Izokibep for the treatment of moderate-to-severe plaque psoriasis: a phase II, randomized, placebo-controlled, double-blind, dose-finding multicentre study including long-term treatment.

BACKGROUND: Monoclonal antibodies to interleukin (IL)-17 have shown strong efficacy in patients with psoriasis. Izokibep is a unique IL-17A inhibitor with a small molecular size and favourable distribution to sites of inflammation. OBJECTIVES: To evaluate the dose response, efficacy and safety of izokibep in patients with plaque psoriasis. METHODS: In this double-blind, randomized, phase II dose-finding study (AFFIRM-35) in adults with moderate-to-severe plaque psoriasis and inadequate response to two or more standard therapies, patients were randomized (1:1:1:1:1) to placebo or izokibep 2, 20, 80 or 160 mg every 2 weeks for 12 weeks. During the remainder of the 52-week core study, patients given placebo were switched to izokibep 80 mg, and dosing intervals were adapted based on Psoriasis Area and Severity Index (PASI) scores for all patients. The core study was followed by two optional consecutive 1-year extension periods for a total duration of 3 years. The primary endpoint was a 90% reduction in PASI score (PASI 90) at week 12. Additional efficacy outcomes and adverse event (AE) rates were evaluated. RESULTS: In total, 109 patients were randomized [safety set, n = 108 (one exclusion criteria failure); full analysis set, n = 106]. At week 12, PASI 90 response rates were 0%, 5%, 19%, 71% and 59% for the placebo, 2-, 20-, 80- and 160-mg izokibep groups, respectively. Rapid dose-dependent improvements were also observed across other efficacy outcomes. During the placebo-controlled period, AEs in the izokibep groups were similar to placebo except for mild injection site reactions. AEs were generally mild to moderate and the drug was well tolerated. Izokibep maintained efficacy at the higher dosage groups for up to 3 years, with no new safety signals. CONCLUSIONS: Data from this phase II study indicate that izokibep is well tolerated and efficacious in the treatment of plaque psoriasis. Higher doses or more frequent dosing could be explored to further enhance response rates.

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.

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. What is already known about this topic? Acne vulgaris, one of the most common dermatological diseases, affects more than 85% of adolescents. There is a medical need for innovative and safe treatment of acne vulgaris. The peroxisome proliferator-activated receptor-γ (PPARγ) is involved in lipid metabolism and specifically in cell differentiation, sebum production and the inflammatory reaction. What does this study add? N-acetyl-GED-0507-34-LEVO (NAC-GED 5%), a PPARγ modulator, significantly improves acne manifestations in patients with moderate-to-severe acne and is safe and well tolerated. The results suggest that the PPARγ receptor is a novel therapeutic target for acne. The results provide a basis for a large phase III trial to assess the effectiveness and safety profile of NAC-GED in combating a disease that afflicts 80-90% of adolescents.