ALG-801 demonstrates superior therapeutic efficacy in sugen-hypoxia model of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance, leading to chronic elevation in pulmonary arterial pressure, right-sided heart failure, and premature death. Despite many available therapies over the last two decades, survival has remained poor with a median transplant‐free survival of approximately six years. ALG-801 is a novel ligand trap designed to selectively sequester a subset of TGF-beta family that critically mediates PAH pathogenesis. ALG-801 potently neutralizes Smad2/3-signaling ligands, including activins and GDF8 (myostatin), and completely spares BMP9, a key Smad1/5/8-signaling ligand, whose function is essential for vascular homeostasis. In Phase 1 trials, ALG-801 has been shown to be safe and well-tolerated across all dosing cohorts and elicit strong pharmacodynamic and biomarker responses. To evaluate ALG-801’s potential to treat pulmonary hypertension, we compared its therapeutic efficacy with sildenafil and sotatercept (ActRIIA-Fc), both approved for use in patients with PAH, in Sugen-Hypoxia (SuHx) rats, a disease model for PAH. In this model, ALG-801 more effectively lowered pulmonary vascular resistance and right ventricular systolic pressure, reduced right ventricular hypertrophy and the Fulton index, decreased pulmonary arteriole muscularization, ameliorated histopathological lesions in the lung, normalized circulating BNP levels, and extended survival. These findings demonstrate that in SuHx PAH model, ALG-801 has a significantly better efficacy than sildenafil or sotatercept. ALG-801 holds a promising potential for treating pulmonary hypertension.