Mortality in Phase III Trial Pulls Plug on HDL-Booster

CLEVELAND, Dec. 4 -- The abrupt halt to clinical trials of torcetrapib, an investigational HDL-boosting agent, raises questions about any drug that inhibits cholesteryl ester transfer protein (CETP), according to cardiologist Steven Nissen, M.D., of the Cleveland Clinic.

Pfizer announced Saturday night that it was halting development of the drug after it was informed that the drug was associated with excess mortality in a large phase III trial.

Earlier in the week an upbeat Pfizer exec told an investors' meeting in Groton, Conn., that the company was gearing up to submit the drug, the first of the new class of CETP inhibitors and a potential billion-dollar product, for FDA approval.

However, said Dr. Nissen, the excess mortality "raises the specter of something uniquely toxic about inhibiting CETP," Dr. Nissen said.

The FDA said Pfizer notified the agency at 4 p.m. Saturday that it was suspending its phase III trial of torcetrapib/Lipitor (atrovastatin).

The trial's data safety monitoring board identified the excess mortality -- 82 deaths in the torcetrapib/Lipitor arm versus 51 in the Lipitor alone arm -- in an analysis reported to Pfizer late Friday. Those data included the monthly safety report as well as a quarterly analysis.

The FDA said it "fully supports Pfizer's decision to suspend this trial" and said that the agency's staff will continue to work with Pfizer and other companies that are developing molecules in the same class to "ensure that appropriate protections are in place."

Dr. Nissen said the data safety monitoring board was chaired by Charles Hennekens, M.D., of the University of Miami. Dr. Hennekens "would not have recommended that the study be halted unless there was a strong and clear signal," Dr. Nissen said.

Asked about a possible mechanism to explain the excess mortality, Dr. Nissen said that earlier studies had confirmed that the drug was associated with a slight increase in blood pressure. But he said that the excess mortality reported was more than would be expected "with a rise of 3 mm of mercury over three years."

The alternative explanation is that the drug promotes creation of "dysfunctional HDL that is proatherogenic and proinflammatory," he said.

If that is the case, "then it will call into question the safety of any drug that promotes HDL by suppression of CETP," he said.

Roche and Merck are also developing drugs that increase HDL by suppressing CETP.

Dr. Nissen was principal investigator of a 1,190-patient trial that used intravascular ultrasound (IVUS) to assess the effect of the torcetrapib/Lipitor combination.

Dr. Nissen said the IVUS study had completed data collection, but he won't know the results until the first week of January.

"Then we will know if this compound increased progression of plaque, regressed plaque, or had no effect on plaque," he said.

Dr. Nissen that however the findings fall out he would publish the findings and report them at the American College of Cardiology meeting in March. Dr. Nissen is president of the ACC.

If the IVUS study demonstrates that torcetrapib "regressed plaque or had a neutral effect," it will be necessary to revisit the issue of blood pressure, he said.

For example, examination of the raw data might reveal that the events occurred in those people who "had the most significant increases in blood pressure -- not the mean increase of 3 mm Hg, but an increase of 10 or 15 mm Hg," Dr. Nissen said.

Pfizer's announcement about torcetrapib comes just days after it announced that it had ended a research collaboration with a European company to develop a new schizophrenia drug -- asenapine.

Both torcetrapib and asenapine had been predicted to be blockbuster drugs.