HS235 Study in Overweight and Obese Participants With Combined Pre and Post-Capillary Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction

Prior treatment

• Hospitalization for any worsening medical condition or major surgery within 4 weeks prior to screening.
• Occurrence of an acute coronary syndrome, percutaneous coronary intervention, or cardiac surgery within 90 days prior to Screening.
• Implantation of a cardiac resynchronization therapy (CRT) device within 90 days before screening.
• History of serious or life-threatening cardiac arrhythmia within 90 days prior to screening.

Other illness

• History of heart transplant or on heart transplant list.
• Systemic hypotension or uncontrolled systemic hypertension.
• History of Pericardial constriction or hypertrophic cardiomyopathy.
• History of significant valvular stenosis or regurgitation.
• Participants with a pneumonectomy or more than moderate Chronic Obstructive Pulmonary Disease (COPD) or mild interstitial lung disease (ILD) or untreated mild obstructive sleep apnea (OSA).

Other

• Planned cardiovascular revascularization or planned implantation of CRT device.

• Participants are eligible to be included in the study only if they meet at least all the following criteria:
• Male or female, ≥ 18 years of age.
• \[Sub-population A only - using a remote PAP sensor\]- Ambulatory PAP monitoring (e.g., CardioMEMS™ HF System or Cordella™ HF System) implanted in the course of standard of care at least 90 days before Screening.
  • Hemodynamic evidence of PH with:
  • mPAP ≥ 25 mm Hg, as measured by the ambulatory PAP monitoring system in supine position by the averaged 7-day values (weekly average) 2 weeks and 1 week before Randomization AND,
  • dPAP ≥ 15 mm Hg, as measured by the ambulatory PAP monitoring system in supine position by the averaged 7-day values (weekly average) 2 weeks and 1 week before Randomization.
  • Hemodynamic evidence of pre-capillary PH based on presence of PVR ≥ 240 dyn\*sec/cm5 or ≥ 3 WU obtained on most recent RHC obtained prior to screening.
• \[Sub-population B only - without a remote PAP sensor\]
  • Hemodynamic evidence of Cpc-PH based on the presence of all the following RHC parameters obtained during the Screening period, prior to randomization:
  • PVR ≥ 240 dyn\*sec/cm5 or ≥ 3 WU, and
  • mPAP \> 20 mmHg, and
  • PAWP \> 15 mmHg but \< 30 mmHg, and
  • dPAP ≥ 15 mmHg.
• Established diagnosis of HFpEF with left ventricular ejection fraction (LVEF) ≥ 45 % as measured by echocardiography during Screening and and no documented LVEF \< 45% during the 2 years preceding Screening..
• New York Heart Association (NYHA) class II or III heart failure symptoms.
• Stable diuretic regimen during the screening period.
• Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) \< 90 at screening.
• 6-minute walking distance (6MWD) ≥ 100 m at screening.
• Body mass index ≥ 25 to ≤ 50 kg/m2 and Body weight ≤140 kg.
• Ability to adhere to study visit schedule and understand and comply with all protocol requirements.