Cardiac Asthma: Causes, Symptoms, and Treatments

SLU Heart Failure Expert Pens Editorial For New England Journal Of Medicine

ST. LOUIS – In patients experiencing a worsening of heart failure, the primary objective of treatment should be the patient-centric goal of symptom relief, says the author of an editorial in the current issue of the New England Journal of Medicine.

Paul J. Hauptman, M.D., a SLUCare cardiologist specializing in heart failure and professor of internal medicine at Saint Louis University School of Medicine, looked at the results of the Trial of Ularitide Efficacy and Safety in Acute Heart Failure (TRUE-AHF), which was designed to evaluate the safety and efficacy of a novel synthetic compound "ularitide" administered very soon after a patient presents with acute decompensated heart failure (ADHF).

ADHF is a sudden worsening of the signs and symptoms of heart failure, which typically includes difficulty breathing (dyspnea), leg or feet swelling, and fatigue.

Hauptman's editorial, "Disease Modification in Acute Decompensated Heart Failure," was published online April 12 ahead of print publication in the New England Journal of Medicine.

Hauptman's review of the TRUE-AHF trial looked at the two hypotheses being tested – that a single infusion of ularitide would improve early clinical outcomes and that a rapid treatment approach to exacerbation of heart failure improves longer-term survival.

"We can conclude that ularitide, like its predecessor nesiritide, has limited short-term effects that wane after the discontinuation of treatment, which lessens the likelihood that there is a constructive avenue for further development of natriuretic peptides," Hauptman wrote in his editorial. "It also appears that we do not have a mandate to establish rapid-response teams for patients who present with acute decompensated heart failure."

Hauptman notes the need for greater consensus on how to define the response to intervention and to determine which patients are in greatest therapeutic need.

"Exacerbations of chronic disease reflect the chronic disease, not the hospitalizations used to manage those exacerbations," Hauptman wrote. "The search for improved understanding of the pathophysiology of heart-failure decompensation continues, and so does the search for better treatments."

Hauptman has a background in clinical and outcomes research in heart failure. He has been an investigator in multiple trials for more than 20 years. In 2014, Hauptman was named the editor-in-chief of the Journal of Cardiac Failure. In 2016, Hauptman was named an inaugural Fellow of the Heart Failure Society of America (HFSA).

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: infectious disease, liver disease, cancer, heart/lung disease, and aging and brain disorders.

Windtree Therapeutics Announces The Start Of Patient Dosing In Phase 2 SEISMiC Extension Study Of Istaroxime In Early Cardiogenic Shock

SEISMiC Extension Study results are anticipated in mid-2024 and expected to provide dose optimization for Phase 3

The Company is also progressing a parallel SCAI Stage C Phase 2 study with istaroxime in cardiogenic shock targeting data in a similar timeframe

WARRINGTON, Pa., Dec. 18, 2023 (GLOBE NEWSWIRE) -- Windtree Therapeutics, Inc. ("Windtree" or the "Company") (NasdaqCM: WINT), a biotechnology company focused on advancing late-stage interventions for critical cardiovascular disorders, today announced that the Company recently enrolled the first subject in its Phase 2 SEISMiC Extension Study of istaroxime in the treatment of early cardiogenic shock. Study results are expected in mid-2024.

Building upon the positive SEISMiC study results, the Extension Study is expected to enroll up to 30 subjects with the objective to evaluate a longer dosing cycle of istaroxime, a novel first-in-class therapy that is designed to improve systolic contraction and diastolic relaxation of the heart while also increasing blood pressure. The study of hospitalized patients with early cardiogenic shock (SCAI Stage B) due to acute heart failure (AHF) will evaluate two dose regimens of istaroxime compared to placebo. Subjects on istaroxime will receive infusions for up to 60 hours with one istaroxime group receiving a tapered decreasing dose over time and the second istaroxime group receiving a consistent lower dose. In the previous SEISMiC study in early cardiogenic shock, patients were infused with drug or placebo for 24 hours. We believe extending the dosing duration of istaroxime has the potential to provide additional benefit and, along with dose titration, is an important factor in determining the optimal dosing regimen to study in a potential Phase 3 trial. The Extension Study will also gather data to characterize the potential benefits of SERCA2a activation in these patients, advancing the Company's clinical and regulatory position for potential Phase 3 readiness.

The Company is also progressing the start-up of a parallel study in more severe, SCAI Stage C cardiogenic shock patients. SCAI Stage C patients have low blood pressure and inadequate blood flow to vital organs. The istaroxime cardiogenic shock SCAI Stage C study is expected to enroll up to 20 subjects with SCAI Stage C cardiogenic shock due to AHF. Multiple physiologic measures associated with cardiac function, blood pressure and safety will be assessed. The Company is targeting data from this study in a similar timeframe as the SEISMiC Extension Study.

"The SEISMiC Extension Study builds upon the positive data from our three Phase 2 studies in acute heart failure and early cardiogenic shock and is expected to determine the best dosing regimen for our anticipated Phase 3 program in cardiogenic shock," said Craig Fraser, Windtree's President and Chief Executive Officer. "Along with data from more severe, SCAI Stage C cardiogenic shock patients coming from a parallel study, program results in mid-2024 are expected to contribute to finalizing our strategy and design for Phase 3 clinical trials and our end of Phase 2 discussions with FDA."

