istaroxime (PST 2744) / Windtree Therap - LARVOL DELTA

Safety and Efficacy of Istaroxime in Acute Heart Failure Related Pre-Cardiogenic Shock: An Updated Systematic Review and Meta Analysis of Randomized Controlled Trials (AHA 2025) - "Istaroxime demonstrates consistent, clinically meaningful improvements in blood pressure, cardiac output, and diastolic function with a favourable safety profile in AHF pre-cardiogenic shock. The inclusion of the SEISMiC trial strengthens the evidence base, supporting further large scale Phase III investigations."

Retrospective data • Review • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypotension

Haemodynamic effects of istaroxime in SCAI stage B HF-related cardiogenic shock: Insights from the SEISMiC trial. (PubMed, ESC Heart Fail) - "In patients with ADHF-pre-CS, istaroxime at doses up to 1.0 μg/kg/min for up to 60 h was associated with sustained improvements in measures of LV performance (API and LVSWI), in parallel with increase in PA compliance and reduction in PA elastance at 48 h. As compared with placebo, istaroxime improved LV contractility and preserved RV contractility, which deteriorated on placebo, over time."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Safety and Efficacy of Intravenous administration of Istaroxime for 48 hours in Patients with SCAI C Cardiogenic Shock due to acute heart failure (HFSA 2025) - No abstract available

Clinical • Late-breaking abstract • Cardiovascular • Congestive Heart Failure • Heart Failure

How palytoxin transforms the Na+,K+ pump into a cation channel. (PubMed, Proc Natl Acad Sci U S A) - "PTX binds to NKA in E2P, occupying the physiological Na+ exit pathway, similar to istaroxime, a new-generation cardiotonic steroid...These structures demonstrate that the architecture of NKA is fundamentally different from "a pore with two gates." Each half of the ion pathway comprises three segments, including a movable component that plays a pivotal role in translocating the bound cations by connecting the constant part to an appropriate inlet. The ion pathway of NKA transforms dynamically, ensuring that the two halves never exist simultaneously."

Journal

SEISMiC-C: A Safety and Efficacy Trial of Istaroxime for Cardiogenic Shock Stage C (clinicaltrials.gov) - P1/2 | N=20 | Active, not recruiting | Sponsor: Windtree Therapeutics | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2025 ➔ Aug 2026 | Trial primary completion date: Dec 2024 ➔ Jul 2025

Enrollment closed • Trial completion date • Trial primary completion date • Cardiovascular • Congestive Heart Failure

Istaroxime Infusion for 24 Hours in Chinese Healthy Volunteers (clinicaltrials.gov) - P1 | N=32 | Completed | Sponsor: Lee's Pharmaceutical Limited | Unknown status ➔ Completed

Trial completion

Development of Small-molecule SERCA2a Stimulators: A Novel Class of Ino-lusitropic Agents. (PubMed, Eur Cardiol) - "Considering the role of SERCA2a depression in HF and the accompanying electrical instability, selective restoration of SERCA2a function provides an appealing approach to HF therapy. Beneficial effects of SERCA2a stimulation by istaroxime have also been recently described in non-cardiac tissues, thus suggesting even broader and unexpected indications for this new class of agents."

Journal • Review • Cardiovascular • CNS Disorders • Congestive Heart Failure • Depression • Heart Failure • Psychiatry

Before the Tipping Point: Istaroxime for Early Heart Failure Related Cardiogenic Shock. (PubMed, J Heart Lung Transplant) - No abstract available

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Safety and Efficacy Intravenous Istaroxime up to 60 hours for Patients with Pre-Cardiogenic Shock. (PubMed, J Heart Lung Transplant) - "In this small study, istaroxime doses of up to 1.0 µg/kg/min for up to 60 hours were associated with improvements in SBP, CO and reduction in wedge pressure and heart rate without increase in arrythmias."

