RESUMO
BACKGROUND: Palmoplantar pustulosis (PPP), a refractory skin disease characterized by repeated eruptions of sterile pustules and vesicles on palms and/or soles, involves interleukin-17 pathway activation. Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, is being investigated for use in PPP treatment. OBJECTIVE: The aim was to assess the efficacy and safety of brodalumab in Japanese PPP patients with moderate or severe pustules/vesicles. METHODS: A phase 3, randomized, double-blind, placebo-controlled trial was conducted between July 2019 and August 2022, at 41 centers in Japan. Patients aged 18-70 years with a diagnosis of PPP for ≥ 24 weeks, a PPP Area Severity Index (PPPASI) score of ≥ 12, a PPPASI subscore of pustules/vesicles of ≥ 2, and inadequate response to therapy were included. Participants were randomized 1:1 to receive brodalumab 210 mg or placebo, subcutaneously (SC) at baseline, weeks 1 and 2, and every 2 weeks (Q2W) thereafter until week 16. Changes from baseline to week 16 in the PPPASI total score (primary endpoint) and other secondary skin-related endpoints and safety endpoints were assessed. RESULTS: Of the 126 randomized patients, 50 of 63 in the brodalumab group and 62 of 63 in the placebo group completed the 16-week period. Reasons for discontinuation were adverse event (n = 6), withdrawal by patient/parent/guardian (n = 3), progressive disease (n = 3), and lost to follow-up (n = 1) in the brodalumab group and Good Clinical Practice deviation (n = 1) in the placebo group. Change from baseline in the PPPASI total score at week 16 was significantly higher (p = 0.0049) with brodalumab (least-squares mean [95% confidence interval {CI}] 13.73 [10.91-16.56]) versus placebo (8.45 [5.76-11.13]; difference [95% CI] 5.29 [1.64-8.94]). At week 16, brodalumab showed a trend of rapid improvement versus placebo for PPPASI-50/75/90 response (≥ 50%/75%/90% improvement from baseline) and Physician's Global Assessment 0/1 score: 54% versus 24.2%, 36.0% versus 8.1%, 16.0% versus 0.0%, and 32.0% versus 9.7%, respectively. Infection was the dominant treatment-emergent adverse event (TEAE); the commonly reported TEAEs were otitis externa (25.4%/1.6%), folliculitis (15.9%/3.2%), nasopharyngitis (14.3%/4.8%), and eczema (14.3%/12.9%) in the brodalumab/placebo groups, respectively. The severity of most TEAEs reported was Grade 1 or 2 and less frequently Grade ≥ 3. CONCLUSIONS: Brodalumab SC 210 mg Q2W demonstrated efficacy in Japanese PPP patients. The most common TEAEs were mild infectious events. TRIAL REGISTRATION: NCT04061252 (Date of Trial Registration: August 19, 2019).
RESUMO
BACKGROUND: KHK4083, a fully human anti-OX40 monoclonal antibody, is a potential novel therapeutic option for moderate to severe atopic dermatitis (AD), targeting the immunopathogenic pathways. OBJECTIVE: Assess the safety and tolerability of repeated doses of KHK4083 in patients with moderate to severe AD, and investigate the pharmacokinetics and immunogenicity of KHK4083. Additionally, assess the clinical efficacy and pharmacodynamics as exploratory objectives. METHODS: In this phase 1, single-center, open-label, repeated-dose study, a total of 22 patients received KHK4083 10 mg/kg IV on Day 1, Day 15 and Day 29, and were followed until Day 155. RESULTS: There were no deaths, serious adverse events (SAEs), or discontinuations due to adverse events (AEs). Common treatment-emergent AEs were mild or moderate pyrexia (11 patients, 50.0 %), and chills (8 patients, 36.4 %). No clinically meaningful changes in the laboratory values, vital signs, and electrocardiogram recordings were observed. The Cmax was 267 ± 53 µg/mL and the t1/2 was 303 ± 88 h at Day 29. The overall assessment of antibodies against KHK4083 (immunogenicity) showed low positive responses. Continued improvement in the Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA) scores were observed throughout the study. The mean and median percent changes in thymus and activation-regulated chemokine (TARC) continued to decrease over time to -70.4 and -78.8 % until Day 155. CONCLUSION: Repeated intravenous infusion of KHK4083 had an acceptable safety profile in patients with moderate to severe AD. Sustained improvement in the symptoms of AD was observed after completion of KHK4083 treatment.
