Roche gives up on cholesterol drug trial, prompting questions about others in CETP class

This week, Roche announced it has discontinued development of its cholesterol drug dalcetrapib, marking the end of the story for a drug once touted as a potential blockbuster candidate and casting doubts on the two remaining prospects for cholesteryl ester transfer protein (CETP) inhibitors currently in clinical trials.

The Swiss drug maker pulled the plug on dalcetrapib after Phase III trials failed to show a clinical benefit, Roche said in a statement. “Lowering cardiovascular risk beyond that which is achieved with intensive statin treatment is a very challenging goal and while we have always stated that dalcetrapib is a high-risk project, we are disappointed by the fact that this drug didn’t provide benefit to the patients in our study,” Roche chief medical officer and head of global product development, Dr. Hal Barron, said.

Roche said it would discontinue its dal-OUTCOMES Phase III trial and three other trials relating to dalcetrapib: dal-OUTCOMES 2, dal-PLAQUE 2 and dal-ACUTE. Two other clinical trials -- dal-PLAQUE and dal-VESSEL -- already had been completed.

Cholesteryl ester transfer protein inhibitors are designed to block CETP, a plasma protein that promotes the transfer of cholesteryl ester from HDL particles (the "good" cholesterol) and other lipoprotein factions to apolipoprotein B-containing lipoproteins, which promote atherosclerosis and heart disease.

Dalcetrapib’s action in blocking CETP was expected to increase levels of HDL, which in turn was supposed to decrease heart disease risk. Roche had been hoping that dalcetrapib would prove a potent weapon in the fight against heart disease, and that it would reach blockbuster status once approved.

Still, CETP inhibitors have had a rocky history: dalcetrapib is the second CETP drug candidate to be dropped by its developer, leaving just two more -- Merck’s anacetrapib and Eli Lilly & Co.’s evacetrapid -- in development.

In 2006, Pfizer halted development on the CETP candidate torcetrapib, which up until that point had been considered the front-runner in the therapeutic class. Pfizer was deep into late-stage clinical testing and had invested an estimated $800 million in the drug before halting the ILLUMINATE trial for safety reasons -- early data from the 15,000-patient trial raised concerns of increased mortality and cardiovascular events in the patients receiving torcetrapib.

There had been hints in earlier-stage trials that torcetrapib raised blood pressure, but investigators hadn’t realized their clinical significance until the ILLUMINATE trial got underway.

Merck scientists, writing in the March 2012 edition of the journal Drugs, noted that other CETP inhibitors currently in development do not raise blood pressure and circulating levels of aldosterone; both those effects, they said, were specifically related to the structure of torcetrapib, and wouldn’t apply to the other CETP inhibitors on the market.

In fact, Roche said specifically in its announcement that “no safety signals relating to the dal-OUTCOMES trial were reported,” and blamed the trial’s failure and abandonment on the lack of clinical efficacy, not on safety problems.

Anacetrapib and evacetrapid don’t appear to raise blood pressure, either. However, there’s some evidence that all CETP candidates -- including anacetrapib and evacetrapid -- raise the levels of circulating C-reactive protein, an indication of inflammation that also can indicate an increased risk of cardiovascular events.

Evacetrapid and anacetrapid are just on the verge of Phase III clinical trials. Results released last November from a phase II clinical trial of evacetrapid indicated that the drug decreased levels of LDL cholesterol either by itself or in combination with statins. That trial provided enough evidence for Lilly to go ahead with planning for its Phase III clinical trial on the drug. Meanwhile, Merck currently is recruiting patients for its Phase III REVEAL trial on anacetrapib. Even if potential safety concerns prove unfounded, neither drug is expected to reach the market for several more years.

Despite an upbeat assessment from Roche that it still has a robust pipeline with 23 late-stage clinical trials reporting in the last 16 months and a significant increase in new molecular entities in late-stage development, the company’s share price fell 3.7 percent on the dalcetrapib news, and financial analysts said they expect Roche stock to underperform in the pharmaceutical sector.

References:

Johns D.G. et al. On- and off-target pharmacology of torcetrapib: current understanding and implications for the structure activity relationships (SAR), discovery and development of cholesteryl ester-transfer protein (CETP) inhibitors. Drugs March 5, 2012, 72:4.

Nicholls S. et al. Effects of the CETP Inhibitor Evacetrapib Administered as Monotherapy or in Combination With Statins on HDL and LDL Cholesterol. Journal of the American Medical Association Nov. 16, 2011, 306:19.