The difficult thing about sepsis is that it is systemic - the infection or trauma can cause inflammation and coagulation that can lead to multiple organ failure, making it notoriously difficult to treat. Anywhere from 30 percent to 50 percent of those who contract the disease die from it.
Similar to its effects on the body, sepsis has historically wreaked havoc on those trying to develop therapies to treat it. ICOS Corp. said Thursday that, based on an interim analysis of the Pafase Phase III trial by an independent monitoring committee, it would no longer pursue the product in that indication.
"We're saying [the trial was stopped] for futility, because Pafase did not reduce 28-day all-cause mortality," said Lacy Fitzpatrick, director of investor relations at ICOS. "This is an interim analysis and we'll have additional data after we have analyzed all the patients in the trial."
However, when asked if this ends Pafase's development in sepsis, Fitzpatrick said, "Yes."
The COMPASS (Controlled mortality trial of platelet-activating factor acetylhydrolase in severe sepsis) trial was designed to enroll 2,500 patients in about 150 centers in nine countries and had the efficacy endpoint of 28-day, all-cause mortality. Bothell, Wash.-based ICOS began the trial in April 2001. Patients given Pafase - a recombinant human serum protein that inactivates platelet-activating factor - along with standard care were compared to those receiving placebo and standard care. In the countries where it is approved, that standard care included Xigris, indicated for the reduction of mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death. Xigris was developed by Eli Lilly and Co., of Indianapolis. Although further analysis is to be done, the committee recommended halting the trial after concluding that Pafase failed to demonstrate clinical benefit. (See BioWorld Today, April 30, 2001.)
"The patients have a lot going on in their underlying condition," Fitzpatrick told BioWorld Today. "It's been known to be a challenge for companies to develop new therapies for."
That's an understatement. The examples of companies that failed the challenge are plentiful. Although Eli Lilly got Xigris through, an incomplete list shows that Xoma Corp., of Berkeley, Calif.; Centocor Inc., of Malvern, Pa.; Immunex Corp., of Seattle; and Celltech Group plc, of Slough, UK, all had sepsis drugs fail in development.
With that history, industry observers might not have had high confidence in any company trying to find a treatment for sepsis, as was the case with Bill Tanner, analyst with Leerink Swann & Co. He said in a research note, "Given the inherent risks of developing a sepsis compound, we have not included revenues from Pafase in our model. We believe that Pafase was not overly distinguishable from Lilly's Xigris, which has produced modest revenues. As such, market perceptions for Pafase have been modest and we believe that the perception of market loss is minimal."
Tanner went on to say that he believed "Pafase would overhang [ICOS's] stock in 2003. With this news out of the way, we believe that ICOS will enter 2003 with a clean slate and is positioned to perform well with the upcoming Cialis launch in Europe and the U.S. in early 2003 and [the second half of 2003], respectively."
Leerink Swann, which holds a position in ICOS, rates the company "market perform," or hold.
Cialis, ICOS's product for erectile dysfunction and female sexual dysfunction, draws the attention of most ICOS investors. For erectile dysfunction, it is approved in Europe and ICOS has a new drug application on file in the U.S. It is in a Phase II trial for female sexual dysfunction. Cialis, an oral PDE5 inhibitor, is often talked about as being a potential blockbuster.
"We expect to have a regulatory decision in the second half of 2003 [in the U.S. for erectile dysfunction]," Fitzpatrick said.
Pfizer Inc., of New York, recently filed a patent infringement suit against ICOS and Lilly - ICOS's development partner for Cialis - as well as against GlaxoSmithKline plc, of London, and Bayer AG, of Leverkusen, Germany, for their erectile dysfunction product, Levitra, in an attempt to protect Pfizer's blockbuster, Viagra. All parties named in the suit have claimed they will "vigorously defend" themselves. (See BioWorld Today, Oct. 24, 2002.)
"We haven't reported anything on that, and since we have ongoing litigation, we won't be commenting on that," Fitzpatrick said.
While Pafase, which is partnered with Japan-based Suntory Ltd., is finished, sepsis as an indication for ICOS is not. It has in development IC14, a monoclonal antibody designed to selectively bind to the CD14 receptors on white blood cells. When bacterial toxins bind to CD14, it can initiate a cascade of immune system responses that might lead to sepsis. IC14 is in a Phase II trial that started in August.
Although Pafase failed in a difficult indication, Fitzpatrick said ICOS has changed little.
"It was not our lead product candidate, but it was one of our late-stage products," she said. "ICOS remains committed to developing therapeutics."
ICOS stock (NASDAQ:ICOS) fell $4.48 Thursday, or 15.1 percent, to close at $25.20.