Heart failure: A1 Adenosine Antagonists for Heart Failure

August 20, 2007 By Grendel Burrell, M.D. [mailto:grendel.burrell@gmail.com]

Preliminary results of the Phase 2, 50-patient, of BG9928 (ADENTRI®), an A1 adenosine receptor antagonist in stable patients with heart failure were reported in 2003 at the American Heart Association’s annual scientific session. Dr. Barry Greenberg, professor of medicine and director of the Advanced Heart Failure Program at University of California, San Diego Medical Center, and colleagues reported the results in the August 14, 2007, issue of the Journal of the American College of Cardiology, in an article titled Effects of Multiple Oral Doses of an A1 Adenosine Antagonist, BG9928, in Patients With Heart Failure: Results of a Placebo-Controlled, Dose-Escalation Study (J Am Coll Cardiol, 2007; 50:600-606, doi:10.1016/j.jacc.2007.03.059 (Published online 29 July 2007)). BG9928 is a selective inhibitor of the A1 adenosine receptor.

The objective of the study was to assess the pharmacokinetics and pharmacologic effects of BG9928 (ADENTRI®) in heart failure patients with systolic dysfunction. Patients were randomized to one of four doses of BG9928 or placebo, administered orally for 10 days, in addition to standard therapies of ACE inhibitors and diuretics for heart failure. The primary end point for this study was the change in sodium excretion. Additionally, changes in potassium excretion, creatinine clearance, and body weight also were evaluated. BG9928I was “well tolerated and resulted in increases in sodium excretion while preserving renal function”, according to the press release issued by Biogen Idec.

Renal function is an important determinant of the management and outcome of both acute and chronic heart failure (CHF). Impaired renal function raises the risk of cardiovascular mortality, all cause mortality, and morbidity in CHF patients regardless of left ventricular ejection fraction. An analysis from Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program (1) shows an estimated glomerular filtration rate (eGFR) of <60 mL/min was independently associated with the study's primary outcomes of cardiovascular death and hospitalization due to worsening heart failure.

According to statistics from the American Heart Association (AHA), there are currently five million people suffering from heart failure in the United States. With the aging population and more patients surviving the early stages of cardiovascular diseases, the prevalence of CHF is increasing, and thus the combination of CHF and renal impairment is likely rising at the same time. With approximately 550,000 new cases of CHF reported in the United States each year, this presents a huge challenge to practitioners. In 2004, 57,700 deaths were attributed to heart failure. The estimated direct and indirect cost of HF in the United States for 2007 alone is $33.2 billion. 

BG9928 demonstrated increased sodium excretion compared with placebo, and natriuresis was maintained over 10 days with little kaliuresis and no reduction of renal function. There was a linear trend in dose response on day 1 (p = 0.04) but not on days 6 or 10. Adjusted creatinine clearance was unchanged over the 10 day period of drug administration. Patients who received 15, 75, or 225 mg of BG9928 experienced a reduction in body weight compared with placebo (–0.6, –0.7, –0.5, vs. +0.3 kg, respectively) at the end of study. Trends toward beneficial effects in clinical measures of heart failure, including body weight, edema, and physician global assessment, were observed in BG9928-treated patients. There were no significant concerns regarding safety during study drug dosing or during the 30-day follow-up period. The adverse event profile of study drug and placebo were similar. Higher doses of BG9928 were not associated with an increase in adverse events (J Am Coll Cardiol, 2007; 50:600-606, doi:10.1016/j.jacc.2007.03.059 (Published online 29 July 2007)).

The Biogen Idec press release states that the company is “moving forward with oral and intravenous formulations of ADENTRI for acute and chronic heart failure”. Biogen is not the only company is working on an A1 receptor antagonist.

NovaCardia is developing KW-3902, another selective adenosine A1 receptor antagonist, for the treatment of CHF patients with renal impairment and fluid overload. Results of the Phase 3 pilot study were presented at the European Society of Heart Failure meeting, June 2007. The presented results indicated that patients treated with KW-3902, daily for up to 3 days, experienced a higher rate of improvement in dyspnea compared to the placebo group, and the results also showed that KW-3902 enhanced diuresis and mitigated deterioration of renal function.

In this pilot study, 24-hours after treatment, 66% of patients in the group who received the 30milligram dose of KW-3902 self-reported marked or moderate improvement in dyspnea compared to 51% in the placebo group. There were no statistical differences or trends in adverse events observed in the pilot study. The results of the study confirmed 30 milligrams of KW-3902 as an appropriate dose for NovaCardia’s two ongoing 600-patient pivotal Phase 3 trials, PROTECT 1 and PROTECT 2. .