Hemodynamic Evaluation of Levosimendan in Patients With PH-HFpEF

Levosimendan and its prolonged active metabolite, OR-1896, have been shown to have favorable
hemodynamic effects in subjects with pulmonary hypertension and right heart failure. Clinical
studies that have been conducted in subjects with right heart failure and pulmonary
hypertension suggest levosimendan may be an effective therapy in treatment of subjects with
PH-HFpEF. This study will provide demonstration of levosimendan/OR-1896's effectiveness in
critical measures of hemodynamic response in weekly administration of levosimendan and the
concomitant response as measured by exercise capacity, subject quality of life, and changes
in functional capacity. These data will support and guide the Phase 3 development of
levosimendan in PH-HFpEF subjects.

Inclusion Criteria:

Criteria to enter Open-label, Lead-in Dose Phase:

- Diagnosis of WHO Group 2 Pulmonary Hypertension (PH) with heart failure and preserved
ejection fraction (HFpEF) confirmed at the time of the diagnosis of pulmonary
hypertension.

- Baseline Pulmonary Arterial Pressure (PAP) ≥35, PCWP ≥20, NYHA Class IIb/III, Left
Ventricular Ejection Fraction (LVEF) ≥40%

- Ability to walk at least 100 meters, but not more than 400 meters in a six-minute walk
test.

- Stable oxygen treatment (if applicable), and medications for heart failure and
respiratory condition

Criterion for Randomization to Double-blind Phase:

- Response to Open-label, Lead-in Levosimendan: Patients who demonstrate a ≥4mmHg
reduction in PCWP from baseline measured at bicycle exercise (25 watts) with no more
than a 10% decrease from baseline in cardiac index

Exclusion Criteria:

- Subject has primary diagnosis of PH other than Group 2 PH-HFpEF

- Previous Percutaneous Coronary Intervention (PCI) or cardiac surgery or symptomatic
valve disease, unless they have a negative stress test in last 12 months)

- Congenital heart disease

- Clinically significant lung disease

- Planned heart or lung surgery

- Cardiac Index >4.0 L/min/m2

- Concomitant administration of pulmonary vasodilator therapy or taken within 14 days

- Dialysis or Glomerular Filtration Rate (GFR) <30 mL/min/1.73 m2

- Liver dysfunction with Child Pugh Class B or C

- Evidence of systemic infection

- Weight > 135kg

- Symptomatic systolic blood pressure (SBP) cannot be managed to ensure SBP >100 mmHg

- Heart rate >= 100 bpm with study drug, symptomatic and persistent for at least 10
minutes

- Hemoglobin < 80 g/L

- Serum potassium < 3.0 mmol/L or > 5.5 mmol/L at baseline

- Patients having severely compromised immune function

- Pregnant, suspected to be pregnant, or breast-feeding