AHA 2010 – A defining moment for CETP inhibitors

Analysis

CETP inhibitors appear to be back on track and the massive potential of the class of drug is once more grabbing headlines, following presentation of the Define trial of Merck & Co’s anacetrapib at the American Heart Association (AHA) meeting today.

Since the spectacular failure of Pfizer’s CETP inhibitor, torcetrapib, four years ago when a large trial was stopped due to a 60% increase in death, the jury has been out on whether the massive adverse events were due to a class effect or specific to the compound. Safety data from the relatively small Define trial appears to have allayed some of those class effect concerns. However, experts at the meeting remain understandably cautious on anacetrapib’s safety and efficacy until the results from a much larger clinical outcome study; data which is unlikely to emerge until 2015.

Raising good cholesterol, cutting bad

Inhibitors of CETP, or cholesteryl ester transfer protein, have the ability to not only reduce levels of low density lipoprotein (LDL), or ‘bad cholesterol’, but also raise the level of high density lipoprotein (HDL), or ‘good cholesterol’, which help clear lipids from the bloodstream.

Current scientific consensus is that elevated LDL and low levels of HDL are both important risk factors for cardiovascular disease; although the thesis that raising HDL is particularly beneficial remains somewhat controversial.

For now though the main focus is on what Dr Christopher Granger, Duke Heart Center and chairman of the data safety monitoring board for the Define trial, refers to as a ‘really remarkable’ effect of anacetrapib in lowering LDL and raising HDL.

In the placebo-controlled trial of over 1,600 patients, anacetrapib more than doubled the level of HDL and cut LDL levels almost in half, despite all patients already receiving LDL-lowering statins, mainly Zocor or Lipitor.

“Personally I’m very impressed with this remarkable doubling of HDL cholesterol and important reduction in LDL cholesterol, on top of statin, and the beneficial effect on triglycerides”, says Dr Granger.

The trial’s lead investigator, Dr Christopher Cannon of the Brigham and Women’s Hospital, claims that anacetrapib has a “knock-your-socks-off effect on HDL and a jaw-dropping effect on LDL”.

Although the study was not large enough to assess the effect of the drug on clinical outcomes, numerically fewer cardiovascular events occurred in the anacetrapib group than the statin-only group; 16 events with anacetrapib versus 21 with statin-only.

All-important safety

Given the major safety scare with torcetrapib, perhaps more importantly the Define trial indicates that anacetrapib does not have the ‘off-target’ effect seen with Pfizer’s candidate.

The 60% higher risk of death and 25% higher risk of heart attack linked to torcetrapib was put down to a raising of aldosterone, a hormone which affects kidney function and blood pressure. In the Define trial, levels of aldosterone and blood pressure did not change.

Indeed, based on a so-called ‘Bayesian analysis’, the investigators conclude that the data confers a 94% confidence level that anacetrapib would not be associated with a 25% increase in cardiovascular events that was seen with torcetrapib.

However, Dr Harlan Krumholz, professor of medicine at Yale University School of Medicine, is a little sceptical of the validity of this Bayesian analysis, mainly given the small population size.

“This small study was underpowered for deaths, if anything there were slightly more deaths in the treatment group, so this study cannot give me much in terms of telling me about the risk of excess death”, says Dr Krumholz. “How sure can you be that there is not a small but clinically important difference?”

Death from any cause occurred in 11 patients receiving the drug, compared to 8 deaths in the placebo group.

Green light

Despite the fact the small trial could not definitively answer safety and efficacy concerns, there is clear consensus that anacetrapib warrants further investigation. The current expectation is that Merck will initiate a 30,000 patient trial next year, but which will not complete until 2015.

“It’s a green light for further study”, says Dr Robert Bonow of the Feinberg School of Medicine at Northwestern University, who would be happy to enrol his own patients, depending on suitability, into a larger study of anacetrapib.

Likewise, Dr Krumholz, despite concerns about the safety analysis used in the Define trial, would give his patients the opportunity to enrol in the planned anacetrapib trial. “I’m bullish on the idea of testing this, we just need to know more”, he says.

Meanwhile Dr Granger is ‘excited’ by the prospect of a larger phase III study. “If I was part of the pharmaceutical investment community, would I be enthusiastic about this? ‘Yes’,” says Dr Granger, a sign perhaps that confidence in CETP inhibitors will gradually return following this data.

“It’s all about probability and I would say this data puts it (anacetrapib) into a relatively high probability of success for a clinical impact”, according to Dr Granger.

Keen interest

All of which sounds like great news for Merck, but even sweeter music to the ears of Roche, which has already started a large-scale clinical outcomes study, dal-OUTCOMES, with its candidate, dalcetrapib. This trial could report in 2013.

The decision to dive straight into a large and expensive trial with dalcetrapib was something of a gamble, so the Define data which alleviates some of the class side-effect concerns will be a relief to the Swiss group.

There is still a very long way for CETPs to travel on the road to redemption, but the Define data could turn out to be an important milestone.

Trial ID NCT00685776 (Define)

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