PD models have highlighted that TGFβ1-mediated activation of myofibroblasts appears to be the common denominator to PD [5], and hence, drugs targeting the inhibition of the TGF-β1 pathway and myofibroblast transformation are of great interest and likely form the new frontier in PD therapy. Drugs that enhance the expression of tissue inhibitors of metalloproteinases and/or inhibit the function of matrix metalloproteinases will provide a new avenue to redress the balance between pro-fibrotic and antifibrotic roles. Studies into next-generation genetic sequencing and transcriptional biomarker regulatory pathways in PD will provide useful insights into the pathophysiology of PD, and assist the development of future regenerative technology including cellular-based therapies to target various anti-fibrotic molecular mechanisms and the potential to be integrated into existing treatment armamentarium for PD. Further research is needed to develop and testing of these novel pathways and this needs to be matched with greater public awareness and patient education on PD to streamline the clinical care pathway for this debilitating heterogeneous and complex psychosexual condition.
