Efficacy and Safety of N-acetyl-GED-0507-34-LEVO gel in Patients With Moderate-to Severe Facial Acne Vulgaris

A Phase IIb Randomized Double-blind, Vehicle-controlled Trial

Mauro Picardo; Carla Cardinali; Michelangelo La Placa; Anita Lewartowska-Białek; Viviana Lora; Giuseppe Micali; Roberta Montisci; Luca Morbelli; Andrea Nova; Aurora Parodi; Adam Reich; Michael Sebastian; Katarzyna Turek-Urasińska; Oliver Weirich; Jacek Zdybski; Christos C. Zouboulis

Disclosures

The British Journal of Dermatology. 2022;187(4):507-514. 

In This Article

Abstract and Introduction

Abstract

Background: Preliminary in vitro and in vivo studies have supported the efficacy of the peroxisome proliferator-activated receptor-γ (PPARγ) modulator N-acetyl-GED-0507-34-LEVO (NAC-GED) for the treatment of acne-inducing sebocyte differentiation, improving sebum composition and controlling the inflammatory process.

Objectives: To evaluate the efficacy and safety of NAC-GED (5% and 2%) in patients with moderate-to-severe facial acne vulgaris.

Methods: This double-blind phase II randomized controlled clinical trial was conducted at 36 sites in Germany, Italy and Poland. Patients aged 12–30 years with facial acne, an Investigator Global Assessment (IGA) score of 3–4, and an inflammatory and noninflammatory lesion count of 20–100 were randomized to topical application of the study drug (2% or 5%) or placebo (vehicle), once daily for 12 weeks. The co-primary efficacy endpoints were percentage change from baseline in total lesion count (TLC) and IGA success at week 12; the safety endpoints were adverse events (AEs) and serious AEs. This study was registered with EudraCT (2018-003307-19).

Results: Between Q1 in 2019 and Q1 in 2020 450 patients [n = 418 (92·9%) IGA 3; n = 32 (7·1%) IGA 4] were randomly assigned to NAC-GED 5% (n = 150), NAC-GED 2% (n = 150) or vehicle (n = 150). The percentage change in TLC reduction was statistically significantly higher in both the NAC-GED 5% [–57·1%, 95% confidence interval (CI) –60·8 to –53·4; P < 0·001] and NAC-GED 2% (–44·7%, 95% CI –49·1 to –40·1; P < 0·001) groups compared with vehicle (–33·9%, 95% CI –37·6 to –30·2). A higher proportion of patients treated with NAC-GED 5% experienced IGA success (45%, 95% CI 38–53) vs. the vehicle group (24%, 95% CI 18–31; P < 0·001). The IGA success rate was 33% in the NAC-GED 2% group (P = not significant vs. vehicle). The percentage of patients who had one or more AEs was 19%, 16% and 19% in the NAC-GED 5%, NAC-GED 2% and vehicle groups, respectively.

Conclusions: The topical application of NAC-GED 5% reduced TLC, increased the IGA success rate and was safe for use in patients with acne vulgaris. Thus, NAC-GED, a new PPARγ modulator, showed an effective clinical response.

Introduction

Acne vulgaris, the most frequent disorder of the pilosebaceous unit,[1,2] affects more than 85% of the adolescent and young adult population, and 650 million people worldwide.[3] The disease produces a substantial psychological and social burden due to frequent relapses and persistence in adulthood.[4,5]

Mild-to-moderate acne is treated with topical agents, including antibiotics, benzoyl peroxide and retinoids. In unresponsive patients or more severe forms of acne oral agents are added, such as antibiotics or isotretinoin.[6–9] These agents act on specific parts of the acne pathogenesis pathway. However, by combining them, different pathways can be targeted at once, increasing the probability and severity of side-effects.[8,9]

Within the last 10 years, limited progress has been made in identifying novel therapeutic acne agents. Only the steroidal antiandrogen clascoterone and the retinoid trifarotene have recently been approved for topical treatment.[10–13] Thus, there is an unmet clinical need for novel, effective substances with an enhanced mechanism of action that target acne pathogenesis pathways simultaneously with reduced side-effects.

Factors involved in acne development include alterations in the hormonal microenvironment, follicular hyperkeratinization, inflammation, dysfunction of the immune response, interactions with the host microbiome and sebaceous gland activity, as well as sebum composition.[6] Alterations in sebum composition affect acne manifestation more than increased sebum secretion.[14] Both innate and adaptive immunity are involved, particularly T helper 17 cells.[6]

Recent research has focused on the hormonal control of sebum production and composition.[15,16] During puberty, hormones such as androgens, insulin and insulin-like growth factor increase sebaceous gland volume. They activate the transcription factor sterol response element-binding protein 1 (SREBP1) through the phosphatidylinositide 3-kinase (PI3K)/AKT pathway, inducing sebogenesis.[15,16]

Sebum production is also controlled by the peroxisome proliferator-activated receptor-γ (PPARγ). PPARγ belongs to a family of nuclear receptors expressed in various cell types that function as transcription factors to regulate cellular differentiation, development and metabolism.[6,11,16] In sebocytes, PPARγ expression strictly correlates with cell differentiation.[17] It was recently discovered that undifferentiated sebocytes, when compared with differentiated sebocytes, are more susceptible to insulin levels comparable to normal serum insulin. Insulin stimulates the activation of desaturase enzymes, with the production of acne-compatible sebum and the generation of inflammatory mediators.[18] In an in vitro model, treatment with the novel selective PPARγ modulator (S)-3-(4-acetamidophenyl)-2-methoxypropanoic acid [N-acetyl-GED0507-levo (NAC-GED)][19,20] promoted sebocyte differentiation, reduced insulin-induced lipogenesis and inflammation, and improved sebum composition. Simultaneously, the ratio of sapienic acid/palmitic acid and lipoperoxide production decreased, as did the production of inflammatory mediators.[21,22]

In this phase IIb double-blind, placebo-controlled study, we evaluated the tolerability and efficacy of topical NAC-GED 2% and 5% in patients with moderate-to-severe acne vulgaris.

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