The JUPITER Results: Will The Planets Align For OTC Statins?

AstraZeneca's JUPITER trial on Crestor (rosuvastatin) greatly expands the pool of patients who may benefit from statin use, which could help make the case for an OTC switch in the cholesterol-lowering class in the future.

The results of the AstraZeneca-funded study - the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin - show a benefit of decreased cardiovascular events in a population of people who do not usually qualify for the therapy because of their lack of hyperlipidemia.

The results could support a reworking of clinical guidelines for cholesterol levels, leading to treatment of people with lower cholesterol than currently recommended. The current 2004 ¹ guidelines of the National Cholesterol Education Program are set to be reevaluated by next year, with data to be considered that includes JUPITER.

New guidelines in turn could shift the risk/benefit in a favorable direction for OTC statins.

JUPITER studied 17,802 healthy men age 50 years and older and women age 60 years and older with levels of low density lipoprotein cholesterol below 130 mg/dL and high-sensitivity C-reactive proteins at or above 2.0 mg/L.

The researchers looked at hsCRP levels as a biomarker for inflammation because they previously were shown to be predictive of CV events. They theorized that because statins lower hsCRP levels in addition to serum cholesterol, people with higher levels and without hyperlipidemia could benefit.

Participants received either placebo or 20 mg of Crestor - a higher potency statin - for 1.9 years, when the scientists determined there was an "unequivocal benefit" and ended the study early.

Participants were monitored for the occurrence of the combined primary endpoint of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina or death from cardiovascular causes. Risk also was significantly reduced by 54 percent for myocardial infarction; by 48 percent for stroke; by 47 percent for revascularization or unstable angina; by 47 percent for the combined endpoint of myocardial infarction, stroke or death from cardiovascular causes; and by 20 percent for death from any cause.

"In individuals not currently qualifying for statins, major cardiovascular events were reduced 44 percent and mortality was reduced 20 percent," Paul M. Ridker, the lead researcher of the study said at the annual scientific sessions of the American Heart Association Nov. 9 in New Orleans. Ridker directs the Center for Cardiovascular Disease Prevention at Brigham & Women's Hospital in Boston. The results were published simultaneously in the New England Journal of Medicine.

Will JUPITER Influence The Future Of Switch?

Eric Brass, director of the Harbor UCLA Center for Clinical Pharmacology and an industry consultant, says he does not see JUPITER having a "direct effect" on statins switching OTC, but said the results may have an impact down the road.

Companies may point to JUPITER's results in future statin switch petitions, says Mary Tinetti, former chairwoman for the Nonprescription Drug Advisory Committee. Tinetti presided over the committee during Merck's third failed attempt to switch its statin Mevacor over the counter in December 2007.

FDA's joint panel of NDAC and the Metabolic Drugs advisory committee advised the agency against the switch due mostly to concerns consumers below the indicated threshold for cholesterol levels would incorrectly self-select (² (Also see "FDA Advisors Say Greater Insight Needed On Self-Selection Of OTC Statins" - Pink Sheet, 17 Dec, 2007.), p. 3).

The proposed OTC Mevacor Daily was indicated for women age 44 and older and men age 45 and older with moderately elevated cholesterol levels and at least one heart disease risk factor, for the prevention of first heart attacks.

Under current NCEP guidelines - the Adult Treatment Panel III Report - cholesterol lowering drugs are recommended depending on LDL levels combined with the patient's other cardiovascular risk factors. Under ATP III, patients with LDL levels under 129 mg/dL - the limit used in JUPITER - are recommended to receive therapy only when they have the highest level of cardiovascular risk factor: coronary heart disease or indication of it.

Saul Shiffman, a health psychology professor at the University of Pittsburgh and consultant to Merck, said guideline changes will take time and require analysis of a lot of research, including the JUPITER results that involve CRP. "The test for C-reactive protein is not currently in routine clinical use, so it will take some time for the medical community to feel comfortable with treatment guidelines based on this test," he noted in an e-mail.

Shiffman said the study results reinforce the significance of closing "the treatment gap," noting it "strengthens the case for OTC availability of statins."

However, Shiffman added, "Because the results were obtained with a specific drug in a specific, select population, [the results] won't generalize directly to the OTC target population that has so far been considered."

Brass said the data may support Merck's argument, made during its most recent switch proposal, that "while the label was based on current guidelines, most of the consumers that did not heed 100 percent of the label directions during consumer research studies still would likely derive benefit from statin use," Brass noted.

The panel rejected this argument, deeming that Merck's consumer behavior study did not show consumers were capable of making appropriate purchase decisions. They said more realistic research of consumer behavior and actual use studies were needed to demonstrate appropriate self-selection.

Brass said the JUPITER results could suggest the safety risk of improper purchases may be outweighed by benefit. "Perhaps in time there will be a greater comfort in these non-heedings that do not represent a safety risk and likely represent an individual benefit. At that point an OTC strategy for improving access to these drugs could be considered."

Tinetti said self-selection remains the key concern with regard to future statin switches. "I personally think that the key issue remains individual persons' ability to determine their risk - including CRP if we are to include the JUPITER study - and their LDL levels," she said in an e-mail.

Tinetti also identified study length as an issue. "Because JUPITER was a short-term trial, it does not address the long-term adverse effects part of the equation," she added.

Merck spokesman Ron Rogers noted in an interview the results are "interesting" and said the firm will examine the results further. Asked whether a fourth switch attempt for Mevacor is in sight, Rogers said it is not in the works, but has not been ruled out.

Bristol-Myers Squibb also failed to switch its statin, Pravachol (pravastatin), to OTC status in 2000. Bayer recently had an active program to develop Pravachol as an OTC, under an agreement with BMS (³ 'The Tan Sheet' July 2, 2007, In Brief).

JUPITER: What Is In The Stars For Statins?

"These are extremely reassuring data for statins as a class," Ridker maintained. In response to questions about a possible class effect with regard to prevention, he noted that all statins lower LDL cholesterol and hsCPR, "but the more potent the statin, the greater the benefit." With rosuvastatin, he said, "we may have just hit the sweet spot by picking the right target and using the right drug."

Over the course of the study, the number of patients needing to be treated to prevent one event was 95. Extrapolating to five years, the number needed to treat is just 25, Ridker reported.

Following the release of the results, AstraZeneca saw shares increase. Many observers believe Crestor, and statins as a class, could see a boost in demand from the study results.

"As is appropriate, the medical community, regulators and guideline committees will now carefully consider these data and any implications for treating patients," according to Howard Hutchinson, chief medical officer for AstraZeneca, in a Nov. 9 release.

The firm plans to file a regulatory submission that includes JUPITER within the first six months of 2009, the release says. If approved, the firm "will begin promotional activities within the approved labeling." A spokesperson for the firm declined to comment further.

AstraZeneca said in its release Crestor has not been indicated for CV events and the usual recommended dose is 10 mg. However, the firm notes the 20 mg dose of rosuvastatin used in JUPITER was "well tolerated in nearly 9,000" subjects and there was no difference for adverse events during the study's course.

Crestor's patent will likely run out in 2016. Generic competition could come as early as 2010, but is unlikely, according to Evaluate Pharma.

- Katie Stevenson ([email protected]). Caroline Helwick, Elsevier Global Medical News, contributed to this story.