We are quickly approaching the one-year anniversary when Pfizer withdrew its much-hyped cholesterol pill during a Phase III trial. Known as torcetrapib, the drug was supposed to be nearly revolutionary because it would raise HDL, the good cholesterol. But instead of preventing heart attacks and deaths, torcetrapib caused them, raising questions about this type of med, known as a CETP-inhibitor, HDL and whether similar pills being developed by Merck and Roche would cause the same problems.

Since then, the study has been picked over and this morning the results were finally disclosed at the annual American Heart Association meeting in Orlando, Florida (you can also read them in The New England Journal of Medicine). The upshot: in part, HDL increases weren’t the problem. But torcetrapib did increase production of a chemical called aldosterone, which is known to cause heart attacks.

“The shocking thing is that Pfizer didn’t know about this effect ahead of time,” James Stein, a cardiologist at the University of Wisconsin who works with Merck, Pfizer and other drug makers, tells Forbes. “We’re back to the drawing board, where we were five years ago. I think it’s going to be five or more years before we find a use for these drugs.”

Pfizer insists there’s no way it could have known about the aldosterone-boosting effects. It had even checked for them in animal studies. “This required the size, scope, and breadth of a large trial,” Steve Ryder, Pfizer’s head of development for cardiovascular and medical diseases, tells the mag. “It’s not a signal that was missed.” Adds Phil Barter, of the Heart Research Institute in Sydney, Australia, and the lead investigator: “I don’t think Pfizer needs to apologize for not finding this out. I cannot think of a way that this could have been picked up.”

Meanwhile, Merck is presenting animal data at the AHA meeting showing that torcetrapib does affect aldosterone, while its own drug, anacetrapib, doesn’t. But further tests are on hold. “We’re still looking through the data and making a decision about how, when, and whether to continue with the program,” says Daniel Bloomfield, senior director of cardiology at Merck. UPDATE: This is what Roche;s Bill Burns, head of ww pharma, tells Bloomberg News: Studies of its med didn’t uncover problems with high blood pressure and the drugmaker is leaning toward moving the drug into late-stage testing.

Both Merck and Roche raced to develop their own drugs that raise HDL; now they must either repeat Pfizer’s bet, which cost the company $1 billion, or abandon their entrants. All the drugs work by blocking the cholesterol ester transfer protein. This causes dramatic boosts in HDL. Torcetrapib boosts levels of HDL by 70 percent and Merck’s drug boosts HDL by 130 percent.

HDL appears to be an even bigger cardiovascular risk factor than bad cholesterol, or LDL, the stuff that Lipitor, Merck’s Zocor, and AstraZeneca’s Crestor are designed to do eliminate. But it’s also complicated. “LDL is very simple. LDL’s bad, lowering LDL’s a good thing,” says Stephen Nicholls, a cardiologist at the Cleveland Clinic. “HDL’s really confusing. It may be that not all HDL is good.”

One prominent doubter of the mechanism was Peter Kim, the research chief at Merck. At an analyst meeting in 2005, he said that the benefits of CETP “have not been proven in outcome studies. And unlike LDL lowering, where there is a general consensus in the field that lower is better, and it doesn’t matter how you lower it, there are different HDL particles that differ in composition and size.”

But Merck kept working on its CETP inhibitor anyway, in a stealth program unbeknown to Wall Street or the public. It was not until shortly before torcetrapib failed last year that news of Merck’s drug leaked out to The Star-Ledger of New Jersey. Merck confirmed that the medicine was in development after the torcetrapib trials had been stopped.

The key question for Merck is how much of torcetrapib’s toxicity was caused by the pill’s accidental effect on aldosterone. Clinicians say it is impossible to know. However, the telltale signs of the aldosterone effect, which included a decrease in blood levels of potassium and an increase in sodium, were also found in studies that used imaging technology to try to understand how torcetrapib affected the arteries.

John Kastelein of the University of the Netherlands, who conducted another set of torcetrapib imaging studies, says he also found evidence of the same problem. But we’ll only know if CETP works, he says, if Merck, Roche or another company conducts further studies on a different drug.

Another set of imaging studies, conducted at the Cleveland Clinic, provides more clues. Nicholls, along with Clinic imaging guru Steven Nissen, found that the patients who got the biggest increases in HDL also had the biggest decreases in the amount of plaque in their arteries. They also found low potassium levels and high sodium levels in patients’ blood, a hallmark of the aldosterone effect.

There are still big doubts about CETP, and the new results add another burning question: could CETP inhibitors affect the immune system? There were nine deaths from infection among patients taking torcetrapib in the 15,000-patient trial, compared to zero among the patients who did not get the drug. HDL plays a role in the immune system, and some experts suggest CETP might disrupt it; others are guessing there’s another chemical being released in the adrenal glands that could cause the problem.

Still, many leading investigators say that it is worth testing new CETP inhibitors–even though the process will take many more years. “It’s ethically responsible and, really, mandatory that these drugs be studied,” Nissen tells Forbes. “We have to get back on course here.”

Barter says “the potential benefits are great.” But any CETP inhibitor will have to be tested in a study at least as big as the 15,000-patient one he conducted. “It has to be not only a demonstration of efficacy, Barter says, “but also that there is no harm.”

Source: Forbes