CHICAGO - With the full presentation of the results of the failed ENHANCE study at the American College of Cardiology annual meeting, a ringing endorsement for statin use and the results of IMPROVE-IT four years away, the door seems almost closed on Merck/Schering-Plough's Zetia (ezetimibe) and Vytorin (ezetimibe/simvastatin).

"Sometimes negative studies can provide very important insights. You've just seen a negative trial that should change practice, especially the way that we in this country have been prescribing ezetimibe," Harlan Krumholz, Yale University, told ACC attendees during an attention-getting panel discussion of trial results.

"This is just one study of ezetimibe, in one that employed measurements of arteries and not clinical endpoints. But this study provides no new evidence to support the use of this drug and it moves us to more uncertainty about the benefit of this drug," he said.

Krumholz and fellow panel members discussed ENHANCE - and endorsed statin use - after lead author John Kastelein presented the final data at the ACC Scientific Sessions in Chicago March 30.

The 720-patient, two-year Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression study failed to demonstrate an impact on progression of atherosclerosis, as measured by carotid intima-media thickness, although it did produce the expected reduction in LDL cholesterol levels.

Has The Impact Already Been Felt?

But despite the latest round of negative publicity, it seems that Merck and partner Schering Plough may have already weathered the worst of the storm. Initial results were released in January, and sales have already taken a hit. Although the final results did not yield any positive take away messages, they also did not deliver any unexpected negative findings.

After the first indication that the study failed to show an impact on atherosclerosis, major medical groups such as ACC and the American Heart Association issued statements urging caution in interpreting the results (¹ Also see "Vytorin Gets Medical Group Support, Congressional Query On ENHANCE" - Pink Sheet, 21 January, 2008., p. 10). FDA announced its own review, but made it apparent that there were no safety signals and labeling is already clear that Vytorin has not shown any reduction in cardiovascular risk (² Also see "FDA To Review Vytorin Data: ENHANCEd Label To Follow?" - Pink Sheet, 28 January, 2008., p. 21).

Major insurance companies have responded to the news about the ENHANCE results by maintaining current formulary placement, but at least one will no longer push the drug in one of its step therapy programs.

For Merck and Schering, the biggest long-term effect may be missed opportunity. By the time that data is available from the ongoing IMPROVE-IT outcomes trial in 2012, generic atorvastatin (Pfizer's Lipitor ) will have reached, and presumably saturated, the market.

While Merck/Schering-Plough had remarkable success in launching Zetia and Vytorin - turning the franchise into a viable alternative to statins and riding the "lower is better" wave of LDL lowering to a notable market share - it will be hard to come back from the hits that the brands have taken from ENHANCE.

ENHANCE Outcomes Measure: Cementing Statins

The overwhelming response to the ENHANCE study has been a cry to return to the solid evidence supporting statins, for which there is already data on both LDL lowering and reduction of cardiovascular outcomes.

"The strongest recommendation we can make on this panel is turn back to statins, especially those with favorable outcomes data. These are remarkable drugs, we know they lower risk. We need to go back to what works. Let's stay with the evidence," Krumholz said.

Cleveland Clinic cardiologist Steven Nissen, a vocal critic of ENHANCE, agreed with the panel's consensus recommendation for a return to statins. "For me, the conclusions of this weren't really a change in practice, they were simply an affirmation of the need to use agents for which we have very solid outcome data, and that's the statins." Nissen said in an interview with "The Pink Sheet" (see chart: " ³ ENHANCE UnderscoresNeed For FDA To Require Outcomes Studies - Nissen "). "But for many cardiologists where the drug was being used first line, this obviously represents a huge paradigm shift."

Unexpected Results Result In Paradox

Simultaneous to the presentation of the final ENHANCE results at ACC, the study was published in the New England Journal of Medicine.

The double-blind, randomized 24-month trial compared effects of daily therapy with 80 mg simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia.

