Neladenoson bialanate hydrochloride

Heart failure with preserved ejection fraction (HFpEF) lacks effective treatments. Based on preclinical studies, neladenoson bialanate, a first-in-class partial adenosine A1 receptor agonist, has the potential to improve several heart failure-related cardiac and noncardiac abnormalities but has not been evaluated to treat HFpEF.

To determine whether neladenoson improves exercise capacity, physical activity, cardiac biomarkers, and quality of life in patients with HFpEF and to find the optimal dose.

Phase 2b randomized clinical trial conducted at 76 centers in the United States, Europe, and Japan. Patients (N = 305) with New York Heart Association class II or III HFpEF with elevated natriuretic peptide levels were enrolled between May 10, 2017, and December 7, 2017 (date of final follow-up: June 20, 2018).

Participants were randomized (1:2:2:2:2:3) to neladenoson (n = 27 [5 mg], n = 50 [10 mg], n = 51 [20 mg], n = 50 [30 mg], and n = 51 [40 mg]) or matching placebo (n = 76) for 20 weeks of treatment.

The primary end point was change in 6-minute walk test distance from baseline to 20 weeks (minimal clinically important difference, 40 m). Key safety measures included bradyarrhythmias and adverse events. To evaluate the effects of varying doses of neladenoson, a multiple comparison procedure with 5 modeling techniques (linear, Emax, 2 variations of sigmoidal Emax, and quadratic) was used to evaluate diverse dose-response profiles.

Among 305 patients who were randomized (mean age, 74 years; 160 [53%] women; mean 6-minute walk test distance, 321.5 m), 261 (86%) completed the trial and were included in the primary analysis. After 20 weeks of treatment, the mean absolute changes from baseline in 6-minute walk test distance were 0.2 m (95% CI, -12.1 to 12.4 m) for the placebo group; 19.4 m (95% CI, -10.8 to 49.7 m) for the 5 mg of neladenoson group; 29.4 m (95% CI, 3.0 to 55.8 m) for 10 mg of neladenoson group; 13.8 m (95% CI, -2.3 to 29.8 m) for 20 mg of neladenoson group; 16.3 m (95% CI, -1.1 to 33.6 m) for 30 mg of neladenoson group; and 13.0 m (95% CI, -5.9 to 31.9 m) for 40 mg of neladenoson group. Because none of the neladenoson groups achieved the clinically relevant 40-m increase in 6-minute walk test distance from baseline, an optimal dose of neladenoson was not identified. There was no significant dose-response relationship for the change in 6-minute walk test distance among the 5 different dose-response models (P = .05 for Emax; P = .18 for quadratic; P = .21 for sigmoidal Emax 1; P = .39 for linear; and P = .52 for sigmoidal Emax 2). Serious adverse events were similar among the neladenoson groups (61/229 [26.6%]) and the placebo group (21/76 [27.6%]).

Among patients with HFpEF, there was no significant dose-response relationship detected for neladenoson with regard to the change in exercise capacity from baseline to 20 weeks. In light of these findings, novel approaches will be needed if further development of neladenoson for the treatment of patients with HFpEF is pursued.

ClinicalTrials.gov Identifier: NCT03098979.

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 Ca2+-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.