The initial hype surrounding rosuvastatin as it emerged from clinical trials was based on the potency of the drug and its ability to provide greater reductions in LDL-C. Based on evidence presented to the FDA's Endocrinologic and Metabolic Drugs Advisory Committee, rosuvastatin reduced LDL-C 43% and 62% across the approved dose range, 5 mg and 40 mg, respectively.

Patients are pleased with the results, especially the patients who have been on statins for nearly 20 years.

However, the FDA has been particularly cautious with the statin class of medications since Bayer was forced to withdraw cerivastatin (Baycol^®/Lipobay^®) in 2001 after reports of increased fatal rhabdomyolysis. Muscle toxicity is a well-known side effect of the statins, but it generally manifests itself as the milder myositis (muscle pain).

"Until Baycol, there had probably been far too much concern and worry over side effects than were justified," Dr W Virgil Brown (Emory University, Atlanta, GA) told heartwire. "Baycol gave some backing to those folks who were insistent on worrying despite the data. Today, I think we understand what Baycol was doing, we understand why it happened, and we know the metabolism of these drugs that we're currently using is different. The FDA has accumulated a huge amount of incidence data on adverse effects, and Baycol was clearly a standout."

Dr W Virgil Brown (Source: Southeast Lipid Association)

AstraZeneca had initially applied for FDA approval for doses ranging from 10 mg to 80 mg. However, a review of the original application revealed safety concerns at the 80-mg dose and led the FDA to conclude that the risks of treatment at 80 mg outweighed the modest incremental reduction in cholesterol.

As a result, AstraZeneca was asked to resubmit more data in 2002 to assess the safety and efficacy of rosuvastatin in 10-mg to 40-mg doses, delaying the drug's launch to market.

The resubmitted rosuvastatin information to the FDA included more than 12 500 patients treated with the drug in phase 2/3 clinical trials, including more patients at the 20-mg and 40-mg doses, and patients previously treated with 80 mg.

Lipid expert Stein, a researcher involved in the early clinical trials with rosuvastatin, said the wealth of available data should alleviate the worry clinicians may have about using the medication, noting more than 1000 patients have been studied on the 80-mg dose.

We know the metabolism of these drugs that we're currently using is different [from Baycol].

"In the post-Baycol era, the companies have decided to err on the side of safety even though at these doses, in certain patients with inherited abnormalities, there is a tremendous cost/benefit ratio," said Stein. "The database should be very reassuring. We know that even at twice the current dose, if the drug were a really harmful drug, you wouldn't have more than 1000 patients on it for over one year."

Recently, AstraZeneca hit a minor stumbling block with Crestor. WellPoint Health Networks Inc, the second-largest private health insurer in the US, announced that it would not reimburse people who use rosuvastatin because of concerns over the safety and benefits of the drug.

The insurer has admitted it is a little gun-shy because of Baycol, noting its skittishness stems from a desire to be cautious and conservative.

Stein, however, isn't buying it.

"All of these companies are more concerned about the money than the drug," he said. "The development program for Crestor was three times that of any other statin, including Lipitor. The number of patients at 80 mg, which is not even a dose that is marketed, was over 1000 patients for one year. The entire database for Lipitor at the time of approval was 250 to 300 patients at 80 mg, which is a dose that is marketed."

Stein told heartwire rosuvastatin is the only drug that has data available at twice the approved dose.

"Some people would say, 'Well, there were side effects at 80 mg,' but there would be side effects at 160 mg of Zocor and 160 mg of Lipitor, too," said Stein.

Brown, however, was more philosophical, and said the WellPoint decision should have been expected. He fully expects the decision to be reversed once the new statin has been on the market for a little while.

All of these companies are more concerned about the money than the drug.

"I'm surprised if anybody is surprised by this. Most of these large contractors, like the VA system, for example, don't even look at a drug until it's been on the market for a year," he said. "This is traditional behavior."

Brown added that if physicians are cautious in terms of prescribing other medications that may affect a patient's metabolism, the statins, as an entire class, are safe. Brown told heartwire that based on the available data, he is comfortable prescribing the maximum dose of rosuvastatin approved by the FDA.

"I think that rosuvastatin at 40 mgbased on the data I've seen from AstraZenecais very safe, and I'm not worried about it," he said. "The proteinuria we see is not unique to rosuvastatin and it doesn't look any different to me at 40 mg from atorvastatin at 80 mg or simvastatin at 80 mg."

One London-based investment analyst familiar with AstraZeneca and Crestor who spoke to heartwire said that while the WellPoint reimbursement decision is not critical, it exposes some potential concerns.

"The question becomes how important is WellPoint," he said. "Arguably, it is not that crucialit is the most aggressivebut is the decision going to make others feel slightly more comfortable coming out with a similar type of comment? If you're a slightly smaller managed care company and a big company like WellPoint makes this decision, it might give you the excuse you require to delay for another 12 months or so. We'll have to see."

(Source: AstraZeneca)

Still, since the FDA approval in August, initial sales figures for Crestor show the drug is off to a promising start. During its first week on the market, Crestor claimed 1% of all new prescriptions for statins, eventually capturing 2% in the first week of October. Several New York and London investment houses remain positive, if not conservative, on the long-term prospects for the new statin.

AstraZeneca has recently completed negotiations with managed care organizations that account for 50% of covered statin lives, or patients who would take statins. In the US, 75% of patients who use statins are covered by these organizations. Formulary inclusion remains a key variable in the success of Crestor, say experts.

