Is Pirfenidone effective and safe in neonates with cardiac fibrosis?

Doctor Beth Allison, Monash University

Vanguard Grant

Years funded: 2026 - 2027

Being born growth-restricted increases lifelong risk of cardiovascular disease. A large body of work, including ours, demonstrates that the cardiovascular system of growth-restricted infants is structurally and functionally distinct from normally grown. In novel work, we have shown persistent increases in intramyocardial vascular collagen in growth-restricted neonates, suggesting early-onset perivascular fibrosis, likely driven by antenatal hypoxia. This maladaptive remodelling may impair myocardial perfusion, reduce vascular compliance, and contribute to the long-term cardiovascular dysfunction seen in growth-restricted newborns. Given that overt cardiovascular dysfunction is not yet evident in these neonates, we have a critical early therapeutic window to prevent progressive cardiac injury.

Pirfenidone is a promising anti-fibrotic therapy with proven efficacy in adult fibrotic disease. Pirfenidone targets inflammatory and fibrotic pathways relevant to neonatal cardiac remodelling, making it an ideal candidate for repurposing in this vulnerable population where no targeted therapies currently exist. Our project aims to demonstrate that our novel therapy, pirfenidone reduced perivascular fibrosis and inflammation in the heart and therefore improving cardiac function at the molecular, structural, and functional levels.

We have an established, large-animal preclinical model of fetal growth restriction that displays critical hallmarks of cardiovascular disease in the neonatal period including, perivascular fibrosis, endothelial dysfunction and right ventricular remodelling. We have assembled a specialist team who together, have the expertise to demonstrate that our novel therapy can be efficacious in FGR neonates. To achieve our aims, we will assess cardiac function in vivo and in vitro (wire myography, langendorff), structure (echo) and cellular mechanisms (RNASeq) in FGR neonates with the novel and current standard treatment. The outcomes of this study will provide fundamental evidence derived from a clinically relevant model that will be used by the team to support our next steps for a larger grant application to assess long-term cardiovascular disease modification and safety of pirfenidone, setting the stage for clinical trials.

Aim: To determine whether postnatal pirfenidone reduces myocardial vascular fibrosis in FGR neonates.

Methods: Using a well-established ovine model of placental insufficiency-induced FGR, we will administer pirfenidone in the early postnatal period and assess cardiovascular histology, gene expression profiling, and functional outcomes and imaging. We will define both the efficacy and safety of treatment during critical periods of cardiovascular development.

Significance: This study addresses a major clinical gap by targeting the earliest stages of cardiovascular disease programming in growth-restricted neonates. Our findings will lay the foundation for future studies of pirfenidone in neonates.