Devalued and Distrusted by John L. LaMattina

Author:John L. LaMattina
Language: eng
Format: epub
Publisher: Wiley
Published: 2012-12-25T16:00:00+00:00

The problem that scientists have faced in this field is that not a lot is known about raising HDL, and so trying to accomplish this feat in the laboratory has proven quite challenging. An exception involves the emerging biology around a protein known as cholesteryl-ester transfer protein (CETP). Back in 1990, a report in the New England Journal of Medicine17 described a Japanese family who, due to a genetic defect, didn’t produce CETP and as a result had very high HDL levels and low incidence of cardiovascular disease. Because of this observation, a number of companies, including Pfizer, sought to come up with an inhibitor of CETP to test in heart patients. The rationale was pretty simple: By inhibiting CETP, the new drug would raise HDL, thereby mimicking the situation in the Japanese family who were born without this protein. Theoretically, the CETP inhibitor would reduce heart disease maybe as well as statins. In a dream scenario, the combination of statins and CETP inhibitors would reverse heart disease, enhancing the quality of life of hundreds of millions of people.

Finding inhibitors of CETP proved to be very challenging, and most companies gave up. Pfizer almost did the same. But through hard work, creativity, and a bit of luck, the CETP inhibitor torcetrapib was found. It successfully cleared preclinical toxicology studies and entered clinical trials in 1999, eight years after the discovery program began. The initial clinical results were astonishing. Patients on torcetrapib had increases of HDL of 100% or more—an unprecedented finding. Even better, torcetrapib also caused a modest decrease in LDL; however, when torcetrapib was added to Lipitor (atorvastatin), not only was the HDL elevation maintained, but LDL drops of 40–60% were seen. The lipid remodeling that was achieved with this combination had never been seen with any therapy.

The combination of torcetrapib and atorvastatin (T/A) became a major focus not just for Pfizer but for the entire cardiovascular field. As the early clinical data for T/A emerged, other companies that had previously given up their efforts in looking for CETP inhibitors jumped back in the hunt. But although T/A uniquely modified the lipid profile of patients with heart disease, its ultimate value was not yet established. The long-term benefits of altering heart disease with CETP inhibition were still hypothetical. Furthermore, at the end of the phase 2 studies, it was found that T/A caused a small but reproducible increase in blood pressure. However, based on the known association between atherosclerosis, blood pressure, and cardiovascular disease, the large increase in HDL was expected to provide benefits that would be far greater than any harm caused by the small blood pressure increase. To prove this, Pfizer had to carry out an extensive phase 3 program that included a multiple-year study in patients with heart disease with the hope of showing that patients with heart disease fared better on T/A than they did with Lipitor (atorvastatin) alone. This was a pretty high hurdle. Pfizer wasn’t content to test T/A versus a placebo; rather,

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