Clinical • Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Colitis induced ventricular alternans increases the risk for ventricular arrhythmia. (PubMed, J Mol Cell Cardiol) - "Stimulating cellular SERCA activity (Istaroxime), normalized the propensity for alternans...Our data demonstrate that active colitis promotes reversible remodeling of ventricular Ca2+ handling properties and increases the propensity for alternans and arrythmia. The changes can be prevented by ACE or AT1R inhibition supporting a cardiac benefit for controlling RAS signaling in patients with active colitis."

Journal • Cardiovascular • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

A multicenter, randomized, double-blind, placebo-controlled, parallel group study on the safety and efficacy of istaroxime for pre-cardiogenic shock (HEART FAILURE 2025) - No abstract available

Clinical • Late-breaking abstract • Cardiovascular • Congestive Heart Failure • Heart Failure

Istaroxime and its metabolite analogue reduce reperfusion arrhythmias in isolated-perfused diabetic rat hearts and anesthetized diabetic rats (HEART FAILURE 2025) - "These results indicate that both istaroxime and the selective SERCA2a activator CVie216 infusion could reduce reperfusion-induced ventricular arrhythmias in diabetic isolated hearts possibly by decreasing calcium overload and SCR. In an in vivo model, the selective SERCA2a activator CVie216 also reduced the incidence of reperfusion arrhythmias. Therefore, selective SERCA2a activation may represent a novel therapeutic mechanism for cardiomyopathy associated arrhythmias."

Preclinical • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Myocardial Ischemia • Reperfusion Injury • Ventricular Tachycardia

Windtree Announces Istaroxime Exclusivity and Intellectual Property Potential Strategy for US (GlobeNewswire) - "Windtree Therapeutics...is pleased to announce it has received advice from intellectual property and FDA experts highlighting a U.S. strategy that can provide 7.5 years of U.S. exclusivity for istaroxime if it is approved by the FDA in cardiogenic shock. Specifically, as a never-before-approved active ingredient, istaroxime may receive New Chemical Entity (NCE) designation from the FDA. If the new drug application is approved with such a designation, istaroxime would be entitled to 5 years of data exclusivity, and a stay of FDA approval of any generic application equal to 7.5 years from the date of istaroxime’s FDA approval should any generic company challenge the patents that Windtree has obtained or is pursuing and if Windtree files a patent infringement lawsuit in response to such a challenge...Istaroxime also has a USPTO issued method of use patent providing protection until 2039....'planned interim analysis of our Phase 2 cardiogenic shock SCAI Stage C study in Q3, 2025.'"

P2 data • Patent • Cardiovascular

Windtree Files Istaroxime Cardiogenic Shock and Prevention of Arrythmias Patent for India (GlobeNewswire) - "Windtree Therapeutics, Inc...announced today that the Company has filed a national phase patent application with the Indian patent office claiming priority to PCT/US2024/058923 entitled, 'ISTAROXIME AND DERIVATIVES THEREOF FOR PREVENTING OR REDUCING THE RISK OF ACUTE MYOCARDIAL ARRHYTHMIA.'"

Patent • Cardiovascular • Heart Failure

Windtree Announces Special Late-Breaking Clinical Science Abstract Presentation on Istaroxime at the Technology and Heart Failure Therapeutics Conference (GlobeNewswire) - "Windtree Therapeutics, Inc...announced that an istaroxime presentation featuring the positive Phase 2b SEISMiC study was given on February 11, 2025 at the Technology and Heart Failure Therapeutics Conference in Boston, MA...Early (SCAI Stage B) cardiogenic shock is characterized by low blood pressure, leaving the patient at risk of developing inadequate blood flow to vital organs leading to high morbidity and mortality. Istaroxime is a novel first-in-class investigational therapy that is intended to improve cardiac function and increase blood pressure to reverse the condition. Istaroxime produces these effects without detrimental effects on renal function and has a generally favorable safety profile."

