Larger-than-anticipated increases in systolic blood pressure with torcetrapib

November 03, 2006

New York, NY - The imaging studies are closer to completion, but the early buzz on torcetrapib is starting to shift from initial excitement to concerns that the novel cholesteryl-ester-transfer-protein (CETP) inhibitor might carry a risk of hypertensive side effects that could offset the benefit of raising HDL-cholesterol levels. Preliminary data released this week show that the drug increases systolic blood-pressure levels more than previously suspected, which is possibly bad news for the drug being heralded as Pfizer's next blockbuster.

As previously reported by heart wire , an early dose-ranging study found that patients with elevated LDL-cholesterol levels but without overt cardiovascular disease taking 60 mg of torcetrapib had an increase in systolic blood pressure of approximately 2 to 3 mm Hg. The newest data show the average increase to be higher, in the 3- to 4-mm-Hg range.

Commenting on the findings for heart wire , Dr Franz Messerli (St Luke's-Roosevelt Hospital, NY) said that while it might be argued that a 3- to 4-mm-Hg increase is not significant, the recent one-million-patient meta-analysis by DrSarah Lewington (Oxford University, UK) and colleagues suggest that an increase of 3- to 4-mm-Hg systolic blood pressure would translate, populationwise, into a 20% higher stroke mortality and a 12% higher mortality from ischemic heart disease [1]. Equally important, he said, is that not all increases in blood pressure are created equal.

"Target organs and patients differ in their responsiveness to small blood-pressure changes," he said. "For instance, the diabetic patient is more susceptible than the nondiabetic patient to small blood-pressure changes. Cerebrovascular disease and diabetic renal disease are distinctly more blood-pressure dependent than is coronary artery disease. Conceivably, therefore, a drug like torcetrapib that elevates HDL cholesterol and blood pressure may still be very useful in the 'uncomplicated' patient with coronary artery disease. However, its usefulness may be more limited or necessitate additional antihypertensive therapy in diabetic hypertensive patients and in patients at risk for cerebrovascular disease."

The preliminary blood-pressure findings emerged from the phase 3 studies being conducted with the drug. The largest of those trials is ILLUMINATE, a randomized, double-blind evaluation of the effect of torcetrapib/atorvastatin (Lipitor, Pfizer) vs atorvastatin alone on the occurrence of major cardiovascular events in 15 000 subjects with coronary heart disease or risk equivalents. The blood-pressure findings emerged from preliminary results of approximately 4000 patients already enrolled in Pfizer's phase 3 clinical trials.

Imaging studies coming at the ACC 2007

Despite the increase in blood pressure, Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) told heart wire that he is not too concerned about the increase and thinks the drug will be a much-needed addition to his clinical toolbox.

"Previously, what we had been told was that the drug increased blood pressure about 2 to 3 mm Hg, but based on what was presented previously, most people have no or minimal change in blood pressure," said Blumenthal. "There is a small subset of people who might have a larger 10- to 15-mm-Hg increase, but generally those are people who start off with real low blood pressures, those in the 100- to 110-mm-Hg range. I personally think the drug will still be a blockbuster, but what is needed, of course, is to see exactly what the drug does to atherosclerosis."

Just exactly what the drug does to atherosclerosis will be known sooner rather than later. In March 2007, Dr Steven Nissen (Cleveland Clinic, OH) is expected to present the results of the ILLUSTRATE study, one of three vascular imaging studies to be presented at American College of Cardiology Scientific Sessions. ILLUSTRATE is a multicenter, randomized, 1200-person study comparing atorvastatin/torcetrapib combination therapy with atorvastatin alone in preventing progression of coronary atherosclerosis as measured by IVUS in coronary heart disease patients.

The effects of the blood-pressure increase on IVUS-derived end points should be evident when the results from this study are in, Nissen previously told heart wire . In the CAMELOT trial, for example, a 5-mm-Hg difference in blood pressure resulted in a significant difference in plaque progression between treatment arms, he said.

"If indeed we see a significant decrease in atherosclerosis over a relatively short period of time, we'll know that at least in the short run, a modest increase in blood pressure is completely overwhelmed by the marked improvement in lipids," said Blumenthal. The long-term effects of the 3- to 4-mm-Hg increase in systolic blood pressure likely won't be known until the results of the large ILLUMINATE study are presented, he said, but added that the modest increase should not pose a problem for clinicians.

"What we expect to see with torcetrapib are HDL-cholesterol increases in the 40% range, maybe as high as 50%," he said. "If we have a drug that significantly decreases plaque volume, then as a cardiologist I know how to treat a modest increase in blood pressure. That's not a problem. There are clearly going to be some people, one in 10 or one in 20, who have rather large increases in blood pressure, although these are predominantly people in the low-normal range. If they go from 140 mm Hg to 160 mm Hg, that would clearly change the need for more medication."

