Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial

Abstract

Background: Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor.

Methods: Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40).

Findings: We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug.

Interpretation: In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease.

Funding: Health Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.

Keywords: Adalimumab; Anti-TNF; Dupuyten's disease; Fibrosis; Myofibroblast.

Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1

Trial profile.

Fig. 2

Box and whiskers plot of log RNA concentration by treatment received. The figure is divided into separate plots for each gene assessed. The box represents the inter-quartile range (IQR) and whiskers extend to 1.5 relevant IQR (Tukey boxplot). The x-axis shows individual patients, grouped by treatment received, with the three repeat measures performed for each patient represented by points stacked within the same column.

Fig. 3

Box and whiskers plot of α-SMA protein concentration by treatment received. The box represents the inter-quartile range (IQR), the horizontal line represents the median and whiskers extend to 1.5 relevant IQR. The x-axis shows individual patients, grouped by treatment received. Samples from each patient were analysed in duplicate on three separate plates and the values for each plate are shown as circles, triangles or squares.

Fig. 4

Box and whiskers plot of pro-collagen protein concentration by treatment received. The box represents the inter-quartile range (IQR), the horizontal line represents the median and whiskers extend to 1.5 relevant IQR (Tukey boxplot). The x-axis shows individual patients, grouped by treatment received, with the three repeat measures performed for each patient represented by points stacked within the same column. The plot includes pro-collagen concentrations reported below the minimum detectable range as zero, 3 of 9 in 35 mg and 2 of 6 in 40 mg adalimumab cohorts.