AstraZeneca's discussions with FDA over the safety profile of its investigational anticoagulant Exanta will center on elevated liver enzyme levels reported during clinical trials.

"A percentage of treated patients showed an elevation of liver enzymes" in Phase III Exanta (ximelagatran) studies, AstraZeneca CEO Tom McKillop told investors during a conference call July 24.

"Any signal of hepatotoxicity must be taken very seriously," McKillop said. "With excellent efficacy demonstrated, we believe that this is now the major remaining issue for Exanta, and it certainly will be a key feature of the regulatory review."

Blood tests taken during the THRIVE Treatment venous thromboembolism prevention study showed a 9.6% incidence of liver enzyme elevation among Exanta patients, versus 2% of patients on enoxaparin/warfarin. The elevations were "transient" and "decreased spontaneously whether treatment continued or was stopped," the company said.

AstraZeneca cautioned investors that Exanta's risk-benefit profile cannot be fully understood until all the data have been analyzed. "The Exanta development program is large by any standards, and we have an immense amount of data to analyze, interpret and write-up in support of the registration package," McKillop said.

"The remaining work includes detailed clinical follow-up, [and] seeking the opinions of world experts and our own researchers into understanding the phenomenon. Since this work is not yet complete, conclusions reached on risk-benefit at this stage is only preliminary."

"While I fully understand your desire to calibrate the liver contribution to the risk side of the benefit-to-risk equation, it's simply not possible, nor sensible, for us to respond to highly detailed questions on individual pieces of the jigsaw at this stage."

AstraZeneca will file NDAs in the fourth quarter for prevention of venous thromboembolism following elective hip or knee replacement surgery, and prevention of stroke in atrial fibrillation patients.

The incidence of elevated liver enzymes could complicate AstraZeneca's plans to position Exanta as a cost-effective alternative to warfarin, which requires regular coagulation monitoring (¹ Also see "AstraZeneca Exanta NDA Filing Set For 2003; Cost-Effective Vs. Warfarin?" - Pink Sheet, 18 November, 2002., p. 18).

AstraZeneca says it expects final labeling to recommend regular monthly liver function monitoring; increases in liver enzyme levels were also seen in the THRIVE III and SPORTIF III studies (² Also see "AstraZeneca Crestor, Exanta Promotions Will Focus On Dosing Advantages" - Pink Sheet, 14 April, 2003., p. 35).

As a first-in-class product, FDA is likely to take a conservative stance on Exanta, as its benefit-risk profile cannot be directly compared to other drugs. Exanta is an oral direct thrombin inhibitor; AstraZeneca describes it as the first breakthrough in the category since warfarin 50 years ago.

One other remaining safety issue, an increased incidence of bleeding among Exanta patients, has been resolved, McKillop told investors. "Very encouragingly, it appears that in chronic use with fixed dosing, bleeding is not a significant problem," he said.

In the THRIVE Treatment study, Exanta showed a favorable trend over enoxaparin/warfarin in the risk of major bleeding, AstraZeneca said: 14 Exanta patients reported major bleeds, versus 25 on standard therapy, for an estimated cumulative risk of 1.3% versus 2.2% in the on-treatment analysis.

AstraZeneca looked for other potential safety issues associated with Exanta use, but "as far as we are concerned, the only issue is liver," McKillop declared. "This drug is an excellent drug, and it will be an interesting discussion with regulators on benefit-risk."

The six-month THRIVE Treatment study demonstrated non-inferiority to enoxaparin/warfarin in VTE patients. The results support data from THRIVE III; the two studies will form the basis of Exanta's regulatory filings in the indication.

AstraZeneca will present data from SPORTIF III at the European Society of Cardiology meeting in September. The open-label trial demonstrated non-inferiority to standard-of-care warfarin. Data from SPORTIF V, a double-blind study in the same patient population, will be discussed at the American Heart Association annual meeting in November.

AstraZeneca Exanta Liver Safety Is Key Approval Issue, Company Says

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