P2b data • Cardiovascular • Heart Failure

SEISMiC: The Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock (clinicaltrials.gov) - P2 | N=90 | Completed | Sponsor: Windtree Therapeutics | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Congestive Heart Failure

Non-MI Pre-Cardiogenic Shock. Failed inotrope trials and potential with istaroxime (CVCT USA 2024) - No abstract available

Cardiovascular

Safety and efficacy of up to 60 h of iv istaroxime in pre-cardiogenic shock patients: Design of the SEISMiC trial. (PubMed, ESC Heart Fail) - "The study results will contribute to our understanding of the role of istaroxime in pre-CS patients and potentially provide insight into the drug's haemodynamic effects and safety in this population."

Clinical • Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypotension

A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study On The Safety And Efficacy Of Istaroxime For Pre-cardiogenic Shock (HFSA 2024) - " SEISMIC B is a pilot, multinational, multicenter, randomized, double-blind, placebo-controlled, safety and efficacy study, which will include up to 30 patients 18 to 85 years of age, hospitalized for early CS due to acute heart failure (ADHF), with persistent hypotension (systolic blood pressure [SBP] 70-100mmHg for two hours) who have not received IV vasopressors, inotropes, or digoxin, and are not on mechanical support. The primary endpoint is SBP area under the curve (AUC) from the start of the infusion to 6 hours. Secondary endpoints include SBP measurements over the duration of drug infusion, changes in invasive hemodynamic measurements such as cardiac output and wedge pressure, as well as mixed venous saturation, clinical outcomes such as length of stay and worsening HF events or death, and changes in laboratory and biomarker assessments. Safety will be assessed both clinically and through Holter assessments."

Clinical • Late-breaking abstract • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypotension • Infectious Disease

Antiarrhythmic Potential Of Istaroxime And A Selective Serca2a Activator In Diabetic Cardiomyopathic Rats (HFSA 2024) - "These results indicate ista and CVie216 infusion reduced IR-induced VA in diabetic isolated hearts possibly through decreasing triggered activity. CVie216 also reduced the incidence of IR arrhythmias in the in vivo model and exhibited even greater antiarrhythmic potential than ista in diabetic isolated hearts. Our study highlights that SERCA2a activation may represent a novel treatment strategy with antiarrhythmic potential in failing hearts with reduced SERCA2a activity."

Preclinical • Anesthesia • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Heart Failure • Reperfusion Injury • Ventricular Tachycardia

SEISMiC-C: A Safety and Efficacy Trial of Istaroxime for Cardiogenic Shock Stage C (clinicaltrials.gov) - P1/2 | N=20 | Recruiting | Sponsor: Windtree Therapeutics | Not yet recruiting ➔ Recruiting | Trial completion date: Jul 2024 ➔ Jan 2025 | Trial primary completion date: Jul 2024 ➔ Dec 2024

Enrollment open • Trial completion date • Trial primary completion date • Cardiovascular • Congestive Heart Failure

SEISMiC: The Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock (clinicaltrials.gov) - P2 | N=90 | Active, not recruiting | Sponsor: Windtree Therapeutics | Trial completion date: Apr 2024 ➔ Sep 2024 | Trial primary completion date: Mar 2024 ➔ Aug 2024

Trial completion date • Trial primary completion date • Cardiovascular • Congestive Heart Failure

Istaroxime follow-on compounds: A new class of selective SERCA2a activators for chronic heart failure treatment. (PubMed, Vascul Pharmacol) - No abstract available

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Intracellular Ca2+ dynamics modulation by istaroxime and its metabolite in pulmonary artery smooth muscle cells. (PubMed, Vascul Pharmacol) - No abstract available

Journal

Rescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics. (PubMed, Nat Commun) - "Treatment with the SERCA2 agonist istaroxime was demonstrated to improve T2D bone mechano-responsiveness by rescuing osteocyte Ca dynamics and the associated regulation of osteoblasts and osteoclasts. Moreover, T2D-induced deterioration of bone mechano-responsiveness is blunted in mice with osteocytic SERCA2 overexpression. Collectively, our study provides mechanistic insights into T2D-mediated deterioration of bone mechano-responsiveness and identifies a promising countermeasure against T2D-associated fragility fractures."

Journal • Diabetes • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Type 2 Diabetes Mellitus • PPARA