Hereditary Hemorrhagic Telangiectasia

This is a Phase 1/2, randomized, double-blind, placebo-controlled, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of subcutaneously administered DIAG723 in adult patients with hereditary hemorrhagic telangiectasia (HHT). The study consists of three parts: Part A (dose escalation): Single ascending subcutaneous doses of DIAG723 are evaluated in sequential cohorts to assess safety, tolerability, and pharmacokinetics. Part B (dose expansion): Multiple doses of DIAG723 administered over 13 weeks are evaluated in patients with HHT to assess safety and preliminary efficacy. Part C (dose expansion): Multiple doses of DIAG723 administered over 13 weeks are evaluated in patients with HHT and concomitant pulmonary arterial hypertension to assess safety and exploratory clinical effects in this population. Participants will be randomized within each study part to receive DIAG723 or placebo. The study includes dose escalation in Part A and dose expansion in Parts B and C.

The purpose of this study is to: * evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of ALN-6400 in healthy volunteers * evaluate the efficacy, safety, tolerability and PD of multiple doses of ALN-6400 in adult patients with HHT

Hereditary haemorrhagic telangiectasia (HHT) is a rare autosomal dominant genetic disease associated with mutations in genes encoding proteins of the transforming growth factor β (TGF-β) family, i.e. endoglin (ENG), activin receptor A (ACVRL1), and SMAD 4 (small mother against decapentaplegic 4). Mutations in any of these genes lead to the onset of arteriovenous malformations (AVMs). The clinical consequences of this syndrome are primarily AVM-associated complications. Major cardiovascular consequences occur in the more advanced stages, but their prevalence is low. Most HHT patients are asymptomatic, and ischemic heart disease has a significantly lower prevalence than in the general population. The limited sample size of studies currently published in the literature makes it difficult to characterize any subclinical cardiovascular alterations in asymptomatic HHT subjects. Alterations in TGF-β family proteins likely result in a protective effect on the coronary circulation against atherosclerosis. A thorough understanding of the potential protective factors against coronary artery disease, underlying HHT alterations, may allow the development of gene therapy models inspired by the HHT phenotype. Some manifestations of extracellular matrix remodelling at the tissue level (i.e. myocardial and valvular) may be more prevalent in HHT patients than in the general population. Finally, any subclinical alterations in cardiac function related to chronic anaemia and possible iron overload due to iron replacement therapy are not yet known. Primary objective of the study will be to perform a complete echocardiographic characterization, using new imaging methods aimed at identifying even subclinical dysfunctions of cardiac mechanics, including a phenotyping of the morphology and function of the valvular systems, as well as paradoxical shunts. Secondary objectives of the study will be: 1) To verify whether there are echocardiographic differences, related to extracellular matrix remodelling, in addition to the presence of shunts, between the various HHT genotypes and to identify any genotype-phenotype correlations. 2)To verify the impact of chronic anaemia and iron supplementation on cardiac mechanics in relation to possible genotype-phenotype interactions. About study methodology, collection and analysis of clinical and echocardiographic data will be obtained from routine cardiac assessments performed as part of the HHT clinical-care pathway.

The Comprehensive HHT Outcomes Registry of the United States (CHORUS) is an observational registry of patients diagnosed with Hereditary Hemorrhagic Telangiectasia (HHT). The purpose of this study is to better understand HHT, the symptoms and complications it causes, and the impact the disease has on people's lives. The investigators will collect long-term information about the participant, allowing us to understand how the disease changes over time, and what factors can influence those changes. Ultimately, this should help improve treatments for the disease. Another important goal of the study is to provide a way to contact people to participate in future clinical trials and other research. The registry will be a centralized resource for recruitment for clinical trials. People in the registry will not be obligated to join any of these additional studies, but if interested, can agree to be contacted if they may be eligible for a study. Participants will: * Be asked to provide permission to collect information from their medical records, including things like demographic information, diagnosis information, family history, test results, treatment information, symptoms, complications, lifestyle and other relevant medical information. * Be asked study-related questions by phone or at a clinic visit. * Be asked study-related questions every year after enrollment for up to 10 years or until the study ends. A member of the study team will communicate with participants by phone or at clinic visits to collect information regarding any changes to their health over the previous year/s including new test results, treatment information, symptoms, and complications from HHT.

The goal of this clinical trial is to evaluate in real life, in patients with Hereditary Hemorrhagic Telangiectasia (HHT), the tolerance of the strategy of use of anticoagulant and/or antiplatelet, by comparing a new exposure period (first trimester of treatment) to a period of reference non-exposure (last trimester before start of treatment).

Patients with hereditary hemorrhagic telangiectasia (HHT) suffer from an inherited disorder leading to systemic vascular malformations. Mutations in several genes of the transforming growth factor (TGF)-β superfamily pathway influence angiogenesis in patients with HHT. The genetic loss of ALK1 or ENG alone are not sufficient to induce AVMs; environmental insults that could trigger angiogenesis (e.g. wounding) are also needed. In this study it will be analyzed if hypoxic induced factors could have an influence on the disease HHT.