FDA fast-tracks molecularly engineered sepsis drug


Lilly's Zovant could be approved for sepsis this year



FDA fast-tracks molecularly engineered sepsis drug

The first molecularly engineered drug to treat sepsis is likely to be a recombinant human activated protein C (rhAPC), manufactured by Eli Lilly under the trade name Zovant. The Food & Drug Administration could approve the product as early as this summer.

A double-blinded phase III trial with nearly 1,700 patients found that rhAPC reduced the relative risk of death from sepsis by nearly 20% during the first 28 days after treatment. The primary side effect is an increased risk of bleeding, said researchers speaking at the 97th International Conference of the American Thoracic Society in San Francisco.

The drug works well in people with severe coagulation effects and those with less coagulopathy, said Gordon Bernard, M.D., associate director of the division of allergy, pulmonary and critical care medicine at the Vanderbilt University Medical Center in Nashville. "I can't find a subset of patients who do not warrant treatment based on these data."

Sepsis covers a variety of symptoms stemming from systemic inflammation, Bernard said. The most common causes are infection and trauma that damages a body cavity. If unchecked, inflammation can lead to multiple organ failure, hypoperfusion or hypotension, and death.

There are about 750,000 cases of sepsis in the United States annually, Bernard said, with a death rate of 30% to 35%.

Precisely how rhAPC reverses sepsis is not clear, Bernard continued. Protein C plays a role in several steps in the cascade leading from systemic inflammation to multiple organ failure. Naturally occurring Protein C is depleted as the body tries to stave off sepsis, but treatment with rhAPC does not seem to affect serum levels of the protein.

What is clear, he said, is that rhAPC shows the same 19.4% reduction in mortality for nearly all patients suffering from severe sepsis. Patients without prior myocardial infarction had a 27% reduction in the relative risk of death.

Results were so positive, Bernard said, that an independent safety committee halted the rhAPC trial after the first interim data analysis. All patients in the trial received rhAPC as a 96-hour infusion.

The risk of severe bleeding was 3.6% compared with 2% for patients receiving placebo. "If you would not want to give heparin because a bleed is potentially unrecoverable," Bernard cautioned, "you probably would not want to give this drug, either."

The FDA put the approval application for rhAPC on a fast track, Bernard said. A Lilly spokesman said no decision has been made on pricing. Bernard warned that Zovant is likely to be expensive—a common complaint with other recombinant human protein products. "If there is no risk of death or organ failure, I would not use this drug," Bernard said. "But if patients are failing before your eyes, rhAPC could make the difference."

Activated Protein C may be the first of many drugs to disrupt the pathways leading to sepsis. As researchers unravel the tangle of signal transducers, receptors, and other elements contributing to sepsis, they find more opportunities to break the chain leading from inflammation to organ failure and death.

"We need to move beyond purely clinical factors such as organ dysfunction," said Edward Abraham, M.D., head of pulmonary sciences and critical care medicine at the University of Colorado Health Sciences Center in Denver. "We should be identifying the biomarkers of sepsis so we can treat the pathways. We want to treat patients before there is risk of death from sepsis."

One of those biomarkers is nuclear factor kappa beta (NF-kB), said Timothy Blackwell, M.D., assistant professor of medicine and cell biology at Vanderbilt University. An inactive form of NF-kB is present in the cytoplasm of most cells.

Once activated by infection or injury, NF-kB triggers production of tumor necrosis factor (TNF), interleukins (IL), colony-stimulating factors (CSF), interferons (IF), and other pro-inflammatory proteins. Blocking the activation of NF-kB should inhibit inflammation and sepsis.

It works, at least in mice. Alex Lentsch, assistant professor of surgery at the University of Louisville, has found that blocking NF-kB production in the liver almost completely eliminates inflammation in the lungs associated with hepatic surgery and other insult.

Another vulnerable link is HMG-1, high mobility group 1 proteins, released by macrophage cells in response to infection or other immune system stimulation. HMG-1 levels are significantly elevated in sepsis patients, said Kevin Tracey, M.D., head of patient-oriented research at North Shore-LIJ Research Institute in Manhasset, N.Y. The highest HMG-1 levels are associated with fatal sepsis. Inactivating HMG-1 blocks inflammation and sepsis in mice, he said. He wants to try an antiHMG-1 monoclonal antibody on human patients.

The MAb may not be needed. Tracey found that stimulating the vagus nerve electrically activates the cholinergic anti-inflammatory pathway. The liver boosts production of acetylcholine, blocking production of pro-inflammatory molecules by macrophage cells.

Fred Gebhart


Fred Gebhart. FDA fast-tracks molecularly engineered sepsis drug.

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