Infectious disease expert weighs in on new drug controversy

By Joe Kuttenkuler

RICHMOND, Va. – Controversy over the nation's first drug to treat the biological causes of sepsis – a potentially deadly blood stream infection – has resulted in a series of articles in the latest issue of The New England Journal of Medicine, which includes a summary of the issues by a Virginia Commonwealth University infectious disease expert.

"Controversy surrounds both the drug study itself and the FDA approval," wrote Richard P. Wenzel, M.D., chair of the VCU School of Medicine’s department of internal medicine, in the Sept. 26 issue of the NEJM.

The drug in question is called recombinant human activated protein C, or HAP-C. It is unique because it is the first drug approved to treat sepsis at its source – inside blood vessels. HAP-C was approved last year in a split vote by a 20-member Food and Drug Administration panel – a decision some in the medical community criticized.

Physicians and researchers have raised concerns about whether changes made to the eligibility requirements for participants and to the cell line used to manufacture the drug while the study was still in progress, may have resulted in better outcomes in the second half of the study. 

"These are brand new issues for us in the drug approval process, so the Journal decided to bring out the controversy and bring on the debate," said Wenzel, a leading authority on bloodstream infections, who also serves as editor-at-large for the NEJM. "The best possible outcome would be to see more data, more studies and then we could be much more confident on the question of whether we really have a drug that works. And in this NEJM series, the company has announced that they plan to do just that."

Sepsis, a potentially deadly bloodstream infection, appears to be on the rise, with about a million cases in the U.S. each year. The infection is classified according to three stages – sepsis, severe sepsis and shock – with the most severe stage of septic shock carrying a mortality rate of about 45 percent. 

Early use of antibiotics can reduce mortality from sepsis, but for two decades researchers have searched for new therapies that target the biological triggers of sepsis.

"The Holy Grail for sepsis has always been to find a drug that targets the real biology of sepsis – where the action is on the inside of the blood vessels," said Wenzel. "This is the first drug that actually works not directly on the organism causing the infection, but on the body's response to the organism, particularly at the level of the blood vessel."

Patients suffering from the two most severe stages of sepsis have reduced levels of activated protein C – a key vascular protein that orchestrates many of the body’s normal regulatory functions. HAP-C targets the reduced protein levels and works to restore the body’s normal physiology. In the study, published in a March 2001 issue of NEJM, death rates for patients who received HAP-C were reported at 24.7 percent, compared to the control group’s 30.8 percent.