Beyond Torcetrapib - A Ray of Hope…

The data on torcetrapib presented at the American Heart Association’s (AHA) Annual Scientific Meeting last week at Orlando suggests that while adverse events with all CETP inhibitors cannot be ruled out, other drugs in the same class still warrant further investigation.

Torcetrapib failed a large Phase 3 trial almost a year ago after it was found to actually increase the risk of death. With its leading brand Lipitor already facing competition from generics and its patents due to expire in 2010, torcetrapib was intrinsic to Pfizer’s plans for the cholesterol market and was also expected to provide an extended lease of life to Lipitor.

The aftermath saw billions of dollars being wiped off Pfizer’s value and the industry was left wondering whether the problem was restricted to torcetrapib or it extended across all CETP inhibitors. Merck and Roche halted research on their own CETP inhibitors, till more information was known on why the drug failed.

Data that was eagerly awaited by the medical fraternity and the pharma industry was first discussed at the Annual Session of the American College of Cardiology in March this year.

Commenting on the findings Dr. Steve Nissen said, “Something ‘strange’ is going on with the novel cholesteryl-ester-transfer-protein (CETP) inhibitor. In all three studies, there were dramatic increases in HDL cholesterol and significant reductions in LDL cholesterol, but this improvement in lipid parameters was offset by significant increases in blood pressure.”

He added, "The addition of torcetrapib to statin therapy has no benefit at all on atherosclerosis progression, but it remains to be investigated whether this is a consequence of the molecule torcetrapib or whether the concept of CETP inhibition is a flawed hypothesis. Additional data from the ILLUMINATE study later this year will hopefully shed more light on this issue.”

Merck reiterated that no adverse effect on blood pressure was seen in early studies of its CETP inhibitor, MK-0859 and Roche said it continued to investigate its experimental drug R-1658, and expected to submit it for regulatory approval after 2010.

The Illuminate study findings presented at the AHA meet this month did not show torcetrapib in very good light. While investigators found apparent pointers towards the drug’s impact on blood chemistry, there is still some uncertainty whether the adverse effects were typical of torcetrapib alone or were a class effect.

The initial results from the Illustrate trial showed that although torcetrapib markedly increased good cholesterol levels, it also substantially raised blood pressure and failed to significantly slow the buildup of plaque.

Torcetrapib also produced unexpected "off-target" toxicity on the adrenal gland, which was instrumental in leading to damage of artery walls and increase blood pressure. This off-target effect might hold the answer to why torcetrapib did not work as well as expected and also its toxicity.

This could rejuvenate interest in this class of drugs and comes as a ray of hope to companies like Merck and Roche that had halted development on their own CETP inhibitors till more details were available on the torcetrapib failure.

Presenting data from a new study at the Drugs Affecting Lipid Metabolism Symposium, Merck said its experimental CETP drug anacetrapib (MK-0859) more than doubled levels of HDL cholesterol and did not raise blood pressure or affect the adrenal gland.

Yale Mitchell, director of cardiovascular disease at Merck Research Laboratories said that the company will decide whether to go ahead with their experimental work on receiving and considering the results of further investigations.

Speaking at the Reuters Health Summit in New York, Roche Chief Executive Franz Humer said that they expect to decide in the coming weeks whether to go ahead with a late-stage trial of R1658. He said, "We've looked at the molecule and are very encouraged there is a way forward. We are certainly thinking about an (annual sales) potential of beyond $3 billion to $4 billion" if the drug succeeds in trials and is approved.

Finding compounds that raise HDL cholesterol has been a priority of drug developers as many patients on drugs that lower LDL cholesterol still experience heart attacks, stroke or sudden cardiac death.

Researchers at the AHA meeting said, "Our study neither validates nor invalidates the hypothesis that raising levels of HDL cholesterol by the inhibition of CETP may be cardioprotective. Thus, the possibility that the inhibition of CETP may be beneficial will remain hypothetical until it is put to the test in a trial with a CETP inhibitor that does not share the off-target pharmacologic effects of torcetrapib."

One year from the torcetrapib failure there is still some hope for the CETP inhibitors and they have not been written off altogether.

- D R Sudhakar