In June 2006, I was meeting privately with a member of Pfizer’s executive leadership team when he shared with me two bits of information that resurfaced in my conciousness today. The first was offered as a bit of coaching (more political than scientific) but has broader application: “Mike, don’t ever presume that you know fully what is going on in another human being.” The second was, “Pfizer will rise or fall on the results of the Torcetrapib trial”.

What made me recall that conversation was an artcle in this week’s New England Journal of Medicine titled “Cholesterol Efflux Capacity, High Densisty Lipoprotein Function, and Atherosclerosis”. (1) In it A.K. Khera and his co-authors begin to unravel the mystery of the failure of torcetrapib on December 2, 2006. That was the day that Pfizer cut off torcetrapib’s trial because of “an imbalance of mortality and cardiovascular events” associated with its use.In the initial data, the company uncovered a 60% increase in deaths among patients taking torcetrapib and atorvastatin (Lipitor) versus taking atorvastatin alone.(2,3)

To say this was a shock to Pfizer, with patent expirations of major blockbusters fast approaching, doesn’t even begin to describe the impact of this finding on the company, its researchers and the many academic investigators who held hope that this combination product (with atorvastin to decrease cholesterol and bad LDL and torcetrapib to increase good HDL) would lower cardiovascular deaths in high risk cardiac patients. A great many of the internal and external scientists at the time presumed to know that this combination would work, based on what was an oversimplified belief in the function of cholesterol, LDL and HDL. In fact, they were confident enough to design the head to head competition between the highly successful Lipitor already in the marketplace, and the newer combination which they felt would have to yeild even better results.

Some months before the conversation above, I was moderating a public scientific session at Pfizer where  Craig Venter was the headliner. In the Q & A session I asked him “What percentage of the scientific knowledge do you believe we currently possess to allow for ideal health care of human beings?” His reply without hesitation, “Less then 1%.” (4)

Which brings me back to this week’s article and HDL. What do we know today, or think we know. A little more. We’re certainly beyond the simplistic notion that simply getting a higher HDL number spells success. Today the focus is on HDL function not the HDL number. We now know that HDL “carries a unique cargo of proteins in patients with coronary disease and that these proteins might make contributions to the proinflammatory and antiinflammatory properties of HDL.” (5)

When HDL is functioning well, it’s protective abilities appear to be related to “its ability to promote cholesterol efflux from macrophage foam cells” that, left in place,  promote inflammation in the arterial wall. How about when HDL shows its other face?  Dysfunctional HDL appears to be involved in atherosclerotic disease progression. How it becomes dysfunctional remains unclear. We do know that “oxidation of apolipoprotein A-1 (one of the proteins carried by HDL which helps remove cellular cholesterol from macrophages) “impairs the ability of this protein to remove trapped cholesterol”.  As for dysfunction of the other bundled proteins, that question remains open. (5)

December 2, 2006 was a humbling day for Pfizer, and one, from which, you can argue they have not yet recovered. So perhaps that exec’s second comment on the “rise and fall” tied to this one single product will turn out to be accurate. We’ll see. But I will remember more the first admonition, which I believe is cautionary for any leader – political (as the events in Arizona illustrated this week), scientific or otherwise. “Don’t presume to know fully what is going on in another human being.” (6)

References:

1. Khera et al. Cholesterol Efflux Capacity, High Density Lipoprotein Function, and Atherosclerosis. NEJM. 364:2, 127-135, 2011.http://www.nejm.org/doi/full/10.1056/NEJMoa1001689?query=TOC
2. Berenson, Alex (December 3, 2006). “Pfizer Ends Studies on Drug for Heart Diseas”. The New York Times.
3. Theresa Agovino (Associated Press) (December 3, 2006). “Pfizer ends cholesterol drug development”. Yahoo! News. Retrieved 2006-12-03.[dead link] Each study arm (torcetrapib + atorvastatin vs. atorvastatin alone) had 7500 patients enrolled; 51 deaths were observed in the atorvastatin alone arm, while 82 deaths occurred in the torcetrapib + atorvastatin arm. (Link dead as of 15 January 2007)
4. Personal Communication.
5. Heinecke J. HDL and Cardiovascular-Disease Risk. NEJM. 364:2, 170. 2011 http://www.nejm.org/doi/full/10.1056/NEJMe1012520?query=TOC
6. Lacey M and Herszenhorn DM. In Attack’s Wake, Political Reprocussions. New York Times. January 8, 2011. http://www.nytimes.com/2011/01/09/us/politics/09giffords.html