Vytorin failed in the primary outcome, the change from baseline in the mean carotid artery intima-media thickness, a surrogate marker for progression of atherosclerosis. The cIMT measurements between the simvastatin monotherapy (0.0058+0.0037 mm) and simvastatin/ezetimibe combination therapy (0.0111+0.0038 mm) were not significant (p=0.29). Secondary outcomes also did not differ between treatment groups. Mean reductions in LDL, triglyceride and C-reactive protein levels were all significantly in favor of the combination arm.

"It is this paradox, which is at odds with our traditional understanding of the relationship between LDL cholesterol and atherosclerosis, that has puzzled investigators and clinicians alike," Jeffrey Drazen and other NEJM editors wrote in an editorial.

The results "dramatically contradict our expectations," Greg Brown, University of Washington-Seattle, and Allen Taylor, Uniformed Services University of the Health Sciences, wrote in a separate companion editorial. "'Lower is better' has been the mantra with respect to LDL cholesterol for the past two decades." But based on these findings, it seems that "benefits of lowering LDL cholesterol may depend not only on 'how low you go' but also on 'how you get there.'"

In a media presentation after the ACC panel, Krumholz said, "This observation does not unravel the lipid hypothesis, but it says that it may matter how we lower cholesterol."

Searching For Explanations

A number of reasons were offered to explain the seeming paradox between the significantly lower lipid levels and insignificant reduction in atherosclerosis progression in the study.

The authors suggested three possible explanations: lack of vascular benefit conferred by ezetimibe even with lowered LDL levels; inability of the measurement technique to accurately reflect changes in atherosclerotic burden; and pretreatment with statins (thereby reducing the potential beneficial effects of lowering lipid levels further).

Regarding the first theory, that LDL lowering with ezetimibe does not have the same benefits as LDL lowering by statins, the study authors note that based on previous studies, "it can be argued that certain lipid-independent effects of statins that are not shared by ezetimibe are involved in the production of a vascular benefit."

"However, several facts argue against the concept that ezetimibe-induced lowering of LDL cholesterol levels does not produce additional vascular benefit beyond that with statins," the article continues, citing other research. "In view of the controversy regarding the lipid-independent effects of statins, the results of ongoing clinical trials comparing statins with combined therapy with ezetimibe are eagerly awaited."

The authors also considered the possibility that pretreatment, including statin therapy, meant that patients in ENHANCE were too healthy to gain any additional benefit from the study treatment.

"There may be limits to the extent to which the lowering of LDL cholesterol levels can result in a further decrease in the progression of intima-media thickness in the context of previous statin therapy and a modest baseline intima-media thickness," they conclude.

However, the editorial by Brown and Taylor examines the statin-naïve subgroup to evaluate this theory: "Among the 19 percent of patients who were not receiving statins at the time of study enrollment, those who were treated with the combined regimen of simvastatin plus ezetimibe did not have a better response than did those receiving simvastatin alone."

The other theory questions the intima-media thickness endpoint. Kastelein et al. maintain that the measurement of IMT is a validated surrogate marker for atherosclerotic vascular disease, and state that "It seems unlikely that we were unable to detect a truly significant change in arterial-wall measures using our measurement technique."

However, Merck opted to halt the ACHIEVE trial of its cholesterol therapy Cordaptive (niacin/laropiprant) that is using the imaging endpoint. The firm announced March 31 that it was delaying further enrollment in the study pending a review of study design. ACHIEVE is measuring IMT using vascular imaging in patients with familial hypercholesterolemia.

Pfizer hit a dead-end using the IVUS imaging endpoint in the clinical program for its HDL raising therapy torcetrapib, which was dropped after failing to make a dent in progression of atherosclerosis (measured by IMT) (⁴ Also see "Pfizer’s Lipitor Extension Shot Down By Failure Of Torcetrapib Silver Bullet" - Pink Sheet, 11 December, 2006., p. 3).

