Analysis of a Phase III trial of pexelizumab indicated that the anti-inflammatory compound being studied by Alexion Pharmaceuticals Inc. reduces heart attacks after heart surgery.
The company on Monday presented results from a 3,099-patient Phase III trial of pexelizumab in patients undergoing coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass at the late-breaking clinical trials session of the American Heart Association Scientific Sessions in Orlando, Fla.
Alexion, and partner Procter & Gamble Pharmaceuticals, in August released preliminary analysis of the Phase III, saying they had narrowly missed the primary endpoint of incidence of death or myocardial infarction (MI) at post-operative Day 30 in the subpopulation of patients (n=2,746) who had only CABG surgery. The remaining 353 participants had CABG together with cardiac valve surgery. (See BioWorld Today, Aug. 6, 2003.)
On releasing the news of the missed endpoint, Alexion's stock (NASDAQ:ALXN) fell $3.49, or 21.8 percent, to close at $12.51. Wall Street on Monday took $1.39, or 7.7 percent, leaving the shares at $16.65.
Leonard Bell, CEO of Cheshire, Conn.-based Alexion, told BioWorld Today the trial revealed that incidence of death or MI was reduced by 18 percent (11.8 percent placebo vs. 9.8 percent pexelizumab, p=0.069.) "It was close - a [ p' value of]0.069 as opposed to a 0.050," he said.
Indeed, one stock analyst participating in a company-sponsored conference call referred to the outcome as "frustratingly close."
The secondary endpoints were promising, as pexelizumab achieved statistical significance in several areas, leading Alexion and P&G to look ahead. Bell told BioWorld Today it is likely the companies will pursue additional trials in heart surgery patients, but said, "What we don't know is whether [additional] trials will be required for approval or whether it will be additional trials that we would be pursuing in any case."
For now, Bell said, he's initiated discussions with the FDA.
"Our objective is to identify a plan that gives us the highest confidence of having the drug approved," he said. "We certainly are, in and of its own right, interested in evaluating pexelizumab further in heart surgery patients. We will determine how that fits in with our regulatory strategy over the next several months. We have been saying since August that we think it is very likely, given the data and a lot of very encouraging things, that we would be well advised to pursue pexelizumab further in heart surgery patients."
According to a statement released by the company, statistically significant reductions were achieved with pexelizumab in each of the six different pre-specified measures of perioperative myocardial damage in the overall intent to treat population (all p<0.05) as well as in the CABG-only subpopulation (all p<0.05).
Also, an effect of pexelizumab on postoperative morbidity and mortality appeared to persist, as pexelizumab was associated with a 25 percent reduction in 90-day mortality (placebo 4.8 percent vs. pexelizumab 3.6 percent, p=0.096) and important prospectively defined secondary endpoint, the statement said.
Alexion and Procter & Gamble Pharmaceuticals, an affiliate of Procter & Gamble Co., of Cincinnati, also are studying pexelizumab in heart attacks. When signed in early 1999, the agreement between the partners was valued at upward of $95 million. Since then, the companies have renegotiated, giving Alexion more responsibility in the U.S. and more profit potential. Bell wouldn't discuss the financial details of the agreement. (See BioWorld Today, Jan. 27, 1999, and Dec. 13, 2001.)
In other news from the meeting:
• Alteon Inc., of Ramsey, N.J., said an independent research team showed that ALT-711, its lead A.G.E. (Advanced Glycation End-product) crosslink breaker, improves overall cardiac function in aged diabetic dogs by restoring left ventricular ejection fraction, reducing aortic stiffness and reducing left ventricular mass. The changes were observed to be associated with a reversal of the overexpression of cardiac collagen seen with aging and diabetes. ALT-711 is in Phase II studies for its potential in treating systolic hypertension and heart failure.
• Angiotech Pharmaceuticals Inc., of Vancouver, British Columbia, said Boston Scientific Corp., of Natick Mass., reported 12-month follow-up data from the Taxus IV trial of its paclitaxel-eluting stent, showing that the benefits reported at nine months were maintained at 12 months, compared to patients who received an untreated stent. Angiotech licenses the drug used in Boston Scientific's Taxus stent system, which is the subject of a Nov. 20 FDA panel meeting.
