Istaroxime-containing intravenous formulation for the treatment of acute heart failure (AHF)
Inventors
Bianchi, Giuseppe • Ferrari, Patrizia • Ferrandi, Mara • Barassi, Paolo
Assignees
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Publication Number
US-11197869-B2
Publication Date
2021-12-14
Expiration Date
Abstract
Compositions for intravenous infusion of istaroxime, or a metabolite of istaroxime, in human patients suffering from heart failure are disclosed. Likewise, methods for extended infusion of istaroxime or its metabolites in individuals with heart failure are disclosed. In particular, some methods disclosed herein include the infusion of istaroxime, or a metabolite thereof, for a period of time that is greater than six hours in order to improve cardiac relaxation without triggering arrhythmogenic events in an individual suffering from heart failure. Other methods include administration of istaroxime until certain plasma concentration thresholds of istaroxime metabolites are achieved. Also disclosed are istaroxime metabolites with selective SERCA2a activation.
Core Innovation
The invention concerns intravenous istaroxime-based therapy for acute heart failure in a human subject, where the administering comprises an intravenous infusion for an infusion period longer than 6 hours. The therapy is designed to improve diastolic function, with systolic contraction described as largely unchanged. Improvement is assessed using one or more echocardiographic indicators of diastolic function, including decreased E wave, increased E wave deceleration time, increased A wave, decreased E/A ratio, increased e′, decreased E/e′ ratio, or any combination thereof.
The disclosed approach emphasizes that longer infusion durations, including options up to about 48 hours, are associated with improved diastolic relaxation parameters compared with administration for 6 hours or less. The unexpected lusitropic benefit is attributed to time-dependent accumulation of istaroxime metabolites PST 2915 (Formula II) and especially PST 3093 (Formula III). The metabolites are described as selective/pure SERCA2a activators, supporting SERCA2a-driven improvement in diastolic function through related cardiac calcium-handling mechanisms stated in the document.
The disclosure also ties infusion duration to plasma exposure of an istaroxime metabolite selected from PST 2915 (Formula II) and PST 3093 (Formula III), including an example threshold associated with achieving plasma concentrations greater than about 5 ng/mL. It further provides dose ranges and selection for intravenous infusion, including at least about 0.2 mcg/kg/min and embodiments in which dosing is about 0.25 mcg/kg/min to about 1.0 mcg/kg/min for longer infusion periods. The document also mentions lack of significant HsTnT change, clinical-trial background (HORIZON), and plasma metabolite accumulation profiles.
Claims Coverage
The document provides two independent claims that cover methods for treating acute heart failure by intravenous infusion of istaroxime, with improvement targeted to echocardiographic indicators of diastolic function. Across these claims, the inventive features focus on infusion period longer than 6 hours, dose thresholds and ranges, and specific diastolic echocardiographic outcomes compared against shorter infusion, with additional refinements including infusion-duration-anchored metabolite exposure.
Intravenous infusion longer than 6 hours at a dose at least 0.2 mcg/kg/min with diastolic echocardiographic improvement
Treat acute heart failure by administering istaroxime intravenously as an infusion for an infusion period longer than 6 hours, at a dose of at least 0.2 mcg/kg/min, and observing or measuring diastolic function wherein the longer infusion results in improvement in at least one specified echocardiographic indicator of diastolic function compared with administration for 6 hours or less.
Intravenous infusion for at least 24 hours at about 0.25 mcg/kg/min to about 1.0 mcg/kg/min with diastolic echocardiographic improvement
Treat acute heart failure by administering a pharmaceutical composition comprising istaroxime intravenously at a dose of about 0.25 mcg/kg/min to about 1.0 mcg/kg/min for an infusion period of at least about 24 hours, wherein administering results in improvement in at least one specified echocardiographic indicator of diastolic function.
Overall claim coverage centers on intravenous istaroxime dosing where infusion duration is extended beyond 6 hours, including embodiments at least about 24 hours, and where treatment produces improvement in specific echocardiographic indicators of diastolic function, with improvement assessed relative to shorter infusion where stated.
Stated Advantages
Improvement in at least one echocardiographic indicator of diastolic function when the infusion period is longer than 6 hours compared with 6 hours or less.
Improvement in at least one echocardiographic indicator of diastolic function with intravenous infusion for at least about 24 hours.
Treatment of acute heart failure in the human subject.
Documented Applications
Treating acute heart failure in a human subject by intravenous infusion of istaroxime with diastolic-function assessment using echocardiographic indicators.
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