Gensia Pharmaceuticals Inc. on Tuesday announced detailedresults of two Phase III clinical trials testing its drug Arasineas a protective agent against the sometimes fatal complicationsof coronary artery bypass graft surgery.

A U.S. trial showed that Arasine provided a statisticallysignificant reduction in heart attacks and other adverse cardiacevents, including strokes, while an international trial did notproduce statistically significant results in the primaryendpoints measured.

Using a strict criterion to define a heart attack, the rate of heartattacks suffered by patients in the U.S. trial who received ahigh dose of Arasine was 72 percent lower than that in patientswho received a placebo (p-value equals 0.018).

In addition, the rate of combined adverse cardiovascularevents (including heart attacks, cardiac death, stroke,congestive heart failure or life-threatening dysrhythmia) was62 percent lower in high-dose Arasine-treated patients vs.placebo-treated patients (p-value equals 0.002). A low dose ofArasine showed no meaningful clinical activity in the trials.

However, according to analyst Gregory Brown of VectorSecurities International in Deerfield, Ill., the company initiallyused a looser definition of what constitutes a heart attack indesigning its Phase III trials. Using the original, less-stringentcriterion, Arasine did not provide a statistically significantprotective benefit in the U.S. trial.

Brown said the company and its investigators then decided --after the Phase III trial had begun -- to adopt a strictercriterion, which is far more "clinically relevant," he said.

"When you strip away the noise and confusion caused by theredefinition issue, this is good data and a real, approvableproduct," said Brown.

The relevance of Gensia's results for cardiovascular surgeonswho will make the decision whether or not to use the drugduring bypass surgery may hinge on the heart attackdefinition. According to medical literature, heart attacks occurin anywhere from 3 percent to 15 percent of patients whoundergo bypass surgery, depending upon the definition used.

Using the strict criteria, the rate of heart attacks in the placebogroup of Gensia's U.S. trial was 5.2 percent (about 10 patientsout of approximately 200), while the rate of heart attacks inthe high-dose Arasine group was 1.4 percent (about threepatients out of approximately 200). Thus, Arasine provided thestatistically significant 72 percent reduction mentioned above.The 5.2 percent placebo heart attack rate was near the low endof the published range.

But using the original, looser definition (which may capturemore "heart attack-like" events that may not be clinicallysignificant), the rate of heart attacks in the placebo groupjumped to 24 percent, while the heart attack rate for theArasine group jumped to 21 percent. The difference betweenthe two groups was not statistically significant. The 24 percentplacebo heart attack rate was "not within a reasonable range,"according to Brown, suggesting that the less-rigorous definitionwas clinically inappropriate.

"We believe the data will be viewed by clinicians as clinicallyimportant in improving patient outcomes by reducing theoverall incidence of adverse cardiovascular outcomes," DavidHale, Gensia's president and chief executive officer, said in aprepared statement.

Some analysts have argued that cardiovascular surgeons maynot view heart attacks as a major problem in bypass surgerysince they occur in a minority of patients. The bottom line, theyargue, is reducing mortality, and not just reducing theincidence of heart attacks or other complications of surgery.Mortality as a result of bypass surgery ranges between 2percent and 3 percent on a national average. Gensia's trial wasnot designed to measure Arasine's effectiveness in reducingoverall mortality due to logistical problems involved in such aneffort.

However, the company reported on Tuesday that in a combinedanalysis of its one Phase II trial and its two Phase III trials (atotal of 1,500 patients), Arasine showed a statisticallysignificant reduction in "early postoperative death," defined asa four-day period beginning on the day of surgery andextending for another three days. In that period, 11 of thepatients who received placebo in the three trials died whileonly one patient who received Arasine died.

The company used the data from its Phase III trials as thebasis of its new drug application (NDA) to the FDA at the end of1992. How regulatory authorities will view the heart attackredefinition matter is unknown.

The company began a third Phase III trial of Arasine toprovide additional support for the use of the drug in bypasssurgery after announcing last September that its internationaltrial failed to prove a statistically significant benefit forArasine (many believe that two statistically significant PhaseIII trials are needed for FDA approval).

At that time, investors reacted harshly, and the San Diegocompany's stock (NASDAQ:GNSA) dropped $13.50 per share inone day, shaving $378 million off its market capitalization. Thestock price has languished in the low 20s ever since.

Investors reacted less definitively on Tuesday, with Gensia'sstock shedding $2.25 a share to close at $20.50 after the trialresults were digested by Wall Street. Roughly 2 million (7percent) of the company's 28 million outstanding shareschanged hands on Tuesday.

"It's a biotech bear market, and people are looking for badnews," said Brown. "The Street may view these resultsnegatively due to concern about how the FDA will interpretGensia's analysis."

But Brown argued that, given the striking results in a narrowlydefined group of patients, the FDA may overlook thediscrepancy between the original heart attack definition andthe revised definition. "However, no one would dare to guesswhat the FDA will or will not do at this point," he added.

Results of Gensia's Phase III trials were presented at theAmerican College of Cardiology meeting in Anaheim, Calif.Results from the international Phase III Arasine trial, whichwas conducted in Canada and seven European countries, werepresented in a poster session, while the U.S. results weredelivered at a plenary session of the meeting. According to acompany press release, Arasine's safety profile in all threeclinical studies was "excellent."

-- Lisa Piercey Business Editor

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