• Biogen Inc., of Cambridge, Mass., reported positive Phase II results from a study of Adentri, an adenosine receptor antagonist, in stable heart failure patients. The randomized, double-blinded, placebo-controlled study met its primary endpoint of demonstrating the oral compound's safety during its 10 dosing days or during an additional 30 follow-up days. The study also showed increases in sodium excretion above baseline and above placebo beginning on the first day and continuing over the 10-day dosing period. The effects were not accompanied by reductions in kidney function or substantial increases in potassium excretion. The company said it plans to meet with the FDA to review the data.
• The Children's Hospital of Philadelphia found that children carrying the apolipoprotein E2 (APOE2) gene variant were significantly more likely to have worse outcomes in a developmental evaluation of cognitive and motor skills compared to children who underwent heart surgery and did not have the APOE2 gene. The gene variant might decrease the ability of neurons to repair themselves following open-heart surgery. APOE2 occurs in about 8 percent of the population.
• Curis Inc., of Cambridge, Mass., said that injection of a gene encoding the Hedgehog protein results in improved cardiac function and increased blood flow to the heart in a model of myocardial ischemia. Researchers at St. Elizabeth's Medical Center in Boston concluded that administration of Hedgehog after a heart attack might promote recovery in patients with acute myocardial ischemia by stimulating new blood vessel growth and reducing fibrosis. Curis' stock (NASDAQ:CRIS) rose 70 cents, or 14.6 percent, to close at $5.49.
• DiaDexus Inc., of South San Francisco, said findings reported by researchers from the University of Ulm Medical Center in Ulm, Germany, demonstrated that elevated levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) are independently associated with an increased risk of coronary heart disease in men with moderately elevated cholesterol. The study is based on the MONICA-Augsburg Cohort, which followed 934 apparently healthy men for 14 years. In that time, 97 suffered a coronary event and their baseline levels of Lp-PLA2 were significantly higher in comparison with event-free subjects.
• The Emory Heart Center in Atlanta reported results from the Cilostazol for Restenosis (CREST) study showing that treatment with the drug reduced stent restenosis by 39.5 percent over standard therapy alone. Data also showed that the beneficial effect occurred in patients with small blood vessels and diabetes, in whom restenosis was reduced from 37 percent to 16.9 percent. Otsuka America Pharmaceutical Inc., part of the Otsuka Group, of Tokyo, markets cilostazol (Pletal) for intermittent claudication.
• Encysive Pharmaceuticals Inc., of Houston, said Phase IIb/III data from its study called STRIDE (Sitaxsentan to Relieve Impaired Exercise) showed that the drug improved six-minute walk distance, NYHA functional class and hemodynamics in both traditional (with limited enrollment criteria) and expanded study populations. The company said it used findings from the randomized, double-blinded, placebo-controlled, 12-week study in 178 pulmonary arterial hypertension patients to design STRIDE II and related trials that it expects to provide the basis for regulatory submissions and product marketing. The 240-patient STRIDE II trial is being conducted under a special protocol assessment with the FDA.
• Genentech Inc., of South San Francisco, said the use of its clot-busting agent tenecteplase (TNKase) in patients experiencing sudden cardiac arrest shows promise as a potential new therapy. In the 50-patient study, return of spontaneous circulation was observed in 26 percent of patients; survival to ICU admission in 14 percent; survival to 24 hours in 6 percent; and survival to hospital discharge in 4 percent. Time from arrest to thrombolysis averaged 31 minutes and was similar among responders and non-responders, while time from thrombolysis to return of spontaneous circulation averaged 7.8 minutes among responders. Genentech provided support for the study, which was conducted at the University of Florida's Shands Medical Centers and the Wake Forest University Baptist Medical Center in Winston-Salem, N.C.
• United Therapeutics Corp., of Silver Spring, Md., said data on the long-term efficacy and survival benefit of Remodulin pointed to clinical improvements and prolonged survival in a cohort of 39 pulmonary arterial hypertension patients treated with the drug for up to 54 months, with mean treatment time of 26 months. The research, conducted at the Free University and Erasme Hospital Brussels, Belgium, also showed that patients improved functional class by more than one of the four NYHA disease severity measurement units and their exercise tolerance improved by more than 150 meters during the study period.