Levosimendan for treating pulmonary hypertension with heart failure with preserved ejection fraction (PH-HFpEF)
Inventors
Rich, Stuart • Randall, Douglas • Hay, Douglas
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11607412-B2
Publication Date
2023-03-21
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 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 comprises intravenously administering levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof, in an amount effective to improve exercise capacity as measured by an at least 10 meter increase in the six (6) minute walk distance.
The disclosed treatment protocol provides a weekly 24 hour intravenous infusion using a peripherally inserted central catheter (PICC) or a port-a-cath. The protocol begins with 0.075 μg levosimendan/kg subject/minute once weekly for 24 hours, followed after three weeks by either an escalated dose of 0.1 μg levosimendan/kg subject/minute for 24 hours or a lowered dose if a meaningful change in blood pressure or heart rate occurs or an adverse event is detected.
A further part of the disclosure defines responder behavior in terms of a ≥4 mmHg reduction in pulmonary capillary wedge pressure (PCWP) during 25W exercise after lead-in. The disclosure also states improvements in hemodynamic parameters including PCWP, right atrial pressure (RAP), and mean pulmonary arterial pressure (mPAP), and improvements in cardiac output and six-minute walk distance.
Claims Coverage
The independent claim covers a levosimendan, OR-1896, or OR-1855 intravenous regimen for PH-HFpEF that targets a clinically meaningful increase in six-minute walk distance, with administration via PICC or port-a-cath and a weekly 24-hour titration/escalation strategy after an initial three-week period. Dependent claims further constrain safety, arrhythmia monitoring, and pharmacokinetic and infusion-rate parameters.
Exercise capacity improvement in PH-HFpEF by levosimendan or metabolites
A method for improving exercise capacity as measured by an at least 10 meter increase in the six (6) minute walk distance in a human subject afflicted with Pulmonary Hypertension with Heart Failure with preserved Ejection Fraction (PH-HFpEF) by intravenously administering an amount of levosimendan, its metabolites OR-1896 or OR-1855, or a combination thereof that is effective to improve exercise capacity by an at least 10 meter increase in the six (6) minute walk distance.
Weekly 24-hour intravenous levosimendan titration via PICC or port-a-cath
The method uses intravenously administering using a peripherally inserted central catheter (PICC) or a port-a-cath and initially provides 0.075 μg levosimendan/kg subject/minute for 24 hours once weekly, wherein after three weeks the subject is either administered an escalated dose of 0.1 μg levosimendan/kg subject/minute for 24 hours or administered a lowered dose if a meaningful change in blood pressure or heart rate occurs or an adverse event is detected.
No more statistically significant serious adverse events than placebo
The method is characterized by administering a treatment that results in no more statistically significant serious adverse events than a matching placebo.
No atrial or ventricular arrhythmias over defined electrocardiographic monitoring window
The method is characterized by observing no atrial or ventricular arrhythmias when comparing baseline electrocardiographic monitoring to 72-hour monitoring after 5 weeks of administration.
OR-1896 steady-state blood level range
The method includes administering levosimendan such that it produces steady-state blood levels of OR1896 between 0.20 ng/mL and 25.00 ng/mL.
24-hour intravenous infusion-rate range
The method includes intravenously administering levosimendan to a human subject at an infusion rate of 0.05-0.1 μg/kg/minute for 24 hours.
Across the independent and dependent claims, the disclosed method centers on improving six-minute walk distance in PH-HFpEF by weekly 24-hour intravenous levosimendan, OR-1896, or OR-1855 delivered via PICC or port-a-cath, with dose escalation or reduction after three weeks based on blood pressure or heart rate changes or adverse events. Dependent claims further require placebo-comparative serious adverse-event outcomes, arrhythmia absence over a specified monitoring window, and constrain OR-1896 steady-state blood levels and infusion-rate parameters.
Stated Advantages
Improves exercise capacity as measured by an at least 10 meter increase in the six (6) minute walk distance.
Produces improvements in hemodynamic parameters including pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), and mean pulmonary arterial pressure (mPAP).
Improves cardiac output and six-minute walk distance.
No significant adverse events versus placebo.
No atrial or ventricular arrhythmias over the monitoring window.
Documented Applications
Treatment of a human subject afflicted with Pulmonary Hypertension with Heart Failure with preserved Ejection Fraction (PH-HFpEF) using intravenous levosimendan, OR-1896, or OR-1855 to improve exercise capacity measured by six-minute walk distance.
Weekly 24-hour intravenous levosimendan dosing administered using a PICC or port-a-cath, with dose escalation or reduction after three weeks based on blood pressure or heart rate changes or an adverse event.
Interested in licensing this patent?