AstraZeneca in a jam after drug setback Analysts say the company will have to do broad studies to prove Exanta's safety, or could end its development.

Posted: September 20, 2004

AstraZeneca P.L.C., Europe's third-largest drugmaker, is facing a dilemma after an expert U.S. medical panel voted against recommending approval of a key new drug, the blood thinner Exanta.

A Food and Drug Administration advisory committee decided Sept. 10 that Exanta's risk of liver and heart damage outweighed its benefits in preventing blood clots. Analysts say the London-based drugmaker will have to conduct extensive new patient studies to prove the drug's safety, or could decide to discontinue its development.

The setback for Exanta took investors by surprise, and shares of AstraZeneca have fallen 11 percent since Sept. 8 as analysts removed U.S. sales forecasts for Exanta from their financial projections.

"They should probably throw in the towel on this drug," pharmaceutical analyst Timothy Anderson of Prudential Equity Group L.L.C. said in a research note to clients.

The FDA, which usually follows its expert panels' advice, will announce its decision on Exanta by Oct. 23.

Exanta is one of three new drugs, including cholesterol-reducer Crestor and lung cancer medicine Iressa, that AstraZeneca has been counting on to offset flagging sales of its once best-selling ulcer medication Prilosec, which has lost patent protection and sales to lower-cost generics. Prilosec sales worldwide declined from $6.1 billion in 2000 to $2.56 billion in 2003.

Exanta has attracted intense interest because it is the first new anticoagulant pill in more than 50 years, since the introduction of warfarin, which Bristol-Myers Squibb Co. markets under the brand name Coumadin.

AstraZeneca said it would continue discussions with the FDA "on a way forward for Exanta," chief executive officer Tom McKillop said in a statement.

But analysts say even if AstraZeneca - which employs 6,000 at its U.S. headquarters in Wilmington - provides more clinical data, regulatory approval is at least two years away and sales could end up disappointing because of the mixed safety and efficacy concerns.

In May, Exanta was approved in 14 European Union countries to prevent blood clots in knee and hip replacement surgeries.

The key issue is how much additional data the FDA will request, Merrill Lynch & Co. Inc. analyst James Culverwell said in a note to clients. "In our opinion, this is likely to be extensive," he said. The FDA panel's concerns may mean the company would have to re-run the entire Phase 3 studies, which "significantly delays potential launch," Culverwell said.

The panel's safety concerns focused on the deaths of three Exanta patients that may have been related to liver injury. The death rate from liver failure was one in every 2,300 patients, FDA reviewers said in documents posted on the agency Web site.

AstraZeneca spokeswoman Rachel Bloom-Baglin said: "We were confident in the data" submitted to the FDA.

"In terms of next steps, we will need to consult with the agency. I'm not going to speculate on the future of Exanta," she said. "Until we have that conversation, any announcement on our next steps would be premature."

AstraZeneca is seeking U.S. regulatory approval to sell Exanta as a short-term treatment for people who have had knee replacements, as a long-term therapy for preventing new blood clots in patients already treated for a blood clot, and for preventing strokes in people with irregular heart rhythm, called atrial fibrillation. The advisory panel rejected the drug for all three uses.

"Although we had been skeptical of Exanta, the outcome was worse than even we had expected," Anderson, the Prudential analyst, said.

Analysts had predicted sales of Exanta could reach $1.5 billion worldwide by 2008. The company estimated the global market for blood-thinner medicines to be $12 billion annually.

Exanta is not the only AstraZeneca drug facing challenges. The company has had to defend itself over safety concerns about another new drug, its cholesterol-lowering medicine Crestor, which the U.S. consumer group Public Citizen wants banned because of a possible link to a potentially fatal muscle weakening condition.

And sales of the new lung-cancer medicine Iressa, approved by the FDA in May 2003, have fallen short of some market forecasts because the medicine is used by a small group of patients with advanced non-small-cell lung cancer after other chemotherapy treatments have failed.

Investors are focused on the company's annual business review Oct. 6 in London, at which executives will discuss prospects for promising new drugs in development and new indications for established drugs.

Anderson listed several challenges for AstraZeneca, including "ongoing competitive pressures" on Crestor and the heartburn medication Nexium, and concern over how regulators will view the safety profile of Galida, a diabetes drug in Phase 3 studies. He wrote that testing of Galida has turned up possible kidney problems.

AstraZeneca officials remain upbeat about their drug research and development pipeline. The company expects to file for FDA marketing approval for Galida and Symbicort (for asthma) in 2006, Bloom-Baglin, the spokeswoman, said.

Culverwell, the Merrill Lynch analyst, said: "The AstraZeneca investment story, in our view, remains well supported by the momentum of the existing business" - with few looming patent expirations on major products and "substantial growth to be derived from drugs such as Crestor, Seroquel, Nexium, Iressa and Atacand."

Contact staff writer Linda Loyd at 215-854-2831 or lloyd@phillynews.com.

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