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CLINICAL RESEARCH: HEART FAILURE

Effects of Multiple Oral Doses of an A₁ Adenosine Antagonist, BG9928, in Patients With Heart Failure

Results of a Placebo-Controlled, Dose-Escalation Study

Barry Greenberg, MD^_*,1,_*, Ignatius Thomas, MD^,2, Dorothy Banish, MD, Steven Goldman, MD, Edward Havranek, MD^||,3, Barry M. Massie, MD^¶,4, Ying Zhu, PhD^#,5, Barry Ticho, MD, PhD^#,5 and William T. Abraham, MD^_**,6

^_* University of California, Advanced Heart Failure Treatment Program, San Diego, California
Medical Research Institute, Slidell, Louisiana
Tchefuncte Cardiovascular Associates, Covington, Louisiana
Tucson VA Medical Center, SAVAHCS, Sarver Heart Center, and University of Arizona, Tucson, Arizona
^|| Denver Health Medical Center, Denver, Colorado
^¶ University of California and San Francisco VA Medical Center, San Francisco, California
^# Biogen Idec Inc., Cambridge, Massachusetts
^_** The Ohio State University Heart Center, Division of Cardiology, Columbus, Ohio.

Manuscript received August 22, 2006; revised manuscript received February 26, 2007, accepted March 20, 2007.

^_* Reprint requests and correspondence: Dr. Barry Greenberg, Advanced Heart Failure Treatment Program, University of California–San Diego, 200 West Arbor Drive-8411, San Diego, California 92103-8411. (Email: bgreenberg{at}ucsd.edu).

Objectives: This study sought to assess the pharmacokinetics and clinical effects of oral BG9928 in heart failure (HF) patients.

Background: Declining renal function during HF treatment is associated with poor outcomes. BG9928, a selective inhibitor of the A₁ adenosine receptor, is proposed to cause natriuresis without causing a decline in renal function.

Methods: A randomized, double-blind, placebo-controlled study was conducted in patients with HF and systolic dysfunction who were receiving standard therapy. Patients were randomized to receive BG9928 (3, 15, 75, or 225 mg) or placebo orally for 10 days. The primary end point was change in sodium excretion. Changes in potassium excretion, creatinine clearance, and body weight also were evaluated.

Results: A total of 50 patients were studied. BG9928 increased sodium excretion compared with placebo, and natriuresis was maintained over 10 days with little kaliuresis. A linear trend in dose response was observed on day 1 (p = 0.04) but not on days 6 or 10. Adjusted creatinine clearance was unchanged over the 10 days. Patients who received 15, 75, or 225 mg of BG9928 had a reduction in body weight compared with placebo (–0.6, –0.7, –0.5, vs. +0.3 kg, respectively) at the end of study. BG9928 was well tolerated. The pharmacokinetic profile of BG9928 was consistent with once-daily dosing.

Conclusions: Oral BG9928 over the dose range of 3 to 225 mg/day produced significant increases in sodium excretion in patients with stable HF without causing kaliuresis or reducing renal function.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   ARB = angiotensin II receptor blocker   AUC = area under the concentration time curve   Cmax = peak concentration   CrCl = creatinine clearance   ECG = electrocardiogram   HF = heart failure   NYHA = New York Heart Association   t = elimination half-life   tmax = time to Cmax

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