Safety and Efficacy of Neladenoson Bialanate, a Partial Adenosine A1 Receptor Agonist, in Patients with Heart Failure and Preserved Ejection Fraction: The PANACHE Trial

Educational Objectives

After completing the activity, the clinician will be better able to summarize the results of a dose-finding randomized clinical trial of a first-in-class partial adenosine A1 receptor agonist for the treatment of patients with heart failure and preserved ejection fraction.

Summary

Interviewer: Allen J. Taylor, MD, FACC

This author has nothing to disclose.

 

Take-home Messages:

• Despite great effort, heart failure with preserved ejection fraction (HFpEF) continues to lack effective treatments. Based on preclinical results, investigators conducted a dose-finding study of neladenoson bialanate, a first-in-class partial adenosine A1 receptor agonist, in patients with symptomatic HFpEF.
• There was no significant dose-response relationship detected for neladenoson with regard to any of the studied primary or secondary endpoints.

 

For as widespread a condition as it is, the therapeutic landscape for HFpEF is pretty barren. It is not for a lack of trying: neurohormonal antagonists (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists), nitrates, and phosphodiesterase type 5 inhibitors have all been studied, but the results in HFpEF have been largely null. Certainly, no treatments have been shown to convincingly reduce morbidity, mortality, or both.

Perhaps one issue is the vast number of targets with this syndrome, given that the effects of HFpEF go well beyond abnormalities in left ventricular (LV) diastolic function. Indeed, HFpEF is much more of a systemic disease, leading to widespread microvascular dysfunction that involves all cardiac chambers, as well as other organs such as the lungs, kidneys, and skeletal muscles.

In addition, LV systolic function is often abnormal, and despite the fact that global LV ejection fraction (LVEF) is preserved, LV longitudinal fiber systolic function (reflecting the health of the subendocardium) is frequently impaired. HFpEF also is associated with markedly reduced reserve capacity, so that cardiac, vascular, and skeletal muscle dysfunction become apparent during exertion.

Given its systemic nature, an ideal HFpEF therapy would target several underlying pathophysiologic effects related to multiorgan reserve dysfunction. Neladenoson bialanate is a partial adenosineA1 receptor agonist shown in preclinical models to improve mitochondrial function in heart and skeletal muscle, enhance SERCA1a (sarco/endoplasmic reticulum 2a) activity (so, improved diastolic function), optimize energy substrate utilization (i.e., cardiac energetics), reverse ventricular remodeling via decreased fibrosis/hypertrophy, increase myocardial capillary density, and provide anti-ischemic cardioprotective effects – all without the adverse effects of full A1 receptor agonists or A1 receptor antagonists.¹

 

PANACHE

Based on this, investigators hypothesized that 20 weeks of therapy with neladenoson would show a positive dose-response relationship compared with placebo. Sanjiv J. Shah, MD (Northwestern University Feinberg School of Medicine), and colleagues designed the PANACHE randomized controlled trial, a phase IIb dose-finding study.

Of 305 patients with symptomatic HFpEF who were randomized, 275 completed treatment. The primary endpoint was change in 6-minute walk test distance from baseline to 20 weeks, with a difference of 40 meters considered the minimal clinically important difference. After 20 weeks of treatment, there was no significant dose-response relationship detected for neladenoson with regard to the primary endpoint.

There was no significant dose-response effect on secondary efficacy endpoints either, including change from baseline to 20 weeks for activity intensity, N-terminal pro–B-type natriuretic peptide level, high-sensitivity troponin T level, and Kansas City Cardiomyopathy Questionnaire overall summary score.

There was no difference in major adverse events for any dose of neladenoson compared with placebo.

The drug did have a pharmacologic effect, based on progressively lower glomerular filtration rates and heart rates with increasing doses and increasing exposure.

 

What Happened?

Dr. Shah, cochair of the study steering committee, said patient selection was not problematic and participants did indeed have HFpEF. There was high compliance, based on blood levels of the drug, and there was a measurable pharmacologic effect. And the drug was very safe.

It turns out that the preclinical evidence was weak in HFpEF. All the preclinical models studied were really models of HF with reduced ejection fraction, Dr. Shah admitted, noting that “we’re starting to get better HFpEF animal models,” which means future preclinical studies may be more reliable. The bottom line, he said, is that “we need stronger preclinical data before we go into patients.”

 

References:

1. Voors AA, Shah SJ, Bax JJ, et al. Rationale and design of the phase 2b clinical trials to study the effects of the partial adenosine A1-receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced (PANTHEON) and preserved (PANACHE) ejection fraction. Eur J Heart Fail 2018;20:1601-10.
2. Shah SJ, Voors AA, McMurray JJV, et al. Effect of Neladenoson Bialanate on Exercise Capacity Among Patients with Heart Failure with Preserved Ejection Fraction: A Randomized Clinical Trial. JAMA 2019;321:2101-12.

 

Readings

Disclosures

AstraZeneca (C); Bayer AG (C); Ionis Pharmaceuticals (C); Merck & Co Inc (C); Novartis AG (C); Pfizer Inc (C); Janssen Global Services LLC (G)

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AC510912

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

More Details - Certification & Accreditation