National Editor

After losing 26 percent of its stock value on rumors that upcoming news regarding its cardiovascular drug would be negative, Esperion Therapeutics Inc. recovered when positive data were published.

Ann Arbor, Mich.-based Esperion's shares fell $6.21 Monday to close at $17.66. Wednesday, the Journal of the American Medical Association published results from the 47-patient Phase II trial, and the company's stock (NASDAQ:ESPR) rose $6.10, or 34.9 percent, to close at $23.60.

Steven Nissen, principal investigator of the study and medical director of the Cleveland Clinic Cardiovascular Coordinating Center, was more than pleased by the outcome of the trial.

"I must tell you, I took everybody in my laboratory out to dinner when we got the data," he said during a conference call, adding that researchers did "a magnificent job. We were fortunate in two respects. One is, the precision of the measurements was superlative, and secondly, the drug effect was huge."

Leading the rollercoaster ride is ETC-216 (ApoA-I Milano/phospholipid complex, also known as AIM), a variant ApolipoproteinA-I (ApoA-I), which is the major protein component of high-density lipoprotein (HDL), the "good" cholesterol.

ApoA-I Milano is noted in a small population of northern Italians with paradoxically low levels of HDL cholesterol. Though this normally would correlate with high risk for cardiovascular disease, carriers of the ApoA-I Milano gene show a reduced risk, presumably due to enhanced reverse lipid transport (RLT), which is the body's process of removing excess cholesterol and other lipids from artery walls and other tissues and transporting them to the liver for elimination.

ETC-216 is the human recombinant version of ApoA-I Milano, combined with a phospholipid to form a complex that imitates the structure and function of HDL, intended to mimic HDL's beneficial properties and enhance RLT.

It works, apparently.

In the trial, patients with acute coronary syndromes (ACS) were divided into groups that received five weekly intravenous infusions of placebo (11 patients), ETC-216 at 15 mg/kg (21 patients) and ETC-216 at 45 mg/kg (15 patients). Plaque volume was measured before treatment and within two weeks after the final infusion using intravascular ultrasound (IVUS), in which a tiny ultrasound probe is inserted into the coronary artery to directly image and measure the size of the atherosclerotic plaques.

The absolute reduction of atheroma volume was 4.2 percent in drug-treated patients vs. baseline, which Martin Auster, analyst with Wachovia Securities in Baltimore, called in a research note "revolutionary." Nissen said the same.

"This change that we saw is really unprecedented," Nissen said, adding that never in the history of regression/progression studies has anything like the 4-plus percent decrease in plaque volume been recorded. Other IVUS endpoints in the trial, such as total atheroma volume and maximum atheroma thickness, also showed statistically significant improvements, the company said.

"What we set as the bar for this study to jump over is that we had to show benefits over and above the best therapy we have currently available," Nissen said. "To do a trial like this and have it be really ethical, you have to give everybody the standard of care."

In all measures, the standard-of-care, i.e. placebo, patients "had p' values that showed no change," he said. "In other words, if you give usual care but give saline instead of ETC-216, absolutely nothing happened. P' values ranged from 0.97 to 0.83, about as close to 1 as you can get. So we know now that the natural history of this disease is neither to progress nor regress in only six weeks" on its own.

With ETC-216, though, it was a different story.

Direct comparison to placebo was not the main point of the current trial, Nissen said, adding that such comparisons "show a trend but they don't reach statistical significance, nor would you expect them to. You can't do a comparison against placebo when you've only got 11 patients in the placebo arm. We would have to have seen an enormous difference for it to reach statistical significance, so we didn't power the trial to look against placebo."

What was "amazing," Nissen said, is that positive results could be shown "with only five doses of the agent given over five weeks. This was obviously a big gamble. It paid off - from my perspective - scientifically, with an unprecedented result."

Furthermore, results were practically undeniable, he said. The chances that the positive data are in error or achieved by chance "is essentially so remote that it's not even worth calculating," Nissen said, characterizing it as "less than one in a trillion that this drug did not produce regression."

Fifty-seven patients were assigned to a treatment group. Of the 10 who did not complete the trial, two were withdrawn for an adverse event, three withdrew consent and five had IVUS studies that were not analyzable.

Overall adverse-event rates were similar in all three treatment groups and ETC-216 was generally well tolerated, the company said.

More studies are ahead for the compound, possibly a larger one directly comparing it to placebo, Nissen said, "although I personally would prefer to move directly to a major morbidity and mortality trial" since the Phase II has answered the question of whether ETC-216 removes plaque.

The absolute reduction in atheroma volume in the combined treatment groups was a 4.2 percent decrease from baseline (p<0.001). When data from low and high doses were combined, ETC-216 reduced the percentage of atheroma volume in the target vessel by a mean of 1.06 percent, compared to baseline.

Esperion reported in June that the Phase II trial had met its primary efficacy endpoint. The company's share price has "fluctuated wildly in recent days between $16 and $25, as some investors had been expecting as much as a 10 percent-plus plaque volume reduction," Auster said in his research note. Though the successful Phase II study with ETC-216 "carries positive implications," he added, it's not the company's lead compound. That drug, ETC-588, is made of naturally occurring lipids that circulate through arteries to help HDL remove accumulated cholesterol and other lipids from cells, including those in the arterial wall. Data from a Phase II study with acute coronary syndrome patients are expected in the first half of next year.