National Editor

Alexion Pharmaceuticals Inc. narrowly missed its primary endpoint in the preliminary analysis of its Phase III heart surgery drug, pexelizumab, but the company said other indicators are encouraging enough to ask the FDA about filing for approval.

But that didn't thrill Wall Street, which took away 21.8 percent from Alexion shares. Its stock (NASDAQ:ALXN) fell $3.49 Tuesday to close at $12.51, after dipping as low as $12.03.

Leonard Bell, CEO of Cheshire, Conn.-based Alexion, declined to estimate when the company will know its next step with the drug, but told BioWorld Today, "What we need to do is complete all of our internal diligence" and begin talks with the FDA.

Full data from the 3,000-patient trial, called "Pexelizumab for Reduction in Infarction and Mortality in Coronary Artery Bypass Graft Surgery," or the PRIMO-CABG trial, won't be disclosed until November at the annual meeting of the American Heart Association.

Embargo rules prevent Alexion from disclosing more about the Phase III results now, Bell said, but noted in a conference call there was "substantial internal consistency in the data set. We think that the sum total of the data of pexelizumab in CABG is supportive of having a clinically meaningful effect."

In the figures that could be disclosed, Alexion's short-acting, single-chain antibody C5 complement inhibitor failed to hit its primary endpoint: reducing death and myocardial infarction at 30 days in patients undergoing CABG who were not undergoing valve surgery at the same time.

Between 10 percent and 12 percent of CABG patients undergo valve surgery at the same time as their bypass graft procedure, but Alexion disqualified them from primary analysis of the trial since Phase II data suggested pexelizumab is less likely to work in that setting.

In the Phase III study, however, the drug did reach borderline statistical significance for both sets of patients - those who underwent valve surgery and those who didn't - in reducing death and myocardial infarction. That "all comers" analysis made up one of the secondary endpoints.

Eric Schmidt, analyst with SG Cowen Securities Corp., called the secondary endpoint finding "ironic" and meaningful in a favorable way. Bell agreed the Phase III outcome is ironic but said the choice to exclude the valve surgery patients from the primary analysis was the right one at the time.

"Based on the data we had from the Phase II with only 30 patients in the group, I don't think we were in a position to judge whether it had a discernible effect in that population," he said.

Although Schmidt acknowledged that approval of the drug based on PRIMO-CABG data is "far from assured," a biologics license application could be filed as early as 2004, and the revenue potential in the U.S. is between $300 million and $500 million. Alexion's clinical advisers believe the company will "receive a green light to at least file for approval," Schmidt wrote in a research note.

Bell was circumspect, but said the worst-case scenario would be that the FDA decides "the data are in no way supportive, in which case you ought to stop. That's a low likelihood."

Pexelizumab is partnered with Procter & Gamble Pharmaceuticals, an affiliate of Procter & Gamble Co., of Cincinnati. Alexion shares equally in development and commercialization, handling about half of sales efforts and taking half the profits. (See BioWorld Today, Dec. 13, 2001.)

Other secondary endpoints in the Phase III trial include psychomotor function, the effect of pexelizumab on death alone and the drug's effect on perioperative (that is, from the time of hospitalization for surgery to the time of discharge) Q-wave and non-Q-wave myocardial infarction. Details on those endpoints are expected at the AHA meeting to be held in Orlando, Fla.

Meanwhile, the company offered only an outline of the Phase III data, with an opinion of what they might mean.

"We believe we have hit a solid triple, and we're now focusing on the best strategy to drive the drug home," Bell said during a conference call, pointing to a significant unmet medical need.

"There are no approved drugs that we are familiar with that limit death or heart attack in this patient population or have been shown to do so," he said.

Behind pexelizumab in the Alexion pipeline is eculizumab, formerly known as 5G1.1, a fully humanized whole antibody (as opposed to single chain), which in Phase I/II and Phase II trials has shown proof-of-principle efficacy in rheumatoid arthritis, lupus/membranous nephritis and dermatomyositis.

Alexion has a manufacturing deal with Lonza Biologics Ltd., of Basel, Switzerland, for eculizumab, which Schmidt said has yielded the most promising data in a Phase I/II study in paroxysmal nocturnal hemoglobinuria, which is associated with a high risk of thrombotic events.

"We would expect over the next several months we would be able to announce our plans [regarding eculizumab]," Bell said.