A Phase 2a Double-Blind, Placebo-Controlled, Randomized Clinical Trial Evaluating the Efficacy and Safety of NuGel, a Novel Topical GPCR19-Mediated Inflammasome Inhibitor, in Patients with Mild to Moderate Atopic Dermatitis: A Proof-of-Concept Study with Post-Hoc Biomarker Analysis

Gyeong Ho Baek¹Bo Ri Kim¹Jung-Won Shin¹Chang Hun Huh¹Jungjoong Hwang²Sungmin Ko²Siwon Kim²Pil-Su Ho²Kyu-Han Kim³Chun Wook Park⁴Seong Jun Seo⁵Chang Ook Park⁶Dongyoon Shin⁷Yeongshin Kim^7,8Youngsoo Kim^7,8Seung-Yong Seong^9*Jung-Im Na^1*

• ¹Department of Dermatology, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi, Republic of Korea
• ²Shaperon Inc., Seoul, Republic of Korea
• ³Department of Dermatology, Seoul National University Hospital, Seoul, Republic of Korea
• ⁴Hallym University Kangnam Sacred Heart Hospital, Seoul, Republic of Korea
• ⁵College of Medicine, Chung-Ang University, Seoul, Seoul, Republic of Korea
• ⁶Severance Hospital, College of Medicine, Yonsei University, Seoul, Seoul, Republic of Korea
• ⁷Proteomics Research Team, CHA Institute of Future Medicine, Seongnam, Republic of Korea
• ⁸Department of Biomedical Science, School of Medicine, CHA Univeristy, Seongnam, Gyeonggi, Republic of Korea
• ⁹Department of Microbiology and Immunology, Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Seoul, Republic of Korea

Current guidelines to treat atopic dermatitis (AD) overlook disease heterogeneity, limiting personalized care. This study assessed NuGel, a topical GPCR19 agonist, for efficacy, safety, and predictive baseline biomarkers in AD patients.In a multicenter, double-blind, randomized, placebo-controlled Phase 2a trial (August 2020-September 2021, five hospitals, 80 participants), patients received placebo, 0.3% NuGel, or 0.5% NuGel twice daily for four weeks.NuGel (0.3% [Nu0.3] and 0.5% [Nu0.5]) was well-tolerated, with no adverse drug reactions or serious adverse events. Nu0.3 showed a significant decrease in EASI score from baseline (-12.2%, [-30.3%, 5.9%], p = 0.04). Treatment with Nu0.5 resulted in a numerically decreased EASI score (-11.9%, [-34.9%, 11.1%], p > 0.05), which is comparable with placebo group (-2.9%, [-21.5%, 15.6%], p > 0.05). No significant difference was observed between groups (p>0.05). Plasma proteomic analysis identified biomarkers associated with blood coagulation, complement activation, and cell adhesion as predictors of response to Nu0.5. Patients with baseline profiles characterized by K2C5 high , ENTP6 low , or CRK low demonstrated significant clinical improvement when treated with Nu0.5 compared to the placebo group. Among these, the CRK low subgroup, comprising 54.3% of the biomarker analysis set, showed a ΔEASI of -61.3% [-99.9, -22.8; p = 0.003] and a ΔIGA of -35.2% [-58.2, -12.1; p = 0.004] compared to the placebo group. The biomarker signature demonstrated high predictive accuracy (AUC = 0.92, p = 0.002). Logistic regression analysis revealed that the threshold of predicted probability derived from the baseline plasma level of K2C5 and ENTP6 successfully stratified 100% of participants who responded to Nu0.5 (ΔEASI from baseline ≤ -50%), whereas none (0%) in the placebo group responded (p = 0.035).Baseline biomarkers, such as K2C5, ENTP6, and CRK, may serve as predictors of clinical improvement in AD patients treated with Nu0.5, highlighting the potential for personalized treatment strategies. Further research is required to validate these findings in larger patient cohorts.Clinical trial registration: https://clinicaltrials.gov/, identifier: NCT04530643.