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

Abstract

BackgroundDupuytren'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.MethodsPatients 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).FindingsWe 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.InterpretationIn 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.FundingHealth Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP.

Cytokine Targeted Therapy for Dupuytren's Disease

“…Previous reports suggest an increased proportion of type III collagen in earlier lesions, which changes to a greater proportion of type I collagen at later stages of the disease [ 8 ]. In the present study, the authors reported that TNF inhibition decreased the protein expression of procollagen type I but no differences were noted in procollagen type III levels due to the low sensitivity of the assay for procollagen type III [ 7 ]. TNF inhibition also did not reduce nodule size or hardness, which is not unexpected as the injection was administered only on one occasion.…”

“…In vitro studies also showed that neutralizing antibodies to TNF downregulates myofibroblast activity [ 6 ]. In EBioMedicine , Nanchahal and colleagues identified TNF as a potential target for clinical translation to treat DD [ 7 ].…”

“…The study reports a phase 2a double-blind, randomized placebo-controlled clinical trial on the efficacy of injecting nodules of DD with adalimumab, a TNF inhibitor [ 7 ]. The authors should be applauded for choosing a local delivery route via intra-nodular injection to assess the efficacy of a biologic, which might become routine in the future to avoid the necessity for surgical procedure.…”

Pharmacological Treatment of Fibrosis: a Systematic Review of Clinical Trials

“…A different approach to the pharmacological treatment of Dupuytren's disease involves targeting TNF with the monoclonal antibody adalimumab. In a phase II placebo-controlled dose-response study, patients with Dupuytren's disease were randomized to receive different dosages of adalimumab or equivalent volumes of saline [112]. After two weeks from intranodular injection, patients who received the highest dose (40 mg) of adalimumab showed significant reductions in α-SMA and procollagen I protein levels, compatible with an inhibition of the myofibroblast phenotype.…”

Could coenzyme Q10 be the treatment for Dupuytren’s disease?

“…They applied different approaches to establish TNF blockade in the tissue samples and rated the antitumour necrosis factor agents adalimumab and golimumab as most promising 4. This work was continued in a randomised dose response proof of concept phase 2a clinical trial 5. The effect of locally injected escalating doses of adalimumab was compared with corresponding volumes of placebo in surgical excised tissue 2 weeks after the injections.…”