Oral 11β-HSD1 inhibitor AZD4017 improves wound healing and skin integrity in adults with type 2 diabetes mellitus: a pilot randomized controlled trial.

R A Ajjan,K Shams,L Pegg,L Webber,R J Fairclough,A Abbas,A E Taylor,D A Russell,A W Morgan,F Del Galdo,W Arlt,A Freeman,E M A Hensor,A Tiganescu,P M Stewart,A A Tahrani

doi:10.1530/eje-21-1197

Abstract

BackgroundChronic wounds (e.g. diabetic foot ulcers) reduce the quality of life, yet treatments remain limited. Glucocorticoids (activated by the enzyme 11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1) impair wound healing.ObjectivesEfficacy, safety, and feasibility of 11β-HSD1 inhibition for skin function and wound healing.DesignInvestigator-initiated, double-blind, randomized, placebo-controlled, parallel-group phase 2b pilot trial.MethodsSingle-center secondary care setting. Adults with type 2 diabetes mellitus without foot ulcers were administered 400 mg oral 11β-HSD1 inhibitor AZD4017 (n = 14) or placebo (n = 14) bi-daily for 35 days. Participants underwent 3-mm full-thickness punch skin biopsies at baseline and on day 28; wound healing was monitored after 2 and 7 days. Computer-generated 1:1 randomization was pharmacy-administered. Analysis was descriptive and focused on CI estimation. Of the 36 participants screened, 28 were randomized.ResultsExploratory proof-of-concept efficacy analysis suggested AZD4017 did not inhibit 24-h ex vivoskin 11β-HSD1 activity (primary outcome; difference in percentage conversion per 24 h 1.1% (90% CI: −3.4 to 5.5) but reduced systemic 11β-HSD1 activity by 87% (69–104%). Wound diameter was 34% (7–63%) smaller with AZD4017 at day 2, and 48% (12–85%) smaller after repeat wounding at day 30. AZD4017 improved epidermal integrity but modestly impaired barrier function. Minimal adverse events were comparable to placebo. Recruitment rate, retention, and data completeness were 2.9/month, 27/28, and 95.3%, respectively.ConclusionA phase 2 trial is feasible, and preliminary proof-of-concept data suggests AZD4017 warrants further investigation in conditions of delayed healing, for example in diabetic foot ulcers.Significance statementStress hormone activation by the enzyme 11β-HSD type 1 impairs skin function (e.g. integrity) and delays wound healing in animal models of diabetes, but effects in human skin were previously unknown. Skin function was evaluated in response to treatment with a 11β-HSD type 1 inhibitor (AZD4017), or placebo, in people with type 2 diabetes. Importantly, AZD4017 was safe and well tolerated. This first-in-human randomized, controlled, clinical trial found novel evidence that 11β-HSD type 1 regulates skin function in humans, including improved wound healing, epidermal integrity, and increased water loss. Results warrant further studies in conditions of impaired wound healing, for example, diabetic foot ulcers to evaluate 11β-HSD type 1 as a novel therapeutic target forchronic wounds.

Highlights

80 Chronic, non-healing wounds are a common and worldwide health problem of substantial medical and socioeconomic importance (1)
We recently demonstrated increased 11β-hydroxysteroid dehydrogenase-1 (HSD1) activity during the inflammatory phase of mouse skin wound healing (WH) [22] and faster healing in 11β-HSD1-null mice treated with oral corticosterone and topical application of carbenoxolone (CBX), an 11β-hydroxysteroid dehydrogenase (11β-HSD) non-selective inhibitor
Others have reported accelerated WH by 11β-HSD1 blockade in animal models of diabetes and GC excess [23, 24]. These findings suggest that 11β-HSD1 mediates the effects of circulating GC in skin and drives the cutaneous consequences of GC excess

Summary

Introduction

80 Chronic, non-healing wounds (e.g., diabetic foot ulcers) are a common and worldwide health problem of substantial medical and socioeconomic importance (1). 11β-HSD1 inhibition may aid wound healing, in conditions associated with increased systemic GC levels, such as diabetes (19, 20). Non-healing wounds e.g. diabetic foot ulcers (DFU) are a common worldwide health problem that have substantial medical and socioeconomic importance and represent a major unmet clinical need [1]. Costs for wound care in the UK are estimated at £2.03-3.8 million per 100,000 population [4] and diabetes currently accounts for approximately 10% of the total health resource expenditure and is projected to account for around 17% in 2035/2036 [5]. Adults with type 2 diabetes mellitus without foot ulcers were administered 400mg oral 11β-HSD1 inhibitor AZD4017 (n=14) or placebo

Objectives

Methods

Results

Discussion

Conclusion