Small Molecule Apelin Receptor agonists for teh treatment of Heart Failure in PAH

SUMMARY The apelin receptorAPLNRagonist program project is seeking to discover an orally active small molecule drug to preserve and improve the heart s right ventricularRVfunction in patients suffering from pulmonary arterial hypertensionPAHa devastating disease with high morbidity and mortalityThere is compelling evidence that RV function is a major determinant of clinical outcomes in PAH patientsDespite thisnone of the current therapies directly improve RV functionperhaps explaining the lack of convincing evidence of a reduction in mortality with any of the current therapeutic mechanismsImpaired apelin APLNR signaling has been found in multiple preclinical and clinical studies to be associated with pathogenesis of PAH and RV failureand infusion of apelin peptide has been found to significantly improve cardiac output without any demonstrated adverse effectsAny potential therapeutic use of the peptide itselfhoweveris limited by its extremely short halflifeestimated to be less thanmin in serumA therapeuticsmall molecule based alternative that can robustly activate APLNR signaling and afford comparable clinical benefits as the peptide long term would represent a potential paradigm shift in our management of patients with PAH and RV failureOur chemistry program will use structure based drug design to improve the pharmacokinetics and drug properties of a published small molecule APLNR agonist with a longer half life in animalsthat also demonstrated robust in vivo activity in single dose acute studiesUsing a recently developed robust model of pulmonary hypertension in which the RV undergoes severepathologic remodeling in ratswe will investigate the therapeutic efficacy of our improved APLNR agonistswith planned advancement into a robust pig based RV failure study in the Phase II of this Program upon the successful completion of Phase I NARRATIVE Our apelin receptor agonist program project is seeking to discover an orally active small molecule drug to preserve and improve the heart s right ventricular function in patients suffering from pulmonary arterial hypertensionNone of the existing drugs for this devastating disease can improve the right ventricular functionand our program has the potential to achieve this paradigm shifting milestone that can improve the clinical outcomes in this patient population