Lilly Asserts The New England Journal of Medicine ``Sounding Board'' Opinion Article Attempts to Turn Back the Clock on Care of Severe Sepsis Patients.

Business Editors & Health/Medical Writers

INDIANAPOLIS--(BUSINESS WIRE)--Sept. 25, 2002

In Rare Written Rebuttal, FDA Reaffirms That Xigris(R) Saves Lives

Eli Lilly and Company (NYSE:LLY) today stated that "Risks and Benefits of Activated Protein C Treatment for Severe Sepsis" (Warren, et al.), an opinion article published in this week's The New England Journal of Medicine(a) is without merit.

The four authors' opinions regarding the protocol design and outcomes from the 1,690-patient Phase III PROWESS trial of Xigris(R) (drotrecogin alfa (activated)) are based on incomplete information and contradict the decisions of the multiple independent authorities that analyzed Xigris clinical data. This includes the U.S. Food and Drug Administration (FDA), the Centers for Medicare and Medicaid Services (CMS), regulatory authorities in 11 other countries(1) and, most recently, the European Committee for Proprietary Medicinal Products whose positive opinion resulted in Xigris approval in the 15 member countries it represents.

"Xigris is a proven lifesaving advance for the treatment of adult patients with life-threatening severe sepsis. To imply otherwise in the pages of one of the world's most prestigious medical journals -- 10 months after the FDA approved this therapy based on the strength of our clinical data -- attempts to turn back the clock on the treatment of severe sepsis. The opinion article's assertions serve only to confuse physicians who are attempting to make the best treatment decisions for their patients with severe sepsis, " said August M. Watanabe, M.D., executive vice president, science and technology, for Lilly.

"Severe sepsis shows no mercy, so I want to offer my patients every advantage in their struggle to survive. There is no doubt in my mind that Xigris, when used appropriately, is an unprecedented, lifesaving advance for this vulnerable patient population," said Greg A. Schmidt, M.D., professor of clinical medicine, clinical anesthesia, and critical care, and director of medical intensive care, University of Chicago.

FDA and CMS Reaffirm Lifesaving Potential of Xigris for Most Vulnerable Patients

In the same issue of The New England Journal of Medicine, the FDA rebutted the questions of Warren, et al., point by point, concluding that the data strongly support that use of Xigris, as labeled, will save many lives.

Based on the PROWESS trial's results, the FDA approved Xigris in November 2001 for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (e.g., as determined by APACHE II(2)).

In his Sounding Board response, "Assessing the Use of Activated Protein C in the Treatment of Severe Sepsis," Jay P. Siegel, M.D., director, Office of Therapeutics Research and Review, FDA Center for Biologics Evaluation and Research, said that extensive review conducted by the agency -- which also included substantial post hoc data evaluations following the Xigris Advisory Committee hearing -- confirmed the principal findings of the PROWESS trial. This review included several specific analyses strongly supporting the conclusion that a protocol amendment made during the course of the trial did not affect the study outcome.

Importantly, the FDA also reported in The New England Journal of Medicine that the most vulnerable severe sepsis patients -- those of advanced age, those who experience acute physiological changes and those with chronic health points (a scoring system that assesses mortality risk) -- are also the patients who benefited the most from Xigris therapy.

"Xigris data has been favorably reviewed and approved for use in 27 countries to date. Challenging the integrity of the PROWESS trial is out of step with the majority opinion among regulatory authorities worldwide. This fact stands on its own," said Watanabe.

"We disagree with the authors' suggestion that we should contemplate denying severe sepsis patients fighting for their lives access to an FDA-approved therapy in order to replicate the proven findings from the largest trial of its kind ever conducted. In our viewpoint, that would be unethical," he said.

In addition, CMS (formerly HCFA) recently selected Xigris as the first and only medical product to be granted new technology status because it provides a substantial improvement in treatment for Medicare patients with life-threatening severe sepsis. Beginning Oct. 1, 2002, this designation will allow hospitals that use Xigris in the treatment of Medicare patients with life-threatening severe sepsis to receive additional reimbursement. In a statement on the decision, Department of Health and Human Services Secretary Tommy G. Thompson said, "In an era of unprecedented scientific breakthroughs, we must do all we can to ensure that all patients have access to the latest in medical innovations."

