Emerging novel therapies for the treatment of hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia is the second most common heritable bleeding disorder worldwide, with a prevalence more than twice that of haemophilia, and is the most morbid inherited bleeding disorder of women. As an autosomal dominant vasculopathy due to dysregulated angiogenic signalling, patients with hereditary haemorrhagic telangiectasia develop telangiectasias and arteriovenous malformations which cause numerous complications. These complications include moderate-to-severe chronic epistaxis, gastrointestinal bleeding, iron deficiency anemia, and requirement for intravenous iron or red cell transfusion. Additionally, incidence of intracranial haemorrhage is high and morbid non-bleeding complications, such as venous thromboembolism, stroke, and liver disease, are common. Despite this serious disease burden, hereditary haemorrhagic telangiectasia remains without licensed therapies worldwide. However, many novel, investigational agents targeting vascular and haemostatic systems are now rapidly undergoing formal development specifically in hereditary haemorrhagic telangiectasia. These agents include the selective AKT1/AKT2 inhibitor engasertib, AKT1-selective inhibitors ATV-1601 and TER-4480, plasminogen siRNA agent ALN-6400, activin receptor-like kinase 1-bone morphogenetic protein receptor type II (ALK1-BMPRII) bispecific clustering antibody DIAG723, and apelin receptor antagonist antibody TX2100. This comprehensive Review provides essential background information and illustrations summarising relevant hereditary haemorrhagic telangiectasia pathophysiology, followed by focused, detailed discussions of each of the novel agents in development, including the mechanisms, therapeutic rationale, clinical trial programmes, and potential therapeutic effects.