About IstaroximeIstaroxime is a first-in-class dual mechanism therapy designed to improve both systolic and diastolic cardiac function. Istaroxime is a positive inotropic agent that increases myocardial contractility through inhibition of Na+/K+- ATPase with a complimentary mechanism that facilitates myocardial relaxation through activation of the SERCA2a calcium pump on the sarcoplasmic reticulum enhancing calcium reuptake from the cytoplasm. Data from multiple Phase 2 studies in patients with early cardiogenic shock or acute decompensated heart failure demonstrate that istaroxime infused intravenously significantly improves cardiac function and blood pressure without increasing heart rate or the incidence of cardiac rhythm disturbances.

About Windtree Therapeutics, Inc.Windtree Therapeutics, Inc. Is advancing late-stage interventions for cardiovascular disorders to treat patients in moments of crisis. Using new scientific and clinical approaches, Windtree is developing a multi-asset franchise anchored around compounds with an ability to activate SERCA2a, with lead candidate, istaroxime, being developed as a first-in-class treatment for cardiogenic shock and acute decompensated heart failure. Windtree's heart failure platform includes follow-on pre-clinical SERCA2a activator assets as well. In pulmonary care, Windtree has focused on facilitating the transfer of the KL4 surfactant platform, to its licensee, Lee's Pharmaceutical (HK) Ltd. And Zhaoke Pharmaceutical (Hefei) Co. Ltd. Included in Windtree's portfolio is rostafuroxin, a novel precision drug product targeting hypertensive patients with certain genetic profiles.

Forward Looking StatementsThis press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. The Company may, in some cases, use terms such as "predicts," "believes," "potential," "proposed," "continue," "estimates," "anticipates," "expects," "plans," "intends," "may," "could," "might," "will," "should" or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such statements are based on information available to the Company as of the date of this press release and are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from the Company's current expectations. Examples of such risks and uncertainties include: risks and uncertainties associated with the success and advancement of the clinical development programs for istaroxime and the Company's other product candidates; the Company's ability to secure significant additional capital as and when needed; the Company's ability to access the debt or equity markets; the Company's ability to manage costs and execute on its operational and budget plans; the results, cost and timing of the Company's clinical development programs, including any delays to such clinical trials relating to enrollment or site initiation; risks related to technology transfers to contract manufacturers and manufacturing development activities; delays encountered by the Company, contract manufacturers or suppliers in manufacturing drug products, drug substances, and other materials on a timely basis and in sufficient amounts; risks relating to rigorous regulatory requirements, including that: (i) the U.S. Food and Drug Administration or other regulatory authorities may not agree with the Company on matters raised during regulatory reviews, may require significant additional activities, or may not accept or may withhold or delay consideration of applications, or may not approve or may limit approval of the Company's product candidates, and (ii) changes in the national or international political and regulatory environment may make it more difficult to gain regulatory approvals and risks related to the Company's efforts to maintain and protect the patents and licenses related to its product candidates; risks that the Company may never realize the value of its intangible assets and have to incur future impairment charges; risks related to the size and growth potential of the markets for the Company's product candidates, and the Company's ability to service those markets; the Company's ability to develop sales and marketing capabilities, whether alone or with potential future collaborators; the rate and degree of market acceptance of the Company's product candidates, if approved; the economic and social consequences of the COVID-19 pandemic and the impacts of political unrest, including as a result of geopolitical tension, including the conflict between Russia and Ukraine, the People's Republic of China and the Republic of China (Taiwan), and the evolving events in Israel and Gaza, and any sanctions, export controls or other restrictive actions that may be imposed by the United States and/or other countries which could have an adverse impact on the Company's operations, including through disruption in supply chain or access to potential international clinical trial sites, and through disruption, instability and volatility in the global markets, which could have an adverse impact on the Company's ability to access the capital markets. These and other risks are described in the Company's periodic reports, including its Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and Current Reports on Form 8-K, filed with or furnished to the Securities and Exchange Commission and available at www.Sec.Gov. Any forward-looking statements that the Company makes in this press release speak only as of the date of this press release. The Company assumes no obligation to update forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release.

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Matt Epsteinmepstein@kendallir.Com

Acute Decompensated Aortic Stenosis: Time For An Urgent TAVI Pathway?

LONDON, England—Patients identified as having acute decompensated aortic stenosis (ADAS) during their index hospitalization do best if their TAVI procedures are done as soon as possible, a single-center study suggests.

Longer hospitalizations in these patients were independently associated with adverse outcomes, said Michael Mc Kenna, MD (Barts Health NHS Trust, London, England), who presented the retrospective analysis here at PCR London Valves 2023.

The findings lend support to TAVI programs that are evolving different triage processes based on patients' presentation and represent a key departure from surgical approaches, which have emphasized stabilization before intervention.

