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

Abstract

Despite major advances in the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF), morbidity and mortality associated with the condition remain high, suggesting the need for additional treatment options, particularly haemodynamically neutral treatments that do not alter blood pressure, heart rate, or renal function. HF with preserved ejection fraction (HFpEF) is also associated with high morbidity and mortality and adequate treatment options are limited; thus there is a critical unmet need for the development of novel therapies for HFpEF. Chronic HFrEF and HFpEF are both systemic disorders that affect not only the heart but several other tissues and organs including skeletal muscle, leading to exercise intolerance and dyspnoea. Partial adenosine A1-receptor agonists represent a novel potential therapy for HF regardless of underlying ejection fraction given their minimal effect on heart rate and blood pressure, and preclinical data demonstrate several possible beneficial mechanisms, including improved mitochondrial function and sarcoplasmic reticulum Ca -ATPase (SERCA2a) activity, enhanced energy substrate utilization, reverse ventricular remodelling, and anti-ischemic, cardioprotective properties. However, data on this class of drugs in humans are scarce, and the optimal dose of the partial adenosine A1 receptor, neladenoson bialanate, has not been defined. Here we describe the design and rationale of two randomized, double-blind, placebo-controlled, parallel-group, dose-finding phase 2b trials, PANTHEON (HFrEF) and PANACHE (HFpEF), that will advance our understanding of the potential benefit and optimal dose of neladenoson bialanate and provide critical information for the planning of future phase 3 trials.

November 2018 at a glance: from prediction of heart failure in asymptomatic subjects to advanced chronic heart failure

“…These effects have been shown in experimental models and small patient groups . Further data are expected from the two phase 2b clinical trials PANTHEON and PANACHE . They are multicentre, randomized, double‐blind, placebo controlled, parallel‐group, dose‐finding phase 2 trials testing the safety and efficacy of 20 week treatment with neladenoson bialanate vs. placebo in HFrEF and HFpEF patients, respectively.…”

“…17 -19 Further data are expected from the two phase 2b clinical trials PANTHEON and PANACHE. 20 They are multicentre, randomized, double-blind, placebo controlled, parallel-group, dose-finding phase 2 trials testing the safety and efficacy of 20 week treatment with neladenoson bialanate vs. placebo in HFrEF and HFpEF patients, respectively. Primary endpoints are the absolute change from baseline in left ventricular EF and N-terminal pro brain natriuretic peptide in PANTHEON and the 6-minute walk test distance change from baseline in PANACHE.…”

“…Primary endpoints are the absolute change from baseline in left ventricular EF and N-terminal pro brain natriuretic peptide in PANTHEON and the 6-minute walk test distance change from baseline in PANACHE. 20…”

November 2019 at a glance. Chronic and acute heart failure: from epidemiology to treatment

“…More than 400 patients with HFrEF were randomized to once daily oral neladenoson bialanate at different dosages or placebo . After 20 weeks of treatment, there was no effect of neladenoson bialanate on changes in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) or LV ejection fraction (primary endpoints) or in LV volumes, troponin T, cardiovascular mortality, and HF hospitalization.…”

Safety and efficacy of the partial adenosine A1 receptor agonist neladenoson bialanate in patients with chronic heart failure with reduced ejection fraction: a phase IIb, randomized, double‐blind, placebo‐controlled trial

“…Heart failure (HF) with reduced ejection fraction (HFrEF) is characterized by impaired mitochondrial function and impaired calcium handling due to a decreased activity of sarcoplasmic reticulum Ca 2+ ‐ATPase (SERCA2a). Activation of adenosine A1 receptors in the heart results in improved mitochondrial function and sarcoplasmic SERCA2 activity and modulates energy substrate utilization . Therefore, adenosine A1 receptor agonists may be beneficial in patients with HF.…”