439 Patients with mild to moderate atopic dermatitis: a first-in-human, open-label, dose-escalating, nonrandomized clinical trial with AMTX-100

Abstract

Abstract Atopic dermatitis (AD) is a chronic skin disease that affects approximately 10% of the global population and is characterized by epidermal disruption, microbial invasion, intense pruritus and cytokine mediated inflammation. The pathogenesis of AD is primarily associated with Type 2 immune responses, including the elevated expression of Th2 cytokines such as IL-4, IL-5, IL-13 and IL-31; however, studies have demonstrated roles for epithelial cell-derived cytokines (IL-25, IL-33 and thymic stromal lymphopoietin) and Type 3 immune responses (IL-17, IL-22 and IL-23). Given that AD is a heterogeneous disease with potential for the activation of multiple cytokines at once, there is a growing interest in multi-factorial approaches to therapeutic intervention. Evidence indicates that transcription of many genes overexpressed in AD is controlled predominantly by stress responsive transcription factors (SRTFs) like nuclear factor-kB (NF-kB), the master regulator of inflammation. Nuclear factor-kB is translocated from cytoplasm to the nucleus by a complex of two nuclear transport shuttles, importin α5 (IMPα5) and importin β1 (IMPβ1) after docking of the nuclear localization sequences (NLS) of NF-kB with its binding domain on IMPα5. Once in the nucleus, NF-kB activates genes containing its DNA consensus sequence producing mRNA, which are translated into proteins. AMTX-100 is a novel, chimeric, 100% human, 28-amino acid peptide that contains cell-penetrating sequences at its amino terminal end derived from the fibroblast growth factor 4 signal sequence and a small stretch of the NF-kB amino acid sequences containing an NLS involved in nuclear transport of large transcription factors (SRTFs) that contain a similar NLS. This study aims to identify the maximum tolerated dose, safety, tolerability and efficacy of topically applied AMTX-100 CF 1.1% in adult patients with mild to moderate AD. AMTX-100 CF 1.1% was administered topically twice daily for 7 days at five dose levels. Each patient’s first dose was administered at the study clinic by trained site staff. Remaining doses were self-administered by patients at home. The applied amount of AMTX-100 CF 1.1% depended on the percentage of the body surface area (BSA) affected with AD. The primary and safety endpoints were evaluating maximum dose toxicity and treatment-emergent adverse events. Exploratory endpoints were percent change from baseline of the treated BSA and validated Investigator Global Assessments (vIGA) at Days 7 and 21. This open-label, dose-escalation clinical trial was conducted between March 3, 2020 and October 7, 2021, at four clinical centers in the USA. The study included an up to 21-day screening, 7-day treatment and 14-day follow-up period. Thirty-five patients were assessed for eligibility: nine were excluded and 26 were enrolled. Eligible patients were at least 18 years old with mild to moderate AD diagnosed for at least 6 months prior to enrollment. Patients were referred from sites’ databases and outpatient centers. No dose limiting toxicities, treatment-related AEs, serious AEs or significant changes in laboratory measurements occurred in any cohorts. The mean BSA affected by AD decreased from baseline at the end of treatment visit and follow-up visit by 37.5% (P = 0.001) and 37.9% (P = 0.027), respectively. Across study cohorts, vIGA-AD scores improved after intervention. The findings for this Phase I portion of an Adaptive Phase I/II protocol provides support for safety, tolerability and efficacy of AMTX-100 CF 1.1% in adult patients with mild to moderate AD. AMTX-100 CF 1.1% has advanced into Phase II study including safety, efficacy, gene expression (skin and blood) and proteomics (blood) measurements throughout the study.