Abstract Body (Do not enter title and authors here): Introduction Faun269g is a ligand gated ion channel discovered using the FaunaBio Platform that shows important protection from hypoxia/reperfusion damage in hibernating lined ground squirrels. FB-1083 a potent and selective orally administered small molecule antagonist of Faun269g which has the potential to treat patients with heart failure with preserved ejection fraction (HFpEF) with pulmonary hypertension (PH). We evaluated FB-1083 in multiple preclinical models of HF-EF and PH.
Methods Human genetic data including UK Biobank and Million Veteran Program were analyzed for target associations to CV diseases. Preclinical studies include in vitro models of compound potency and cardiomyocyte mitochondrial function and in vivo efficacy studies in rodent models of PH (Sugen/hypoxia in Sprague Dawley rats) and HFpEF (aged obese ZSF1 rats) dosed with oral FB-1083 at 10 mg/kg, BID.
Results Human data show a rare noncoding variant in the regulatory region of Faun269g is significantly associated with HFpEF (p = 7.9 × 10^-5). Missense variants in Faun269g are associated with elevated levels of beta-hydroxybutyrate (p = 2.69 × 10^-3), a ketone body known to enhance cardiac output and mitochondrial efficiency. A cis-eQTL associated with increased Faun269g expression correlates with higher PA:A on cardiac MRI (p = 3.7 × 10^-3). Structure-based design was used to invent FB-1083; it inhibits human Faun269g ion channel activity with an IC50 of 0.179 nM that is >5,000-fold selectivity over other related receptors and safety targets. FB-1083 treated human iPSC-derived cardiomyocytes stressed by glucose and oxygen deprivation are protected from loss of cell viability, lowering of ATP/ADP ratio and elevated reactive oxygen species. In the rat Sugen/hypoxia model, FB-1083 significantly reduced mean RVSP by ~50% (p<0.001 vs vehicle) and improved TAPSE (p<0.01). In obese ZSF1 rats, FB-1083 significantly improved diastolic function (E/A ratio, p<0.05; E/e' ratio, p<0.05) and attenuated adverse cardiac remodeling (reduced LVPWd, p<0.05; reduced IVSd, p<0.05) compared to vehicle.
Conclusion Human genomic and preclinical data demonstrate FB-1083’s promising efficacy and safety for treating PH and HFpEF driven, in part, by targeting mitochondrial dysfunction in models of HFpEF and PH.