In deciding whether to approve AstraZeneca's Crestor (rosuvastatin) for wider use, FDA will need to say what role high sensitive C-reactive protein levels will play in determining who should take the statin as a preventive measure. Until then, the size of Crestor's market opportunity for the pending claim remains somewhat unclear.

The agency now has a tough call to make given that members of FDA's Endocrinologic and Metabolic Drugs Advisory Committee offered differing views on the use of hsCRP as a qualifier for statin therapy during a Dec. 15 meeting in Gaithersburg, Md.

High sensitive C-reactive protein is a marker of inflammation thought to be a predictor of heart disease. AstraZeneca's JUPITER study evaluated rates of CV events in participants given Crestor 20mg as a preventive measure who had LDL-C less than 130 mg/dL, but who were at an increased CV risk as identified by age and elevated hsCRP levels. The majority of patients also had at least one other risk factor. Overall, the study showed improved outcomes in patients treated with Crestor (¹ Also see "Will JUPITER Change Statin Use?" - Pink Sheet, 10 November, 2008.).

Elevated hsCRP, on its own, currently is not a CV risk factor recognized by the U.S. Preventive Services Task Force or The Annals of Internal Medicine.

This means the JUPITER study could be a game changer if FDA decides that hsCRP should be used to determine who takes Crestor for primary prevention. Since AstraZeneca's sNDA is based on the study, which included hsCRP as an enrollment criterion for otherwise healthy participants, it's nearly unthinkable that Crestor could gain approval for wider use without language on the marker.

The drug maker is seeking to expand Crestor's indication for the prevention of cardiovascular disease in adult patients who meet the traditional statin criteria, and also those who are at an increased risk based on the presence of elevated high sensitivity C-reactive protein levels (² Also see "Crestor Advisory Committee For Primary Prevention Of CV Disease To Focus On Adverse Events" - Pink Sheet, 14 December, 2009.).

At the time of the meeting, AstraZeneca's proposed indication did not include language around specific hsCRP levels or use criteria, but Chief Medical Officer Howard Hutchinson told reporters that discussions on these are ongoing with FDA.

Benefits Outweigh Risks, But For Whom?

Twelve members of FDA's advisory committee voted that the JUPITER study supports the use of rosuvastatin in men aged 50 years and older and women aged 60 years and older; those with a fasting LDL less than 130 mg/dL; hsCRP levels at or above 2.0 mg/dL; triglycerides less than 500 mg/dL; and individuals with no prior history of cardiovascular or cerebrovascular events or CHD risk equivalent as defined by NCEP ATP-III guidelines. Four committee members voted "no," including committee chairman Kenneth Burman, Washington Hospital Center, with one abstention.

But many members took issue with the wording of FDA's question. They noted that though the defined population generally experienced benefit while taking Crestor, certain subgroups did not. For the latter, therapy could add risk without much gain.

Two outstanding questions are: who exactly should take the statin as a preventive measure, and how large is this group?

FDA estimates that 6.5 million adults in the U.S. would be eligible for statin therapy based on JUPITER inclusion and exclusion criteria, though this number may shift depending on the label AstraZeneca ultimately receives. For AstraZeneca, wider use of Crestor would be a significant commercial gain as more generic statins enter the market.

Temporary voting member Thomas Wang, Massachusetts General Hospital, pointed out that as more physicians start measuring CRP, and more patients are found to have elevated levels each year, the target population for Crestor will grow beyond those estimates.

JUPITER Praised For Diversity

Questions also were raised about how much weight elevated hsCRP should carry in terms of prescribing the drug. "If your criteria [for treatment] are only that you need to be older than a certain age and have a CRP above a certain level, you've basically eliminated global risk stratification, if you don't really assess any of the other risk factors," Wang said. "Do we or don't we need global risk stratification and do we or don't we need a measurement of CRP?" he asked.

Voting member Abraham Thomas, Henry Ford Hospital, took a more definitive stance on the use of hsCRP.

"Without CRP as an entry criteria, how would you know which subjects with an LDL less than 130 would be at risk; other data suggest low LDL and low CRP don't increase risk for events, so why would you subject patients to that medication cost and side effects without using CRP as a differentiating agent?" Thomas asked.

Speaking for the sponsor, Christie Ballantyne, Baylor College of Medicine, stressed that hsCRP is an important measure because it enabled the JUPITER study to evaluate Crestor, and show benefit, in participants who otherwise would not have been eligible for treatment.

"The group with the low LDLs and high CRPs is enriched; it has more women, it has more African Americans, it has groups that have not been addressed typically," Ballantyne said. Though these two criteria are a "simplistic approach," they do enable a population that may have otherwise been overlooked to experience a treatment benefit, he said.

This point did not go unnoticed. Committee members and speakers who participated in the open public hearing portion of the meeting lauded the inclusion of women and minorities in JUPITER.

Labeling Should Not Ignore Subgroups

Still, some members stressed repeatedly that subgroup analysis is critical when recommending use of a preventive therapy in otherwise healthy individuals.

"I think to some extent it has [identified a new target population], but I don't think that the target is the whole population that was involved in JUPITER," said Drug Safety and Risk Management Advisory Committee member Susan Heckbert, University of Washington. She pointed out that participants with no additional risk factors, aside from those that got them into the study in the first place, did not appear to have a benefit on the drug, and so should not receive it.

"I think the reason we have to look at subgroups is because there's an adverse effect here that I think we've concluded is probably real [referring to reports of diabetes] and I don't think it's responsible to just say, everybody who got into JUPITER, yeah they should be treated," she added.

An overarching recommendation was to include language on this in the label.

"I think a number of us have been saying that any labeling that includes something new like CRP should simply say that there's a restriction on how far you go and there may be a very low risk population for whom there is lower risk or no benefit, and an increased risk of diabetes, and they shouldn't take the drug. I don't think it's more complicated than that," concluded temporary voting member William Hiatt, University of Colorado.

Post-Market Safety Studies Likely

Increased rates of investigator-reported diabetes in the JUPITER treatment group raise concerns among a number of committee members, but Burman noted that this is "probably a class effect" with statins that requires further long-term study.

"When further studies are performed with statins, a more quantitative analysis of diabetes and weight should be included in the analysis," he said.

FDA also asked for comment on 13 gastrointestinal deaths observed in treatment group compared to one in the placebo group. 18 patients who reported a "confusional state" while taking Crestor, and an observed increased risk of investigator-reported diabetes.

The committee agreed that it is unlikely that the 13 GI deaths in JUPITER represented a safety signal, but that a prospective study going forward would be helpful. Additionally, they surmised that when future studies are performed with statins it would be important to further evaluate any reported "confusional states."

Following the meeting, AstraZeneca said in a statement that the "advisory committee discussions and suggestions, including those made by panel members for additional studies and/or follow-up analyses, will help guide our ongoing dialogue with the FDA regarding our request for an indication that supports the use of Crestor for the prevention of cardiovascular disease in patients with an increased risk of experiencing cardiovascular events."

- Carlene Olsen ( ³ c.olsen@elsevier.com )

Crestor Advisory Meeting Weighs Value Of C-Reactive Protein Risk Marker

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