Washington Editor

Shares in Northfield Laboratories Inc. lost about half their value after further pivotal study analyses showed that the oxygen-carrying red blood cell substitute PolyHeme missed its dual primary efficacy endpoints of superiority and non-inferiority a month after injury, as well as its primary safety endpoint.

"The difference in mortality at 30 days between patients who received PolyHeme beginning at the scene and continuing for up to 12 hours following injury and control patients who received the standard of care, including early blood, was not statistically significant," Chairman and CEO Steven Gould said of the safety analysis during a conference call. In addition, he pointed to the missed efficacy data.

The margin to assess non-inferiority, using the upper limit of the confidence interval, was set at 7 percent more than control, but in the primary modified intent-to-treat population, the upper limit of the confidence interval was 7.65 percent. It fell to 7.06 percent in the as-treated population and 6.29 percent in the per-protocol population. That latter group includes only the 586 patients both appropriately randomized and correctly treated among the entire 714 patients enrolled in the study.

Previously, when an earlier analysis showed the per-protocol confidence interval to be 5.8 percent, Gould said that the company would proceed with filing a biologics license application based on those results. (See BioWorld Today, Dec. 21, 2006.)

He said those latest data underscore prior findings that show that PolyHeme can sustain life "when transfusion is necessary but blood is not available." Therefore, Gould concluded that the latest results "are best understood" in the context of bleeding patients who do not have early access to blood transfusions, such as the 47 million Americans who live more than an hour from a trauma center where blood is available. "Mortality rates in those individuals would be considerably higher than those observed in the control patients in this [urban] trial," he said, "where transit times are relatively short."

The trial was designed to seek an indication for use in the treatment of life-threatening red blood cell loss when transfusion is required and red blood cells are not available, not for use interchangeably with blood.

The modified intent-to-treat population analyzed patients as they were randomized, not based on the actual treatment they received, even though 41 randomized patients received the incorrect treatment. Therefore, the 21 patients randomized to PolyHeme who did not receive it were analyzed in the PolyHeme group, and the 20 patients randomized to control who instead received PolyHeme were analyzed in the control group. Therefore, the as-treated population analyzed patients based on the treatment they actually received.

The per-protocol population leaves the 128 patients who had major protocol violations related to eligibility or treatment regimen out of its analysis, and since the remaining 586 were treated exactly as specified in the protocol, Northfield said they represent the clearest opportunity to assess a treatment effect. Specific results from the per-protocol population showed 31 deaths (11.1 percent) in the PolyHeme arm compared to 28 (9.1 percent) in the control arm.

There were 47 deaths (13.4 percent) for PolyHeme patients in the modified intent-to-treat group compared to 35 (9.6 percent) in the control group, and 46 deaths (11.1 percent) among PolyHeme patients in the as-treated population compared to 36 (9.1 percent) in the control arm.

In terms of safety analyses that raised questions, Gould pointed to the 11 PolyHeme patients who had heart attacks compared to three in the control group based on investigators' diagnoses. But because of difficulties in making an accurate heart attack diagnosis in trauma patients for multiple reasons, he said an independent panel would review the high number of study patients with abnormal electrocardiograms or elevated cardiac enzymes, heart attack indicators found in about 75 percent of them, to reconcile the disparity between that high percentage and investigators' relatively low overall heart attack diagnoses.

Those latest data have not been submitted to the FDA or reviewed by the agency, though Gould said Northfield's next step would be to prepare a formal summary for the FDA.

The company, of Evanston, Ill., has encountered numerous bumps in the road in developing the human hemoglobin-based product. Among them, the FDA rejected an original marketing application in 2001. Each setback has hurt Northfield's stock value, and accordingly, its shares (NASDAQ:NFLD) closed at $1.90 on Wednesday, down $2.35, or 55.3 percent.

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