Washington Editor

GAITHERSBURG, Md. - A treatment for sepsis has eluded scientists and biotechnology companies for nearly two decades, and the tide may not have turned Tuesday when a government panel said Eli Lilly and Co. failed to prove its potential blockbuster is safe and effective.

In a 10-to-10 vote, the Anti-Infective Drugs Advisory Committee was split on whether Xigris was safe and efficacious. It did not vote on whether to recommend approval.

"We are shocked at the vote based on previous discussions with the FDA and others in academia," Elaine Sorg, a critical care business unit leader with Lilly, said after the vote.

William Macias, a medical director with Lilly, said the company was stunned because it had reviewed the data with key opinion leaders around the world and they all had embraced it.

But all is not lost for the Indianapolis-based company, known best in recent years for its success with the antidepressant Prozac, because the FDA makes the final decision and is not bound by the committee's vote. (The vote total never was formalized; some observers counted the vote as 10-9 against the drug, with one abstention.)

If approved for a general indication, Xigris is expected to be a $1 billion to $2 billion drug. Xigris is under priority review with an Oct. 27 FDA deadline. If approved it would be the first sepsis drug on the market.

At least 20 products over the years have been tested for the indication, and time after time the candidates have failed in various stages of clinical testing.

Label Could Be Limited

Although Lilly wants to give Xigris to all adults suffering from sepsis, the consensus on the 20-member committee was that Xigris should be limited to the most severe sepsis patients who have poorer prognoses.

"There is an effect from this drug," said Lyman Reller, the committee chairman and director of clinical microbiology at Duke University Medical Center in Durham, N.C. "I think it is in higher-risk patients. I don't think the data allows general approval at this time."

Michael O'Fallon, chairman of the department of health sciences research at the Mayo Clinic in Rochester, Minn., who voted in favor of the product, said part of his concern about Xigris focused on the design of the trial. "Their basis was whether someone died. I think we need to look at quality of life," he said.

Xigris, formerly called Zovant, is a genetically engineered version of the human activated protein C molecule, which helps balance the forces behind sepsis, including inflammation, coagulation, and suppression of fibrinolysis (the body's clot-busting system). Lilly said Xigris differs from the natural form of activated protein C by specialized chemical attachments composed of complex carbohydrates that are not found in other biotech treatments such as insulin.

People suffering from sepsis are unable to regulate inflammation and coagulation, leading to tissue damage, organ failure, and sometimes death. The condition is triggered by trauma, surgery, burns or illnesses like cancer and pneumonia. Currently it is treated with antibiotics.

Sepsis strikes about 750,000 people annually, killing about 215,000, according to statistics provided by Lilly. It is considered the leading cause of death in noncoronary ICU patients.

Lilly presented safety and efficacy data from a Phase III randomized, placebo-controlled trial of nearly 1,700 adults with severe sepsis. (Severe sepsis is associated with at least one failed organ.) Treatment with Xigris resulted in a reduction in 28-day all-cause mortality compared to placebo-treated patients (25 percent vs. 31 percent, respectively, p=0.005).

On the safety side, the number of patients experiencing serious bleeding adverse events in Phase III was 3.5 percent (30/850) in those receiving Xigris, and 2 percent (17/840) in those receiving placebo.

Identifying adverse events in sepsis patients is difficult because the indication is associated with so many other illnesses, Robert Lindblad, a medical officer with the FDA, told the panel.

Add that to the fact that sepsis is largely a misunderstood disease, said William Lyons, a physician from Falls Church, Va. Lyons addressed the panel during the public hearing, saying he doesn't think Xigris should be approved.

"I think Xigris will be used off-label and they only had a 6 percent reduction in mortality. That is not going to make a difference. I submit that 6 percent is not clinically significant," Lyons said.

On the other hand, Thomas Smirniotopoulos, a physician from Alexandria, Va., told the panel he couldn't imagine why Xigris would not be approved. "My belief is that it would be useful for patients who are going into organ failure. We may need some restraint on how it is used, but we need to move forward to fight this serious problem."

Sepsis A Well-Researched Indication

And although Lilly may be the first on the market, there is competition angling to win a share. ICOS Corp., of Bothell, Wash., and its partner, Suntory Ltd. of Japan, are developing their own sepsis product known as Pafase. Currently in Phase III trials, Pafase is a recombinant human serum protein that inactivates platelet-activating factor, a pro-inflammatory mediator that has been found in excess amounts in the blood and lungs of patients with severe sepsis and severe trauma. (See BioWorld Today, April 30, 2001.)

Beginning in the mid-1980s, a series of biotechnology companies tried - and failed - to develop a sepsis treatment. For example, Xoma Corp., of Berkeley, Calif., and its marketing partner, Pfizer Inc., of New York, abandoned trials of an E5 monoclonal antibody for sepsis after an interim analysis of 1,000 patients in a Phase III trial failed to support continuation of the study. At the time of the failure, Xoma representatives said the all-cause mortality hurdle is so high that is difficult to succeed, particularly given the fact that the patients are suffering from other illnesses. (See BioWorld Today, April 28, 1997.)

Others that failed in the indication were Synergen Inc., of Boulder, Colo.; Centocor Inc., of Malvern, Pa.; Immunex Corp., of Seattle; Cortech Inc., of Denver; and Celltech Group plc, of Slough, UK.