istaroxime (PST 2744) / Seismic Pharmaceuticals - LARVOL DELTA

RESCUE HF-CS: Randomized Evaluation of Istaroxime for Stabilization in Acute Heart Failure-Cardiogenic Shock (clinicaltrials.gov) - P2/3 | N=600 | Recruiting | Sponsor: Seismic Pharmaceuticals Operations LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure

Early changes in dyspnea with 24-h istaroxime infusion among patients with acute heart failure. (PubMed, J Cardiovasc Med (Hagerstown)) - "Among patients with AHF, 24-h istaroxime infusion was associated with a significantly higher probability of dyspnea improvement compared with placebo through 24 h, with results being numerically more pronounced among patients with worse dyspnea at baseline."

Clinical • Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Pulmonary Disease

Istaroxime in Acute Heart Failure and Early Cardiogenic Shock: A Calcium-Cycling Approach to Inotropic Therapy. (PubMed, Int J Mol Sci) - "Istaroxime represents a mechanistically distinct approach to inotropic therapy, shifting the paradigm from calcium amplification toward partial restoration of calcium cycling. Its clinical relevance will depend on whether this strategy can translate into improved patient outcomes-an objective that has thus far eluded the entire class of inotropic agents."

Journal • Review • Cardiovascular • Congestive Heart Failure • Heart Failure

Istaroxime's Effect on Hemodynamics and Arrhythmias in Cardiogenic Shock: A Pooled Analysis of SEISMiC Trials. (PubMed, JACC Heart Fail) - No abstract available

Journal • Retrospective data • Cardiovascular • Congestive Heart Failure • Heart Failure

RESCUE HF-CS: Randomized Evaluation of Istaroxime for Stabilization in Acute Heart Failure-Cardiogenic Shock (clinicaltrials.gov) - P2/3 | N=600 | Not yet recruiting | Sponsor: Seismic Pharmaceuticals Operations LLC

New P2/3 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

Early management of acute heart failure. (PubMed, Curr Opin Crit Care) - "Integrating these advances may optimize early emergency department management, personalize care, and improve outcomes in AHF."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders

Istaroxime - update of data in early Cardiogenic shock and decompensated heart failure. (PubMed, Expert Opin Investig Drugs) - "Its advantages stem from a favorable safety profile compared with traditional inotropes, along with proven efficacy in raising systolic blood pressure (SBP) and enhancing central hemodynamics. These effects are mediated through its unique ino-lusitropic mechanism, achieved without increasing heart rate."

Journal • Review • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypotension

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