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-12343350-B2
Publication Date
2025-07-01
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 document relates to compounds having a formula (III) and pharmaceutically acceptable salts, esters, solvates, hydrates, or polymorphs, together with istaroxime and istaroxime metabolites. The disclosed focus connects istaroxime and istaroxime metabolites, particularly PST 3093, to SERCA2a activation for acute heart failure and heart failure, emphasizing PST 3093 as a pure SERCA2a activator.
The approach frames treatment concepts around achieving therapeutically meaningful diastolic relaxation and improving diastolic function, including monitoring of heart function parameters and relating treatment to plasma exposure of an istaroxime metabolite such as PST 3093. The problem described in the background is the need for treatment options for acute heart failure and heart failure, including conditions linked to diastolic dysfunction.
The document describes preferred treatment regimens that maintain plasma levels of PST 3093 over time, including accumulation periods longer than 6 hours and infusion durations selected from at least about 6, 12, 24, 36, or 48 hours. It also describes continued metabolite accumulation after discontinuation of istaroxime, and a sequential higher-dose then lower-dose concept to modulate the istaroxime-to-metabolite ratio while targeting plasma thresholds for the metabolite.
Claims Coverage
The independent claim family includes a compound defined by formula (III) and treatment methods for acute heart failure. The inventive features center on the defined compound structure and form variants, intravenous administration, measurement of diastolic relaxation, plasma metabolite exposure thresholds, and infusion-duration options.
Compound of formula (III) with acceptable forms
A compound having a formula (III), or a pharmaceutically acceptable salt, ester, solvate, hydrate, or polymorph thereof.
Intravenous acute heart failure treatment with diastolic relaxation and metabolite exposure
A method for treating acute heart failure by intravenously infusing a pharmaceutical composition containing a pharmaceutically acceptable carrier and a compound of formula (III), including measuring one or more parameters of heart function comprising diastolic relaxation and relating the treatment to plasma concentration level(s) of an istaroxime metabolite, including diastolic-function improvement.
Plasma concentration level tied to an accumulation period
An acute-heart-failure method where the administration achieves a plasma concentration level of an istaroxime metabolite greater than about 5 ng/ml and relates the accumulation period longer than 6 hours to maintaining metabolite exposure.
Infusion duration options for acute heart failure
An acute-heart-failure method where the intravenous infusion duration is selected from at least about 6, 12, 24, 36, or 48 hours.
Overall claim coverage includes a compound defined by formula (III) and treatment methods for acute heart failure characterized by intravenous administration, measurement of heart-function parameters comprising diastolic relaxation, and relating efficacy to plasma concentration levels of an istaroxime metabolite such as PST 3093 with defined infusion-duration options.
Stated Advantages
Unexpected selective improvement of cardiac diastolic relaxation with minimal change in systolic contraction with prolonged infusion durations.
Improved diastolic function indicated by left ventricular echocardiographic indexes such as E/A and E/e′ and measures related to pulmonary capillary wedge pressure (PCWP).
Reduced arrhythmogenic risk associated with Na+/K+ pump inhibition.
Improves diastolic relaxation in acute heart failure, as assessed by measuring heart-function parameters including diastolic relaxation.
Demonstrates a SERCA2a-stimulating activity for PST 3093.
Documented Applications
Treatment of acute heart failure using intravenous infusion of istaroxime or related metabolite exposure with measured diastolic-relaxation improvement.
Treating acute heart failure in an individual having heart failure using intravenous administration of a pharmaceutical composition containing istaroxime-related compound(s), with measurement of diastolic relaxation and plasma exposure of an istaroxime metabolite (e.g., PST 3093).
Heart failure treatment framed around SERCA2a activation via istaroxime metabolites, including preferred use of PST 3093 as a pure SERCA2a activator.
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