Nobody wins all the time–not even the world’s largest drug company. Yet
‘s failures are as instructive as its successes.
Take, for instance, avasimibe, a once-promising drug to treat heart disease at the boundary between the artery wall and cholesterol plaque. Avasimibe’s twisted path to the dustbin highlights the practical quandaries drug companies are likely to encounter as they search for new ways to prevent heart attacks, the number-one killer in the developed world. Avasimibe hit many of the hurdles such drugs can face: It weakened other heart medicines; its effect was difficult to measure; and Pfizer
even may have shortchanged it in a clinical trial. Eventually, Avasimibe was replaced by Pfizer’s current lead compound, a drug to raise good cholesterol.
“If you have two or three approaches in the fire…then most companies don’t have the money for all of them,” says
, a University of Pennsylvania researcher who designed similar drugs for
. If one drug is not working as well as another, why throw money at it? “They’ll either let it sit or kill it outright,” Billheimer says.
In fall 2000, Pfizer finished its $116 billion purchase of
, the biggest hostile takeover ever. The prize in the deal was Lipitor, a cholesterol-lowering agent that is the best-selling drug in the world today, with $9 billion in worldwide annual sales–as much as Hollywood’s 2003 take at the U.S. box office. But blockbuster drugs can fade like has-been movie stars when their patents expire. Lipitor’s ticket could be up as soon as 2011. It is never too early to prepare for the generics.
At a meeting with analysts in December 2000, then-research chief
described avasimibe as the first drug ever to try treating artery disease at its root. Stock analysts were quick to grasp the importance of the treatment. On its own, it could be a blockbuster. But if it worked well with Lipitor, avasimibe could provide a powerful one-two punch. Patients might be lured onto a combination of the two drugs–and then cheaper generics wouldn’t steal them away. Moreover, the new pill would be even more effective than Lipitor at preventing heart attacks. (Drugs like Lipitor cut heart attacks by perhaps one-third.) That could mean years more of torrid sales.
First, avasimibe had to work. It had been developed at Warner-Lambert by
, a scientist in the same group that invented Lipitor. (Krause later left to work at
, which recently was bought by Pfizer.) The pill targeted a protein called acyl-CoA cholesterol acyl-transferase, or ACAT. There are actually two versions of this enzyme. One, found in the liver and intestines, seems to be involved in creating low-density lipoprotein, the bad cholesterol; research on this eventually led to Zetia, a drug sold by
that doesn’t hit ACAT but does lower cholesterol.
Billheimer, then at DuPont, and others thought there were enough cholesterol-lowering pills out there. The second ACAT enzyme, however, looked like pharmaceutical gold. A drug that inhibited this enzyme might prevent cholesterol from being stored in the artery wall, allowing the body itself to remove cholesterol plaques.
, a professor at Wake Forest University, says avasimibe probably hits both versions of ACAT. But its big advantage was that it is very water soluble, meaning that blood could carry the drug into the arteries at doses high enough to do its work.
Another problem reared its head, though. How does one measure that a drug is preventing plaques from forming on arteries?
Existing heart drugs work by affecting measurable risk factors like cholesterol or blood pressure. But the U.S. Food and Drug Administration would never approve a pill because it inhibits ACAT. Pfizer could run a giant survival trial, but that would take years and cost hundreds of millions of dollars without any evidence that the drug actually works.
Another approach was to use an ultrasound probe to measure the amount of cholesterol plaque in arteries both before and after treatment. Pfizer enlisted
of the Montreal Heart Institute to start such an experiment in 2001. Patients were to be followed for two years. But Pfizer cut the trial short, so that some patients’ artery plaque was measured after only 18 months. That would seem to decrease the likelihood of a statistically significant result.
A Pfizer researcher also published a paper in the Journal of Pharmacology and Experimental Therapeutics that showed that avasimibe increased the activity of a liver enzyme called CYP3A4. The enzyme is involved in removing several heart drugs from the bloodstream–including Lipitor. That could mean that avasimibe, which was meant to work with Lipitor, could actually decrease Lipitor’s effectiveness. The paper was submitted to the journal in February 2003, but Tardif says Pfizer had known about the interaction for several years.
“This was a strategic decision that Pfizer made, and it was not related to the finding you’re describing,” says Tardif of the changes to his trial. “We’ll be reporting the findings at the [American College of Cardiology] meeting and then publishing a full paper about the results.”
In any case, avasimibe had made an amazing journey in three years. At the end of 2000, it seemed like one of the most promising drugs presented at Pfizer’s analyst meeting. By 2001, it was sharing center stage with a drug to raise good cholesterol, which also would be combined with Lipitor. In 2002, it was relegated to a mention in a question-and-answer session with analysts. In Oct. 22, 2003, it was listed as dead in the disclosures section of a Pfizer release.
“We didn’t see a beneficial effect and we ended the program,” said
, Pfizer’s director of research, in December 2003. It was a quiet kill–analysts at some banks still have a placeholder for avasimibe in their models. A Pfizer spokesman confirmed that avasimibe is dead, but declined to comment further on this story.
The ACAT approach isn’t dead: Japan’s
is working on a far more potent ACAT inhibitor. But for Sankyo and other companies, such as
, trying to come up with the next cardiac blockbuster, avasimibe should stand as a warning of what could go wrong. A small drug interaction, the vicissitudes of measuring how well these medicines work and pure bad luck can all play a role in killing a program. Pfizer, for its part, moved on to its good cholesterol pill. Plus it has a spate of backup compounds–including some that avasimibe inventor Krause developed after he left for Esperion.