Pirfenidone Plus M-DDO Gel in Moderate and Severe Acne

Summary

Acne vulgaris is a complex skin disorder involving multiple abnormalities of the pilosebaceous unit. Acne is the most common skin disease during puberty and worsens throughout adolescence. However, epidemiological studies suggest that acne can arise at any age, most frequently affecting individuals between puberty and 30 years of age, with 79%-95% of subjects aged between 16 years and 18 years and 80% of subjects between puberty and 30 years of age. Acne is considered the main reason for consultation with the dermatologist in institutional and private clinical practice. Clinical features include seborrhoea, non-inflammatory lesions, inflammatory lesions and various degrees of scarring. There are many classifications of acne and scarring severity. Moderate to severe acne is about 15-20%. Facial acne scarring affects both sexes equally and occurs to some degree in up to 95% of cases. There is a significant correlation between the initial acne grade and the overall severity of scarring at all sites and in both sexes. This would suggest that treatment aimed at reducing the severity of acne might reduce the incidence of scarring. Both superficial inflammatory acne lesions as well as deep nodular lesions seem capable of producing scars. Conventional therapies recommended for the treatment of acne vulgaris include retinoids, benzoyl peroxide (BPO), antibiotics, and hormonal therapy. Combination therapy using agents with complementary mechanisms provides the opportunity to target multiple pathogenetic causes of acne vulgaris. The combination in gel with 0.1% adapalene and 2.5% BPO is a once-daily treatment of acne vulgaris. In several double- blind, randomized controlled trials (RCTs), the Adapalene-BPO (A-BPO) combination therapy applied once daily for 12 weeks significantly reduced the number of both inflammatory and non-inflammatory lesions in subjects with moderate acne vulgaris. In Mexico there is an available commercial product of this combination (Effezel®; Galderma). The limitation of this topical therapy is the low tolerability by patients as they can experiment several levels of irritation, erythema, dryness, desquamation, burning, and itching), and patients are advised to expect these side effects, which contribute to discontinue therapy if it becomes severe. On the other hand, 5-methyl-1-phenyl-2-(1h)-pyridone or pirfenidone (PFD) is a wide-spectrum antifibrotic drug that modulates diverse cytokines action, involving TGF-β, TNF-α, epidermal growth factor, platelet-derived growth factor, VEGF, IGF-1, fibroblast growth factor, interferon-γ, interleukin (IL)-1, IL-6, and IL-8 and it has shown promising effects in vitro and in vivo settings. Also, PFD has proven effective in the prevention and regression of pulmonary fibrosis, peritoneal sclerosis, hepatic cirrhosis, uterine fibromyoma, left ventricular fibrosis, renal interstitial fibrosis, and breast capsular contracture in experimental models. A recently open phase II clinical trial evaluated the therapeutic use of PFD gel in localized scleroderma. Results showed it acts on both the inflammatory and the fibrotic phases. The other component of Zaxcell is modified-diallyl disulfide oxide (M-DDO) an antimicrobial and antiseptic agent, which has been proved in patients with chronic diabetic ulcer as a potent germicide and has show to increase the beneficial effect of PFD preventing infections, accelerating and improving ulcer resolution. (Observations not published). According to this, the investigators believe that Zaxcell (PFD + M-DDO) could play an important role in the modulation of inflammatory and scarring process in acne. The investigators hypothesis is that PFD in patients with moderate to severe acne modulates amplification of the inflammatory response, regulating the inflammasome activation, macrophage polarization and its activity in regulating the wound healing process of the skin in an early fashion. Zaxcell is an innovative gel with a synergetic mode of action that could modulate the inflammatory response. Furthermore, has antiseptic properties and regulates the process of wound healing, fibrogenic and scarring process. In vitro and in vivo studies provide an initial body of evidence on the safety and clinical benefits of PFD, the main component of Zaxcell as a promising candidate for the treatment of moderate to severe acne.

Timeline

Start

2017-03-27

Primary completion

2019-01-31

Completion

2019-03-31

Publications

• Background Gollnick HP, Finlay AY, Shear N; Global Alliance to Improve Outcomes in Acne. Can we define acne as a chronic disease? If so, how and when? Am J Clin Dermatol. 2008;9(5):279-84. doi: 10.2165/00128071-200809050-00001.
• Background Kang S, Cho S, Chung JH, Hammerberg C, Fisher GJ, Voorhees JJ. Inflammation and extracellular matrix degradation mediated by activated transcription factors nuclear factor-kappaB and activator protein-1 in inflammatory acne lesions in vivo. Am J Pathol. 2005 Jun;166(6):1691-9. doi: 10.1016/s0002-9440(10)62479-0.
• Background Macias-Barragan J, Sandoval-Rodriguez A, Navarro-Partida J, Armendariz-Borunda J. The multifaceted role of pirfenidone and its novel targets. Fibrogenesis Tissue Repair. 2010 Sep 1;3:16. doi: 10.1186/1755-1536-3-16.
• Background Zhou R, Jiang X. Effects of adapalene-benzoyl peroxide combination gel in treatment or maintenance therapy of moderate or severe acne vulgaris: a meta-analysis. Ann Dermatol. 2014 Feb;26(1):43-52. doi: 10.5021/ad.2014.26.1.43. Epub 2014 Feb 17.
• Background Rodriguez-Castellanos M, Tlacuilo-Parra A, Sanchez-Enriquez S, Velez-Gomez E, Guevara-Gutierrez E. Pirfenidone gel in patients with localized scleroderma: a phase II study. Arthritis Res Ther. 2015 Jan 28;16(6):510. doi: 10.1186/s13075-014-0510-4.
• Background Holland DB, Jeremy AH. The role of inflammation in the pathogenesis of acne and acne scarring. Semin Cutan Med Surg. 2005 Jun;24(2):79-83. doi: 10.1016/j.sder.2005.03.004.

Drugs

Indications