"Expediting TAVI in ADAS patients may result in significantly lower rates of heart failure hospitalizations, cardiovascular mortality, and all-cause mortality over medium-term follow-up," Mc Kenna said. Based on these observational data, his hospital has piloted an urgent care pathway for TAVI in ADAS, known as ASTRID-AS (Assessment and Treatment of Decompensated Aortic Stenosis), which he likened to acute MI and acute stroke programs. "Time to TAVI is potentially a modifiable risk factor in patients with ADAS," he said.

Mc Kenna estimated that up to one-third of aortic valve replacements entail patients who present with ADAS, with this subgroup facing a higher risk of prolonged hospitalizations, acute kidney injury, and long-term mortality. Mc Kenna and his colleagues became interested in these patients because they don't always have overt heart failure (HF) symptoms; they may have preserved ejection fraction, yet they present with very advanced AS, he said. Current practice, however, can lead to unnecessary delays—his own center does not have an emergency department, so patients are already arriving a few days into their acute decompensation. And their transfer typically happens after the patient has been stabilized and sent for cardiac imaging, which might be staggered over days or weeks. Moreover, patients found to have asymptomatic AS are typically managed with a watch-and-wait strategy.

"Based on previous studies, people had always assumed there was an element of time," said Mc Kenna. "There's always this kind of paradigm of people thinking that, with asymptomatic severe aortic stenosis, you can just leave them basically untreated in terms of interventional treatment until they develop symptoms, or until the echocardiographic parameters become so severe. . . . We've lived with [that paradigm] for so long and I think maybe that's the difference between aortic stenosis and other kinds of more urgent conditions."

Prior studies of patients with aortic stenosis and cardiogenic shock have supported a role for urgent balloon angioplasty versus a wait-to-stabilize approach, he noted. The aim of this study was to take that one step further with an urgent TAVI pathway.

Time to TAVI

The analysis included all patients with ADAS undergoing urgent TAVI during their index hospitalization, excluding any patients who had a prior ADAS diagnosis. Patients were then stratified according to whether their time to TAVI was shorter or longer than the median delay.

As Mc Kenna showed here, 276 patients were admitted with ADAS, with a median time to TAVI of 22 days (ranging from 12 to 32 days). Procedural complications, he noted, were no different according to time to TAVI, mean ejection fraction at admission was 55%, and follow-up was a mean of 3.1 years.

Overall rates of HF hospitalization/all-cause mortality were 58% for these ADAS patients following TAVI, while rates of HF hospitalization/CV mortality were 35%.

When patients were stratified, however, according to whether they waited more than 22 days to TAVI, or 22 days or less, those with shorter delays had significantly lower rates of all-cause death or HF hospitalization out to 4 years. When patients were further stratified by quartile of delay to TAVI, those in the lowest quartile—less than 13 days—were significantly less likely to die or be hospitalized.

"Oftentimes we think it seems sensible that we should medically stabilize someone and have them kind of optimized before we go into urgent TAVI, but it's a question of whether or not those kinds of assumptions actually are reflected in clinical practice," Mc Kenna told TCTMD. "We're conscious of the fact that this is one center, it's a retrospective cohort study, but I suppose it does raise the question of whether we should be taking that as gospel or whether we should be exploring this more."

Different Waiting Lists

Commenting on the study for TCTMD, Guillaume Bonnet, MD, PhD (Cardiovascular Research Foundation, New York, NY, and University Hospital of Bordeaux, France), who presented two cases of emergency TAVI procedures here at the meeting, said other centers are also rethinking the approach to unstable AS patients.

While he is not convinced that ADAS patients make up one-third of the TAVI population, he said the subset is not insignificant, and warrants attention. "I think there is a shift in the pathway of aortic stenosis care," he said. In the early days of transcatheter aortic valve interventions, procedures were typically planned weeks in advance. Now, triage protocols and advanced training allow for more-rapid identification, workup, and imaging of patients who need TAVI not within weeks, but within hours or days. "Now, for many reasons, there is clearly a place to do some procedures in an emergency fashion," Bonnet said.

This break from the stabilize-first approach, pioneered by surgeons, speaks to a growing evidence base supporting the leveraging of less-invasive procedures to be used emergently, not just for aortic stenosis, but also mitral regurgitation, Bonnet added. In his own case-based presentations at PCR London Valves, Bonnet made the case for "Shock Heart" teams made up of the surgeon, interventionalist, anesthesiologist, and ICU cardiologist who are on call at any given time and who can make quick decisions as to whether a decompensated AS patient needs urgent transcatheter repair.

Such teams, he stressed, need to share the same mindset regarding the benefits and rationale for treating these patients emergently, and be available on call for weekend or after-hours consultation, just as is done for acute MI. Rather than disrupting waiting lists, he said, hospitals may want to think of these kinds of aortic stenosis patients according to entirely different pathways of care—two different waiting lists.

Patrick W. Serruys, MD, PhD (University of Galway, Ireland), commenting on the data following Mc Kenna's presentation, said the study carried an "important message." It's long been assumed that patients should be "compensated" before heading to aortic valve replacement, sometimes even getting sent home from the hospital and then brought back. This small, single-center study implies that presumption needs a second look, he said.

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