PERFECT-FIT

Pulmonary Hypertension (PH), particularly Pulmonary Arterial Hypertension (PAH), presents a fatal complication in chronic diseases, affecting 1 in 50,000 individuals, predominantly at a young age and more often in females. The underlying genetic link involves mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, disrupting BMP signaling. The PHAEDRA-IMPACT consortium aims to understand PH and PAH. The Research The research focuses on understanding PAH through the transforming growth factor-β (TGFβ) signaling pathway, particularly influenced by mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, prevalent in heritable and some non-hereditary PAH cases. The PHAEDRA initiative identified compounds that modulate the TGFβ/BMP balance, showing efficacy in restoring endothelial function and reversing pulmonary vascular remodeling in preclinical models, though not curing PAH, making early detection crucial. PHAEDRA has identified biomarkers for timely diagnosis and personalized treatment. PHAEDRA-IMPACT will enhance early detection using non-invasive risk assessments, imaging, and biomarker profiling to detect pre-capillary PH. Precision medicine will guide tailored therapies based on advanced imaging and biomarker analyses, addressing disease progression variability among predisposed individuals. Additionally, patient-derived induced pluripotent stem (iPS) cells will be used in 3D culture models of lung and heart tissues to uncover PAH mechanisms and identify therapeutic targets. This comprehensive approach aims to advance our understanding of PAH pathogenesis, accelerate drug development, and enable personalized treatment and preventive strategies for individuals at risk or affected by PH. Origin This consortium was funded through the Impulse Grant program by the Dutch Heart Foundation.

The aim of the LoDoCo2 (Low Dose Colchicine for secondary prevention of cardiovascular disease) trial was to investigate the effect of low dose colchicine (0,5 mg once daily) on the risk of myocardial infarction (fatal or non-fatal), stroke, or the need for coronary bypass or stent placement. While the precise mechanism through which colchicine mitigates major cardiovascular events remains incompletely understood, it is hypothesized that its anti-inflammatory effects contribute to risk reduction among patients with established atherosclerotic disease. LoDoCo2 stands out in several respects. It represents a large-scale randomized clinical trial conducted entirely by a non-academic network of cardiologists and a consortium of pharmaceutical companies with a focus on drug repurposing. This trial underscores the potential value of older, often cost-effective medications in advancing the development of new innovative drugs. The Research Following a median follow-up period of 3 years, the addition of colchicine to standard treatment resulted in a 30% reduction in risk of myocardial infarction (fatal or non-fatal), stroke, or the need for coronary bypass or stent placement. Patients treated with colchicine exhibited similar side effects compared to those receiving a placebo. Furthermore, no interactions were found with other commonly used drugs such as (potent) statins. In 2021, certain international guidelines had already incorporated colchicine into the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Subsequently, in 2023, the Food and Drug Administration (FDA) approved Lodoco® (colchicine) for reducing the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular (CV) death in adult patients with established atherosclerotic disease or multiple risk factors for CV disease. This approval was based on published data regarding the effects of colchicine on cardiovascular events, along with insights from the LoDoCo2 trial. The LoDoCo2 investigators anticipate that colchicine will become the standard treatment for patients with coronary artery disease. The origin The LoDoCo2 trial is based on based on LoDoCo, a small Australian trial that assessed the benefits of administration of a low dosis colchicine on coronary artery disease (CAD). Colchicine is a relatively inexpensive medication commonly used for the treatment of inflammatory disease, e.g. gout. The LoDoCo2 trial was executed with a similar protocol in Australia and the Netherlands. LoDoCo2 is special in many ways; it is a large randomised clinical trial fully run by a non-academic network of cardiologists (WCN), funded by The Dutch Heart Foundation and ZonMw (Goed Gebruik Geneesmiddelen) and a consortium of pharmaceutical companies with focus on drug repurposing. Although the recruitment of patients already started before the start of the DCVA, the DCVA always has provided strong support, also in the route towards implementation. This drug-repurposing clinical trial shows that a collaborative statement from the DCVA and its partners is needed to change rules and regulations in order to make this effective, safe and cheap old treatment available for patients.