The Critical Care Perspective

Severe sepsis occurs when an infection (bacterial, viral, fungal or parasitic) -- often the result of trauma, surgery, burns or cancer -- triggers a cascade of immune system responses that can lead to acute organ dysfunction and often death. One of every three sepsis patients will die within one month. Before FDA approval of Xigris, treatment options for patients with severe sepsis were limited to treatment for the infection and supportive care, such as mechanical ventilation, and kidney dialysis. When added to conventional care, Xigris can further decrease mortality in these severely ill patients.

The number of severe sepsis cases has been rising significantly over the past few decades -- growing nearly 300 percent over the past 25 years(3) -- and the incidence is expected to continue climbing. This year alone, more than 750,000 Americans will develop severe sepsis, and at least 215,000 of them will die from the disorder -- about as many as die as a result of an acute heart attack. Research suggests more than 6.8 million new cases of severe sepsis will occur in the United States between 2003 and 2010. Approximately 95 percent of these will be among people who are 65 or older with the majority of these cases -- nearly 60 percent -- occurring among people aged 65-75.(4) Nonetheless, sepsis can strike regardless of a person's age.

More About Xigris

Xigris (drotrecogin alfa (activated)) is a recombinant form of human Activated Protein C. It is administered by intravenous infusion and is available in 5 and 20 mg vials.

In November 2001, the FDA approved the use of Xigris for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (e.g., as determined by APACHE II). The relative risk of death for patients receiving Xigris and who were at high risk of death (as defined by an APACHE II score of greater than or equal to 25), was reduced by 29 percent (p=0.002) in the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial involving 1,690 patients.

Efficacy of Xigris has not been established in adult patients with severe sepsis and a lower risk of death. Safety and efficacy have not been established in pediatric patients with severe sepsis. Lilly is undertaking large-scale trials to investigate the use of Xigris in lower risk patients and in children, with severe sepsis, and the optimal use of low-dose heparin with Xigris.

Bleeding events are common in patients with severe sepsis. In the PROWESS trial, bleeding was the most common adverse reaction associated with Xigris therapy. Serious bleeding events, including intracranial hemorrhage, were observed during the 28-day study period in 3.5 percent of Xigris-treated patients and 2.0 percent of placebo-treated patients. The difference in serious bleeding occurred primarily during infusion.

For complete Xigris (drotrecogin alfa (activated)) prescribing information and labeling, call 800-423-2313 or visit www.Xigris.com.

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers -- through medicines and information -- for some of the world's most urgent medical needs. Additional information about Lilly is available at www.lilly.com.

Certain of the matters discussed herein with respect to clinical studies and Lilly's products may constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements are based on current expectations, estimates and projections about the industry, management beliefs and certain assumptions made by management. Investors are cautioned that matters subject to forward-looking statements involve risks and uncertainties, including economic, competitive, governmental, technological and other factors discussed in the company's filings with the Securities and Exchange Commission, which may affect the business and prospects of the company. More specifically, there can be no assurance that this product will achieve commercial success or that competing products will not preempt any market opportunity that might exist for the product.

Xigris(R) (drotrecogin alfa (activated), Lilly) DR24933

References

(a) The New England Journal of Medicine, Sept. 26, 2002, Vol. 347,

No.13, pp.1027-1030.

(1) Argentina, Australia, Colombia, India, Israel, Mexico, Peru,

Romania, Singapore, South Africa, Switzerland

(2) Acute Physiology and Chronic Health Evaluation Score

(3) Society of Critical Care medicine web site

(www.sccm.org/pressroom/sepsis_info.html)

(4) Angus D, et al. Epidemiology of severe sepsis in the United

States: analysis of incidence, outcome, and associated costs

of care. Crit Care Med 2001; 29(7): 1303-1310.