Levosimendan for treating pulmonary hypertension with heart failure with preserved ejection fraction (PH-HFpEF)
Inventors
Rich, Stuart • Randall, Douglas • Hay, Douglas
Assignees
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Publication Number
US-11701355-B2
Publication Date
2023-07-18
Expiration Date
Abstract
This invention relates to the treatment of Pulmonary Hypertension with heart failure with preserved ejection fraction (PH-HFpEF). More specifically, embodiments of the invention provide compositions and methods useful for the treatment of PH-HFpEF employing the use of levosimendan.
Core Innovation
The described invention relates to a method for improving exercise capacity in a human subject afflicted with Pulmonary Hypertension with Heart Failure with preserved Ejection Fraction (PH-HFpEF). The method improves exercise capacity as measured by an at least 5 meter increase in the six (6) minute walk distance, using levosimendan and/or its metabolites OR-1896 and OR-1855, or combinations thereof.
A central concept is oral administration of levosimendan and/or its metabolites to achieve improvement in six-minute walk distance in PH-HFpEF. The method specifies orally administering levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof, at a daily dose from 1 mg to 4 mg per day.
The described approach further includes refinements that connect the oral treatment to defined safety and exposure criteria. These refinements include steady-state blood levels of OR1896 within a specified range and electrocardiographic monitoring constraints intended to avoid atrial and ventricular arrhythmias, while also defining responder criteria based on pulmonary capillary wedge pressure (PCWP) reduction during exercise in the described clinical context.
Claims Coverage
The document includes one independent claim. The coverage focuses on orally administering levosimendan (and/or metabolites OR-1896 and OR-1855) to improve exercise capacity in PH-HFpEF as measured by six-minute walk distance, with dependent claim refinements defining oral dosing, regimen duration, safety/monitoring, and pharmacokinetic exposure constraints (e.g., OR1896 steady-state blood levels).
Oral dosing to improve six-minute walk distance in PH-HFpEF
Orally administering levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof to a human subject afflicted with PH-HFpEF to improve exercise capacity by an at least 5 meter increase in the six (6) minute walk distance.
Daily oral dose range for levosimendan or metabolites
Orally administering levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof at a daily dose from 1 mg to 4 mg per day.
Capsule-based oral administration with specified mg amounts
Orally administering a capsule containing up to 1 mg, 2 mg, 3 mg, or 4 mg of levosimendan and/or its metabolites OR-1896 and OR-1855, or a combination thereof.
Minimum once-daily oral treatment duration
Orally administering levosimendan once daily for at least 14 days.
Arrhythmia-free safety during electrocardiographic monitoring
Carrying out the method such that, compared with baseline electrocardiographic monitoring, no atrial or ventricular arrhythmias are observed during 72-hour monitoring after 5 weeks of administration.
Steady-state OR1896 blood level range
Administering levosimendan such that it produces steady-state blood levels of OR1896 ranging from 0.20 ng/mL to 25.00 ng/mL.
Overall, the claim set is directed to orally administering levosimendan and/or OR-1896/OR-1855 to PH-HFpEF subjects to achieve a six-minute walk distance improvement of at least 5 meters, with dependent claim refinements specifying an oral daily dose range, capsule mg amounts, once-daily duration, ECG-based arrhythmia monitoring constraints, and OR1896 steady-state blood level range.
Stated Advantages
Improves exercise capacity in PH-HFpEF as measured by an at least 5 meter increase in six-minute walk distance.
Defined clinical findings in the described context include lowering PCWP, right atrial pressure, and mPAP and increasing cardiac output.
In the described clinical context, six-minute walk distance was improved and quality of life was improved.
In the described context, the therapy was described as safe/tolerable with monitoring and without observed atrial or ventricular arrhythmias under specified electrocardiographic monitoring.
Documented Applications
A method of improving exercise capacity in a human subject afflicted with Pulmonary Hypertension with Heart Failure with preserved Ejection Fraction (PH-HFpEF) using oral administration of levosimendan and/or metabolites OR-1896 and OR-1855 to increase six-minute walk distance.
A described clinical context uses a Phase II multicenter randomized placebo-controlled HELP study and an open-label extension, including hemodynamic and exercise-capacity outcomes in PH-HFpEF.
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