As far as approval, Blumenthal said the increase in blood pressure might cause the FDA and other regulatory agencies to wait for the clinical-outcome studies, but he personally does not believe such a delay will be necessary if the IVUS study shows a significant affect on atherosclerosis. "We have so many people with severe atherosclerosis, claudication, and angina that I'd like to have that drug on the market if the short-term studies look safe," he said.

Messerli told heart wire that only a comprehensive outcome study would allow experts to quantify the risk/benefit ratio of torcetrapib and identify its place in the cardiovascular arsenal. He noted that it should be remembered that the increased risk of cardiovascular morbidity and mortality associated with some COX-2 inhibitors could also be caused, at least to some extent, by an increase in blood pressure.

When a good press release goes bad . . . 

When Pfizer issued a press release trumpeting positive lipid changes with the use of torcetrapib, it's unlikely the company wanted the type of coverage that appeared in New York Times and the Wall Street Journal[2][3].

In advance of the American Heart Association (AHA) 2006 Scientific Sessions in Chicago, IL, next week, the company released early data from its 400-patient Heterozygous Familial Hypercholesterolemia (HeFH) study showing that torcetrapib significantly increased HDL cholesterol 56% and lowered LDL cholesterol 27%. The Pfizer release said these data support the fundamental premise that torcetrapib can manage total cholesterol as it is able to successfully treat elevated LDL and decreased HDL levels.

The company also brought attention to the new data from phase 3 studies conducted with torcetrapib, noting there was an approximate 1-mm-Hg increase in blood pressure above the already observed 2- to 3-mm-Hg increase seen in phase 2 studies. Pfizer emphasized that the data are far from complete and early results apply to less than 25% of patients in the entire clinical program.

Not surprisingly, instead of taking Pfizer's good-news train all the way to the station, the New York Times and the Wall Street Journal focused their reports on this higher-than-previously-suspected increase in systolic blood pressure. According to the Journal, the blood pressure rise clouds "the outlook for the most important medicine in the company's research pipeline."

Both stories focus their attention on the financial pressure Pfizer is facing with the loss of patent protection for Lipitor in 2010. Although atorvastatin generated more than $12 billion in sales last year, the blockbuster statin is expected to face stiff competition from the generic market. The company, according to Journal reporter Scott Hensley, is currently spending $800 million on clinical trials with torcetrapib, hoping the drug can fill the void caused by the loss of Lipitor.

Regarding the increase in blood pressure, Dr Steven Nissen (Cleveland Clinic, OH) told the Journal, "This level of blood-pressure increase is clearly cause for concern." Next steps, however, will be to determine whether the large increases in HDL cholesterol and modest LDL decreases offset the risks associated with the blood-pressure increase. In addition, Dr Antonio Gotto (Weill Cornell Medical College, New York) told the Times that the increase was a worry. "It doesn't mean the death knell for the drug, but it would probably mean that one would want to see evidence on clinical events before approving the drug."

Last week, Bloomberg News reporters Shannon Pettypiece and Michelle Fay Cortez reported that torcetrapib might face approval delays [4]. Pfizer told analysts on October 19, 2006 that US regulators have requested long-term studies showing the drug prolongs lives and prevents cardiovascular disease before approving it. "The FDA has been clear that approval on imaging alone is not a guarantee and in fact is pretty iffy," said Dr John LaMattina, president of global research and development at Pfizer. "So a lot depends on what the imaging looks like and the nature of the effects."

Pfizer plans to submit its torcetrapib application to the FDA in late 2007, and it could take more than one year for approval. If the agency asks for more data, those clinical end-point studies will not be completed until late 2009, pushing back a possible approval to 2010 or 2011. One analyst said Pfizer could lose as much as $25 billion in revenue by 2011 when patents expire on six drugs.

Pfizer penalized

November 13, 2005 - In an interesting twist to the torcetrapib saga, physicians attending the American Heart Association 2006 Scientific Sessions in Chicago, IL, will not have any opportunity to review the newest data because the AHA has slapped Pfizer with a penalty for violating the meeting's embargo policy.

As a result, data from the HeFH study was withdrawn from the program. Based on the AHA's policies, this information was under strict embargo until after the presentation.

"We have a policy that has some enforcement," AHA president Dr Raymond Gibbons told the Newark Star-Ledger. "Early discussion of the material by a select few who have access encourages a selective view. It allows a sponsor to give its spin, and we don't want that to happen."

Blumenthal reports receiving clinical research support from Pfizer, Merck, AstraZeneca, and KOS within the past 24 months. Messerli is on the speakers' bureaus for Pfizer, Novartis, Abbott, GSK, Boehringer-Ingelheim, Forest Laboratories, Bristol-Myers Squibb, Bayer, and Merck. Neither Blumenthal or Messerli report stock options related to any of these respective companies.


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