Phase Ib Study Of Hs135, A Novel Activin And Gdf Inhibitor, In Patients With Obesity-related Heart Failure With Preserved Ejection Fraction And Pulmonary Hypertension Leveraging Remote Pulmonary Artery Pressure Monitoring Technology

Abstract

Rationale

Heart failure (HF) with preserved ejection fraction (HFpEF) has become the predominant type of HF. Obesity-related HFpEF is the most common phenotype, associated with an especially high burden of symptoms and physical limitations, and a poor quality of life. Pulmonary hypertension (PH) is a common feature of obesity-related HFpEF. HS135 is a novel decoy trap for Activins and Growth Differentiation Factors (GDFs), including myostatin, which are genetically and clinically validated targets in PH, obesity, and HF. HS135 is differentiated from other Activin and GDF targeting mechanisms via its potential for best-in-class multi-specific potency which results in increased therapeutic window and qualitatively differentiated efficacy in PH, HF and body composition in pre-clinical models. Therefore, HS135 holds promise as a potential novel treatment option for patients with obesity-related HFpEF and PH. HS135-003 is a Phase 1b clinical trial to assess the preliminary safety and efficacy of HS135 in patients with PH and HFpEF (PH-HFpEF). The innovative trial design employs remote pulmonary artery (PA) pressure sensor technology which allows for frequent monitoring of PH-related hemodynamics.

Methods

This ongoing, randomized, double-blind, placebo-controlled, multiple ascending dose study is actively enrolling up to 40 adult male and female patients diagnosed with PH-HFpEF at centers in the US. Patients with a CardioMEMS™ HF System implanted as a part of standard care and a BMI of ≥30 kg/m² are eligible. Several dose levels of subcutaneous HS135 will be explored in sequential fashion with a primary endpoint of safety. Secondary endpoints will include change from baseline up to week 24 in mean PA pressure and mean PA diastolic pressure measured using CardioMEMS™. Additional assessments of hemodynamics, patient-reported symptoms and physical limitations, exercise function, as well as echocardiographic, morphological, body composition and biomarker measurements will be assessed. Patients who desire and can benefit from HS135 therapy will be offered to enter an open label extension period upon completion of the initial treatment period.

Results

In progress.

Conclusion

This is a Phase 1b trial in progress to assess the preliminary safety and efficacy of the novel Activin and GDF inhibitor HS135 in obese patients with PH-HFpEF. Ambulatory PA pressure measurements in addition to patient-reported outcomes, measures of exercise function, biomarker and body composition endpoints are expected to provide valuable data to evaluate safety, identify efficacy signals and inform further development.