Amgen's Aranesp did not meet endpoints and increased risk of stroke; firm accused of kickbacks

Leading US biotechnology firm Amgen suffered a double dose of bad news on October 30, when the firm revealed that its blockbuster anemia drug Aranesp (darbepoetin alfa) did not meet critical endpoints in a Phase III study and that it is being accused of illegal kickbacks in the promotion of the product.

Aranesp has lost sales since 2006 when high doses of the drug were linked to increased rates of heart attack and death in kidney patients. Its sales fell 25 percent to $3.1 billion in 2008 from $4.1 billion in 2006. Worldwide turnover of the drug decreased 19% to $685 million in the third quarter of 2009, falling 27% in the USA to $333 million (The Pharma Letter October 22).

Amgen reported that results from TREAT (the Trial to Reduce Cardiovascular Events with Aranesp Therapy), a large, randomized, double-blind, placebo-controlled, Phase III pivotal study of patients with chronic kidney disease (CKD) not on dialysis, moderate anemia and type-2 diabetes, published in the New England Journal of Medicine and presented at the annual meeting of the American Society of Nephrology (ASN), failed to meet primary objectives of demonstrating a reduction in all-cause mortality, cardiovascular morbidity, including heart failure, heart attack, stroke, or hospitalization for myocardial ischemia, or end-stage renal disease (ESRD).

The primary endpoints of the study were a composite of time to all-cause mortality or cardiovascular morbidity (including heart failure, heart attack, stroke, or hospitalization for myocardial ischemia) and a composite of time to all-cause mortality or ESRD. Among the components of the primary cardiovascular composite endpoint, the risk of stroke increased by almost two-fold in patients in the Aranesp arm (101 patients [5.0%] versus 53 patients [2.6% percent]; hazard ratio, 1.92; 95% confidence interval, 1.38 to 2.68; P<0.001). although stroke is a recognized risk with erythropoiesis-stimulating agent (esa) therapy, and has been identified in warnings in us labeling since 2001, the risk observed in treat is of higher magnitude than that seen in previous clinical trials in ckd patients not on dialysis. the company admitted.>

A post hoc analysis indicates that there were no significant differences between treatment arms in the incidence of cancer or of all-cause deaths in patients who developed cancer during the trial. However, this analysis also showed an excess in overall mortality among patients in the Aranesp arm with a history of cancer. This finding requires further investigation.

Illegal kickbacks alleged by several states

Meantime, Amgen has been accused by New York and some other US states of engaging in illegal kickbacks to promote sales of Aranesp, reports the New York Time and other media.

In a law suit filed Friday by 14 states and the District of Columbia, they claim that Amgen, in effect, provided free samples to doctors and clinics by putting tiny extra amounts of the drug in each vial. The medical practices could then make a profit by billing insurers, including state Medicaid programs, for the extra drug. The litigation also contends that Amgen conspired to offer incentives, such as weekend retreats and non-existent consultancy agreements, to increase prescriptions for the product.

'In an egregious violation of the law, Amgen allegedly bribed medical providers and left taxpayers footing the bill for free drug samples,' Andrew Cuomo, attorney general of New York, whose office led the investigation, said in a statement. "Drugs should be prescribed to patients on the basis of need, effectiveness, and safety, not on a corporate giant's promise of an all-expense paid vacation," Mr Cuomo said. "In an egregious violation of the law, Amgen allegedly bribed medical providers and left taxpayers footing the bill for free drug samples," he added.

The law suit, which was filed in federal court in Boston by 14 states and the District of Columbia, also names drug distributor AmerisouceBegen. The case joins a whistle-blower suit with similar allegations filed in 2006 by Kassie Westmoreland, a former Amgen sales representative.

Amgen spokesman David Polk said: "We believe that the allegations are without merit, and we look forward to the opportunity to examine these matters with the states before the court." He added that the company has a solid compliance program and a code of conduct called "Do The Right Thing," noting that the company expects that all employees to follow it at all times.