Amgen announces phase 3 ivabradine data for treatment of chronic HF

Amgen (NASDAQ: AMGN) today announced data from the Phase 3 SHIFT (Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial) study evaluating ivabradine in patients with chronic heart failure (HF) were presented at the 18^th Annual Scientific Meeting of the Heart Failure Society of America (HFSA) in Las Vegas. A post-hoc analysis from the SHIFT study confirmed low systolic blood pressure (SBP) is associated with poor outcomes in chronic HF, and that ivabradine reduced the primary composite endpoint of cardiovascular death or hospitalization for worsening HF in this subgroup with low baseline SBP. Safety was similar across the three SBP groups. Results were published in the July 2014 issue of the European Journal of Heart Failure.¹

Ivabradine is an oral drug that inhibits the I_f current ("funny" current) in the sinoatrial node, the body's cardiac pacemaker.² It works to slow the heart rate without negative effects on myocardial contractility or ventricular repolarization.²

"Despite standard of care, chronic heart failure remains a disabling condition with a poor prognosis for patients at risk for hospitalization," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Analyses from the pivotal SHIFT study complement the main trial findings that form the basis of our U.S. submission package for ivabradine. We recently received a priority review designation for ivabradine from the FDA and are working with the agency to potentially bring this important treatment option to certain patients with chronic heart failure in the U.S. as soon as possible."

In August 2014, the U.S. Food and Drug Administration (FDA) granted ivabradine priority review designation, which is assigned to applications for drugs that treat serious conditions and would, if approved, provide significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions compared to available therapies.³ FDA will target a priority review Prescription Drug User Fee Act (PDUFA) action date of Feb. 27, 2015.

The SHIFT study is a large, multi-center, randomized, double-blind, placebo-controlled, outcomes trial that compared ivabradine to placebo on top of standard-of-care therapies, including beta-blockers, in more than 6,500 patients with symptomatic chronic HF in sinus rhythm with reduced left ventricular function and heart rate >70 beats per minute (bpm).

At HFSA, Amgen presented a post-hoc analysis of the SHIFT study that evaluated the efficacy and safety of ivabradine across three different blood pressure groups, divided according to SBP: low SBP (<115 mm Hg; n=2,010), intermediate SBP (115-130 mm Hg; n=1,968) and high SBP (>130 mm Hg; n=2,427). The analysis confirmed chronic HF with low SBP is associated with poor outcomes, and that ivabradine reduced the primary composite endpoint of cardiovascular death and hospitalization for worsening HF independent of baseline SBP. Safety was similar across the three SBP groups. The most common adverse events were phosphenes and bradycardia, which occurred more frequently with ivabradine.

"Low blood pressure is a common condition in chronic heart failure that complicates management and is associated with negative outcomes such as death and hospitalization," said Jeffrey S. Borer, M.D., professor of medicine, cell biology, radiology and surgery, State University of New York, Downstate Medical Center. "The analysis from the SHIFT study showed consistent results regardless of systolic blood pressure, which provides further evidence that ivabradine has the potential to improve clinical outcomes, on top of standard therapy, in certain patients with chronic heart failure."

Additional findings presented at the HFSA meeting included data from a pre-specified Holter electrocardiography sub-study (ECG-Holter sub-study), which evaluated 501 patients from the SHIFT trial to better understand the relationship between heart rate and safety/incidence of adverse events while taking ivabradine on top of optimized HF therapy, including beta blockers. Results showed that at eight months, 24-hour heart rate was significantly reduced by 9.5 + 10.1 bpm in the ivabradine group (n=254) versus 1.2 + 8.9 bpm in the placebo group (n=247) (p<0.0001). Higher rates of at least one episode of heart rate less than 40 bpm were also reported in the ivabradine group (p<0.0001). No increase in significant pauses, second/high degree atrioventricular block or arrhythmias was observed in the ivabradine group in this sub-study.

Heart failure is a common condition that affects approximately 26 million worldwide, including approximately 5.1 million people in the U.S.^4,5 It is the leading cause of rehospitalization in Medicare beneficiaries over age 55,⁶ and approximately 50 percent of people diagnosed with HF in the U.S. die within five years of diagnosis.⁵ Projections show that by 2030, the prevalence of HF will increase 25 percent from 2013 estimates.⁵ Despite broad use of standard treatments, the prognosis for HF is poor.⁷

SHIFT Study Design
SHIFT (Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial) is a large, multi-center, randomized, double-blind, placebo-controlled, outcomes study involving more than 6,500 patients in 37 countries. The Phase 3 SHIFT study compared ivabradine to placebo on top of standard-of-care therapies (including beta blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), diuretics and/or aldosterone antagonists), in patients with symptomatic chronic HF in sinus rhythm with reduced left ventricular function and heart rate >70 bpm. After a run-in period of 14 days without study treatment, eligible patients were randomized to receive ivabradine or placebo, with a starting dose of 5 mg daily. After a 14-day titration period, at Day 14, the dose was increased to 7.5 mg twice daily, unless the resting heart rate was 60 bpm or lower. If resting heart rate fell below 50 bpm or patients experienced signs or symptoms of bradycardia, the dose was reduced to 2.5 mg twice daily. The double-blind treatment period lasted approximately 12-48 months.

The primary endpoint was the composite of cardiovascular death or hospitalization for worsening HF. The first secondary endpoint was the composite of cardiovascular death or hospitalization for worsening HF in patients receiving at least 50 percent of the target daily dose of beta blockers at randomization. Other secondary endpoints included all-cause death, any cardiovascular death, hospitalization for worsening HF, all-cause hospitalization, any cardiovascular hospitalization and death from HF, and the composite of cardiovascular death, hospitalization for worsening HF or hospitalization for non-fatal myocardial infarction.

The SHIFT study, which completed in May 2010, was funded by Les Laboratoires Servier and coordinated by the SHIFT executive committee, an international group of HF experts.