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Stanford BIO 230 - Lecture Notes

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11/12/2007 12:49 PMGoogle Image Result for http://www.rsc.org/images/OPINION-LOWE-250_tcm18-73393.jpgPage 1 of 2http://images.google.com/imgres?imgurl=http://www.rsc.org/images…rcetrapib%26gbv%3D2%26svnum%3D10%26hl%3Den%26safe%3Doff%26sa%3DGChemistry WorldOpinion: In the pipelineDerek Lowe looks at the recent failure of Pfizer's cholesterol drug, torcetrapib, and asks what itmeans for the future of pharmaceutical researchThe biggest story in the drug industry for 2006 took until December to announce itself, and manypeople immediately wished they'd never heard of it. Pfizer's massive clinical failure with torcetrapibwas more than enough of a catastrophe for everyone. The drug, which saw its first clinical tests in 1999, appeared to sail through subsequent trials whichproved torcetrapib could boost the amount of 'good' cholesterol, or high-density lipoprotein (HDL), inpatients. But on 2 December, Pfizer announced that the latterstages of Phase III trails had shown an increased risk ofmortality and cardiovascular events in people taking thedrug, and immediately stopped all clinical trials. The drug works by inhibiting cholesteryl ester transferprotein (CETP), which regulates the exchange ofcholesterol and triglycerides between plasma lipoproteins.Less CETP activity essentially means more HDL, whichhelps to reduce the build up of fatty atheroscleroticplaques that block blood vessels. This mechanism nicelycomplements drugs that reduce the body's levels of low-density lipoprotein, such as Pfizer's own blockbusterstatin, Lipitor. Inhibiting CETP has been a target for drug development teams for many years now. A number ofcompanies have had compounds in this area, but many have fallen by the wayside, often forreasons that haven't been made clear. One difficulty has surely been the nature of the protein itself.Built for binding lipids, most of the compounds that can alter its function have to be large and greasythemselves, and that never helps a drug's chances. Those properties mark a compound as a foreigninterloper, and affect everything from the time the compound reaches the gut to the rate it's clearedfrom the bloodstream. People are spending hundreds of millions of dollars to find out more about CETP. Roche (with theirpartners at Japan Tobacco) and Merck are known to be in the clinic with CETP inhibitors of theirown. It must not have been a fun weekend around their clinical departments when the Pfizer newsbroke. If torcetrapib's failure had immediately doomed the competing compounds, at least the painwould have been over with in one shot. But all the competing companies are going to have to live ina thick atmosphere of fear and hope for some time, because - as could be carved in stone over thedoors of clinical research departments everywhere - it isn't that simple. For one thing, it's not clear whether torcetrapib failed because of its CETP activity, or just because itthere was something odd about torcetrapib itself. And there's an added complication - the troubleonly showed up in the patients that were also getting Lipitor, which means that drug-drug (ormechanism-mechanism) interactions can't be ruled out yet. What really obscures things is that Roche's compound seems to act on CETP through a differentmechanism, and thus probably through a different binding site. We're going to know a lot more aboutHDL and cholesterol trafficking by the time all this is over, and we'll certainly have paid to find out. There's a lot of money riding on such mysteries, and yet no one has the slightest idea howeverything will play out. It's this 'place-your-bets' atmosphere that drives upper management insaneall across the business. Compared to some industries, it's like making a living by staggering blindlyaround in a casino, waving a wad of cash in one hand and a fistful of test tubes in the other. It's11/12/2007 12:49 PMGoogle Image Result for http://www.rsc.org/images/OPINION-LOWE-250_tcm18-73393.jpgPage 2 of 2http://images.google.com/imgres?imgurl=http://www.rsc.org/images…rcetrapib%26gbv%3D2%26svnum%3D10%26hl%3Den%26safe%3Doff%26sa%3DG© Royal Society of Chemistry 2007 In the pipeline To read moreRelated LinksExternal links will open in a new browser windowaround in a casino, waving a wad of cash in one hand and a fistful of test tubes in the other. It'stempting to think that modern management techniques, better scientists, or more software mustsurely make this stuff manageable, but nothing has worked so far. Just ask Pfizer. The largest drug company in the world just lost what could have been their biggest-selling drug ever, and only time will tell whether the clinical disaster was avoidable. But for now,everyone in the field is holding their breath, because nothing's obvious and nothing's for certain. Youcould carve that in stone, too. Derek Lowe is an experienced medicinal chemist in the pharmaceutical industry, working onpreclinical drug


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