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Developments in Dupuytren’s disease
CAMBRIDGE, Mass.—180 Therapeutics LP has announced positive results from a Phase 2a clinical trial of the anti-TNF monoclonal antibody, adalimumab, in patients suffering from Dupuytren’s disease. The results were published in an article in EBioMedicine, published by The Lancet. Dupuytren’s disease is a fibrotic condition of the hand which causes the fingers to contract towards the palm, leading to discomfort, pain and loss of hand function and mobility, in severe cases, possibly even necessitating digit amputation. Dupuytren’s disease affects approximately 4% of the population of Western Europe and the USA, and pharmaceutical treatment is limited.
“Whilst the mainstay of treatment remains surgical excision (fasciectomy) of the diseased tissue or cords, approximately 40% of patients in the USA are treated by disruption of the cords using collagenase or needle fasciotomy. Generally patients undergo these treatments when digits are flexed to 30° or more and hand function is impaired. The recurrence rate following surgery is 21% within 5 years and these individuals may require more extensive surgery involving excision of the diseased tissue and overlying skin (dermofasciectomy). Post-operatively, some patients require prolonged hand therapy and splintage. Complications occur in approximately 20% of patients undergoing surgery,” according to the article.
“Alternative, less invasive techniques to disrupt the cords with a needle or collagenase digestion are associated with rapid recovery of hand function with minimal therapy. However, recurrence rates are high, affecting 85% of patients treated with percutaneous needle aponeurotomy and 32% of those treated with collagenase at 5 years. The complication rate is 20% following needle aponeurotomy and over 70% after collagenase injection, the majority being minor and mostly transient,” the article continues. “The ideal therapy would be directed towards patients with early stage disease to prevent progression to development of cords and subsequent flexion contractures of the digits. Our systematic review highlighted the lack of robust evidence for treatments proposed for early stage DD for which there is currently no approved therapy.”
Research by the scientific founders of 180 Therapeutics, Professors Sir Marc Feldmann and Jagdeep Nanchahal, MD, PhD, uncovered the role of tumor necrosis factor (TNF) in driving the development and activity of myofibroblasts, the cells responsible for the fibrosis that cause the fingers of patients with Dupuytren’s disease to curl irreversibly into the palm. The Phase 2a clinical trial was conducted by researchers at the Kennedy Institute, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK, working with clinicians at NHS Lothian, Scotland.
The randomized, dose response, placebo-controlled Phase 2a trial recruited 28 patients with Dupuytren’s disease who were scheduled to receive elective surgery to remove diseased tissue from their hands. Two weeks prior to surgery, patients received a single injection of the anti-TNF drug adalimumab at various dose levels, or placebo. The tissue removed during surgery was then analyzed in the laboratory. Adalimumab, at a dose of 40mg, reduced expression of the fibrotic markers, α-smooth muscle actin (α-SMA) and type I procollagen proteins, at 2 weeks post injection, suggesting anti-TNF therapy may have utility in treating early Dupuytren’s disease by preventing activity of disease causing myofibroblast cells. The treatment was found to be well-tolerated.
“Our results show that two weeks following administration of 40 mg of adalimumab in 0.4 ml into Dupuytren's nodules there was down regulation of the myofibroblast phenotype as evidenced by lower expression of α-SMA and pro-collagen type I proteins,” the article notes. “These findings represent the clinical translation of our in vitro data based on human tissue where we showed that tumour necrosis factor (TNF) selectively converts precursor palmar fibroblasts from Dupuytren's patients to myofibroblasts via the Wnt signalling pathway, and anti-TNF is inhibitory. Like all fibrotic conditions, Dupuytren’s disease is characterised by the deposition of excessive collagenous extracellular matrix which is remodelled and contracted by α-SMA-expressing myofibroblasts, that aggregate in nodules.”
“Our study has demonstrated that the anti-TNF drug, adalimumab, injected directly into the diseased tissue of patients may be effective in targeting the pro-fibrotic myofibroblast cells responsible for Dupuytren’s disease,” explained Jagdeep Nanchahal, MD, PhD, University of Oxford Professor of Hand, Plastic and Reconstructive Surgery, who led the study. “This brings new hope to people who suffer from this common disabling condition, with its frequent recurrences, who currently have few treatment options other than surgery or collagenase for late stage disease.”
The study was supported by the Wellcome Trust, UK Department of Health and 180 Therapeutics. Based on these clinical Phase 2a findings, the company, together with the Wellcome Trust and Department of Health, is now supporting a Phase 2b clinical trial of adalimumab injected directly into the fibrotic nodules of patients with early stage Dupuytren’s disease, which will assess efficacy to retard disease progression over 18 months.
“Based on results so far we are very optimistic about the likelihood of clinical efficacy in our ongoing Dupuytren’s Phase 2b clinical study. This is because our approach has been based on investigating human diseased tissue in the lab, the same approach which provided the rationale for the translational path we pioneered in rheumatoid arthritis which showed the first dramatic clinical benefit of anti-TNF in patients afflicted with rheumatoid arthritis,” said Professor Sir Marc Feldmann, co-founder of 180 Therapeutics and a Lasker Award winner.