Questions Remain Unanswered

Speaking at ACC, Kastelein noted that the study does not offer any means to evaluate the possible reasons for its failure. "Phase III trials are never meant to really definitely determine the reason for this failure, so lessons remain unknown."

"Critics may opine the reasons for these findings. They may include the possibility that the measures were not precise enough or the population is different, but the most likely explanation that we keep coming back to is that in this study the compound did not work," Krumholz said.

"It lowered LDL but it did not reduce progression of atherosclerosis as we saw in these prior studies where they used statins, or more intensive statin therapies, and the effect was well-seen."

Prescription Patterns Also Analyzed

Another study appearing in NEJM side by side with the ENHANCE findings compared prescription patterns for ezetimibe in the U.S. and Canada, and was held up with ENHANCE to criticize Merck and Schering's marketing practices.

"Now, with knowledge of its effect on LDL, but no information on the progression of atherosclerosis or patient outcomes," Krumholz - a co-author on the study - asked at ACC, "how have we used this drug? We in the U.S. have embraced the medication. Amid an aggressive marketing campaign the drug has been rapidly adopted into practice and become one of our favorite options for patients who need medications to treat their hypercholesterolemia."

Lead author Cynthia Jackevicius et al. analyzed prescribing trends and expenditures of ezetimibe and other lipid-lowering agents from 2002 to 2006 in the U.S., which allows direct-to-consumer advertising, and Canada, which does not.

"Despite the absence of data regarding clinical outcomes," the article states, "ezetimibe was heavily promoted."

In 2006, 824,000 prescriptions were dispensed in Canada, compared with 33.6 million prescriptions in the U.S. Annual expenditures in 2006 for ezetimibe in Canada were $64.7 million, compared with $2.7 billion in the U.S.

The researchers found that reliance on statins predominated in Canada, while statins were initially displaced by ezetimibe in the U.S., followed by a rapid growth in the use of Vytorin, which "markedly altered the approach to the treatment of hyperlipidemia and increased drug costs. The effect on ... clinical outcomes is uncertain."

Total weekly prescriptions dropped below 373,000 for Vytorin in early March, down from around 420,000 when the ENHANCE data was released on Jan. 14. Total weekly Zetia prescriptions have also dropped from around 320,000 Jan. 14 to below 273,000.

The differential use of ezetimibe may have been due to pharmaceutical promotion, the article concludes, but it acknowledges access to prescription drugs and formulary coverage may also have played a part.

What Vytorin's Future Holds

Falling prescription numbers and sales are just part of the fallout for Vytorin - which already includes congressional inquiries and class action lawsuits (see chart: " ⁵ And The Fallout Continues... ").

But with its unquestioned efficacy in LDL lowering and an outcomes trial underway, there are still chances for Vytorin. Merck and Schering have already started a new marketing strategy, called the "49 Plan."

The event-driven IMPROVE IT study has already enrolled more than 11,000 patients of a targeted sample size of 18,000. A joint statement released March 28 announced the sample increase, up from 10,000 patients, and the new estimated completion date. Data are now expected in 2012, one year later than originally planned, but the companies maintain "it is not possible to determine with precision an exact date that the trial will end."

"When outcome studies are finally finished, we may recognize that this drug is in fact an effective intervention for our patients, that it reduces cardiovascular risk. The ENHANCE results make that less likely, but it's not impossible," Krumholz speculated.

"It could also be that ezetimibe is just an expensive placebo, and its principal harm is that it drains precious resources from our health care system, and also maybe leads people to use less of the drugs that we know are effective and are beneficial."

"So where does that leave us? ENHANCE is an important negative study that provides no new support for a widely prescribed drug, and the surprising findings of ENHANCE remind us how little we know about the balance of clinical risk and benefit for this drug, even as we know it lowers LDL," Krumholz concluded.

- Becky Jungbauer (r.jungbauer@elsevier.com)

No Surprises From ENHANCE At ACC Mean Vytorin Hopes Hang On IMPROVE-IT

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