Trouble for Pfizer Inc. with its Phase III anti-cholesterol drug torcetrapib put would-be competitor Isis Pharmaceuticals Inc. in the catbird seat, and had industry observers chirping about even higher branches - such as the one occupied by the Canadian firm Resverlogix Corp., which also enjoyed a stock-price spike in recent days.

Under the radar for about six years, Resverlogix discovered and developed a group of synthetic compounds (or small molecules) that are Apo-A1 transcriptional activators that also act on such targets as inflammation.

Apo-A1 is the major cardio-protective protein of high-density lipoprotein (HDL), which plays a critical role in preventing the advance of cardiovascular disease and helping to push back atherosclerosis by boosting removal of cholesterol from the body.

"There's been a lot of quiet talk, but we've never published," said Donald McCaffrey, co-founder, president and CEO of Resverlogix. "You can't harpoon a whale if it doesn't surface."

The firm's coming-out party took place at the American Heart Association meeting in Chicago, where Resverlogix officials set up a panel of opinion leaders made up of "the best of the best," he said. "We had 10 thumbs-up in the room."

Pharma firms, especially in the wake of the Pfizer trouble, are taking notice. "We have always been positioned to sell [early] rather than license to a pharma company," McCaffrey said. "Our business model has always been predicated on doing that around the time of first administration to man, which we announced a month ago."

By mid-last week, he told BioWorld Financial Watch, he had spoken with seven of the world's top 15 pharma firms. "It got extremely heated in the last few days," he said. "I even got a phone call at home on Sunday." He would not specify whether Pfizer was among them, but said, "That's a pretty good guess."

CEOs of other firms with products of interest to big pharma "would kill to have the cards I've got in front of me," McCaffrey added. Resverlogix plans to sell rights on the cardiovascular side, but retain other therapeutic areas.

Pfizer, just after telling Wall Street that the firm will get rid of 20 percent of its sales force in the face of pressure from competitors and the loss of patent exclusivity, halted development of torcetrapib, an inhibitor of the cholesterol ester transfer protein (CETP), because of high death rates in Phase III studies. Shares of Pfizer, already in a tailspin, fell another 10 percent on the torcetrapib setback, while Isis' stock rose almost 9 percent on the news.

Torcetrapib, gained in the $1.3 billion buyout of Esperion Therapeutics Inc. three years ago, was combined in trials with the statin Lipitor (atorvastatin), Pfizer's blockbuster that goes off patent in 2010.

"One of the people who joined [Resverlogix] 3 years ago is the scientific co-founder of Esperion, Jan Johansson," McCaffrey said. Appointed senior vice president of clinical affairs, Johansson would stand at "any podium anywhere in the world and discuss how far superior our technology is to Esperion's," McCaffrey said.

Consumer groups and some clinicians balked at Pfizer's plan for the torcetrapib/Lipitor combo pill, since it would block prescribing a different - cheaper, possibly generic - statin to combine with torcetrapib. Critics pointed also to the possibility of new side effects when the two drugs are paired in a single product, since many had worried about torcetrapib's potential to increase blood pressure, as shown in Phase II trials.

Pfizer, though, had budgeted $800 million for Phase III trials in 25,000 patients. One trial would test 1,500 patients to determine if the torcetrapib/Lipitor combo slowed the growth of the arterial plaque. Another trial, in 13,000 patients, was to last five years and determine if the pill lowers the number of heart attacks and strokes. The trials would have used surrogate endpoints of plaque regression as measured by intravascular and carotid ultrasound.

Even before the 82 deaths in drug-treated patients (51 also died in the control group) caused Pfizer to stop all clinical work, skeptics had questions. The surrogate endpoints might not be adequate to show efficacy, and the hike in HDL cholesterol in Phase II studies doesn't guarantee benefit to vessel walls.

Some noted that Phase II results failed to show the combo drug helped fecal sterol excretion, vital to reverse cholesterol transport. Resverlogix has an advantage there, too. "We show atherosclerotic plaque leaving the body," McCaffrey said, although the study, like others conducted by Resverlogix, has not been published.

Had Pfizer's smaller Phase III trial proved that torcetrapib/Lipitor helps plaque regression, Pfizer still stood a good chance of the FDA insisting that approval be delayed until the bigger study of mortality and morbidity was finished - which would push market clearance out to 2009, just in time (maybe) to provide the Lipitor boost.

These, of course, are moot points now, and speculation turns on whether Isis, Resverlogix or another firm will strike a license deal with Pfizer.

Isis has ISIS 301012, which has proved promising as a monotherapy and in combination with statins. The drug inhibits production of apoB-100 and could work well as an add-on therapy in patients who have achieved maximal lipid lowering on statins but still haven't hit their lowest low-density lipoprotein (LDL)-cholesterol levels.

The company presented data from two Phase II studies at the American Heart Association meeting in Chicago. The first showed that patients with high cholesterol receiving statins achieved a 51 percent reduction in LDL when given the compound at 300 mg/week for five weeks. Patients also showed a 42 percent reduction in total cholesterol and a 41 percent reduction in triglycerides beyond levels achieved with statins alone.

The second, an ongoing study of ISIS 301012 as a single agent, showed that increasing the dose from 200 mg/week to 300 mg/week resulted in reduced atherogenic lipids and improvements in LDL, total cholesterol and triglycerides of 62 percent, 46 percent and 43 percent, respectively.

Another to cash in somewhat on Pfizer's setback could be Oscient Pharmaceuticals Corp., which over the summer bought the once-daily, cholesterol-lowering fenofibrate Anata from Reliant Pharmaceuticals Inc. for $78 million.

An adjunct treatment for hypercholesterolemia and hypertriglyceridemia (in combination with dietary changes), Antara has proven its mettle in knocking down triglycerides and boosting high-density lipoprotein cholesterol. In November, the FDA approved Reliant's supplemental new drug application for Antara's new dosing regimen, which lets patients take the 130-mg dose with or without food.

Leading the $1 billion market, with 95 percent, is Abbott Laboratories Inc. and its blockbuster Tricor. AstraZeneca plc and Abbott are collaborating to develop a single-pill, fixed-dose combination therapy of either TriCor or its next-generation version (known as ABT-335, now in Phase III trials) with Crestor (rosuvastatin), AstraZeneca's anti-cholesterol pill.

"Fenofibrates have been around for years, and there are issues with them," McCaffrey said, nodding to long-term toxicity. "We use them as a positive control in some of our tests," he allowed.

The Apo-A1 approach, on the other hand, "makes a lot of sense when you look at the big picture." As people age, "after 30 years of cheeseburgers and bad diet," their bodies produce less Apo-A1. Pfizer's CETP target is "unvalidated, still, and I don't know if it will ever be validated now," whereas Apo-A1 has been carefully tested and has emerged as "the single most important factor in cardiovascular risk," McCaffrey said, and Resverlogix's compound is "activating up to a 150 percent increase in 24 hours."

An investigational new drug application filing is expected next year, he said, by which time Resverlogix likely will have sold the cardiovascular rights to a major pharma firm.

"It's [turned into] an acute program, where we always thought it would be chronic," McCaffrey said, so an acute indication for urgent use will be sought first, with a label for chronic therapy to follow. "That gets them to revenues two to three years earlier," he said.