Many formularies use a three-tiered copayment system. The first tier includes generic drugs. The second tier includes medications with no generic substitute or brand-name drugs listed on the formulary. The third tier includes brand-name drugs with generic substitutes or brand-name drugs that are not on the formulary.

Because AstraZeneca remains "cagey" about the exact formulary status of Crestor with these managed care organizations, some analysts feel it might be too early to tell how the drug is going to do.

"What we don't know at the moment is what level are they on the formulary," said the London analyst. "Is it tier two or tier three? I would imagine it is a combination of the two of them. The IMS prescription data we've seen so far imply a market share of about 1.5% or so. AstraZeneca always does its count on the data and they're talking about a dynamic market, which to be honest is not something anybody can really calculate. But it's talking about a dynamic market and a market share at the moment of 2%. That seems fine."

Dr Christie Ballantyne (Source: Baylor College of Medicine)

Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX) told heartwire that the place for rosuvastatin within the cholesterol-fighting arsenal is future cholesterol target levels. Newer, more aggressive LDL-lowering targets will make rosuvastatin an attractive option for clinicians looking to bring cholesterol levels down.

"The issue for Crestor has been where exactly does this drug fit in," said Ballantyne. "I believe it fits in as a new tool to really knock LDL down. The whole issue of how much is that tool going to be used really depends where the field ends up and how aggressive we have to be. If we have to be aggressive then you'll see a lot of usage and a lot of uptake."

He said that while most clinicians accept the premise that "lower is better," there haven't been any head-to-head outcome studies comparing statins that result in average reductions in LDL with statins capable of larger reductions.

If I have a patient that comes in with LDL values of 200 and needs a 50% reduction, not very many drugs can do that.

"The key issue is whether the present cholesterol target levels are going to be what we are looking at as our targets in the future," said Ballantyne. "If lower LDL ends up being better, then all of a sudden everything is going to be shifting and we're going to have to start reducing LDL cholesterol by more than 50%. That's just real tough to do."

Brown agreed.

"I think most physicians are trying to follow the adult treatment panel guidelines, and I think they're reasonable, and rosuvastatin has been particularly helpful in that regard," he said. "If I have a patient that comes in with LDL values of 200 and needs a 50% reduction, not very many drugs can do that. Lipitor, many times, can get it done, but the other option we have is a combination of two or three drugs. If we can, it's certainly cheaper to use a single drug to bring those values down."

Aside from the potency of the drug, AstraZeneca has also decided to offer all doses of rosuvastatin for the same price.

The starting 10-mg dose of rosuvastatin will cost $2.62 a pill, slightly higher than the list price for the 10-mg starting dose of best-selling Lipitor, which is $2.47. However, as the dose of Lipitor increases, so does the price: the 20-mg dose of Lipitor costs $3.64. AstraZeneca intends to offer all doses of rosuvastatin at a flat price, making its price lower than atorvastatin when weighted for actual prescriptions written.

"For many patients it is a more affordable option, especially for patients who don't have insurance. They're getting a bigger bang overall, as well as getting a lot more bang for their dollar," said Stein.

Numerous investment housesamong them Credit Suisse First Boston and UBSexpect Crestor to reach global sales of $3.3 billion by 2007. The growth is based on a relatively modest new prescription market share of 10% in 2004, rising to just over 20% by 2007. Goldman Sachs remains slightly more bearish, pegging the five-year projected market share at 16%.

The market always, always, always goes to the drug that has the most effective LDL reduction at the starting dose and at the top dose. That's it.

One of the big questions, however, is whether Crestor, or more accurately, AstraZeneca, can compete with Lipitor and Pfizer. Some investment reports see the preliminary sales figures as encouraging signs, but it may still be too early to tell.

"It's a little premature to be using [early sales figures] as some sort of guide, saying it is better than Lipitor, or that it's in line with Lipitor, or whatever else," said the London-based analyst. "It's slightly irrelevant at the moment. The important thing is going to be if you look three or four months down the road to find out what the sustainable market share is going to be and what the sustainable growth looks like."

Undoubtedly, said the analyst, AstraZeneca will face an aggressive pitch by Pfizer, something that may be challenging in a market that is currently in a slowdown. Prescription growth has slowed in the past 12 to 18 months, he said.

While the market may have slowed, Stein told heartwire the efficacy of rosuvastatin would be the most important determinant of success in the long term.

"Everybody accepts that the benefits of statins are a class effect and the market always, always, always goes to the drug that has the most effective LDL reduction at the starting dose and at the top dose. That's it. That's what determines the market share," said Stein. "Lipitor was a drug that sold itself. It was number one with cardiologists before Pfizer got its sales force in place because the drug was the most effective."

As of September 26, 2003the latest day industry data were available8953 new prescriptions of Crestor were written compared with 361 763 new prescriptions of Lipitor and 161 884 prescriptions of Zocor.

Studies with hard clinical end points involving rosuvastatin are forthcoming but are not expected for several years. One studyJustification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)will investigate the effect of rosuvastatin on the reduction of CV morbidity and mortality among individuals with normal LDL-C and elevated CRP.

With major end-point studies coming, the additional "support" AstraZeneca is providing the new statin should help rosuvastatin find its niche in the crowded cholesterol-fighting market.

"We all know that Pfizer has over 20 phase 4 studies with Lipitor, but the huge studies that AstraZeneca has with Crestor, if not matching it, are certainly very significant investments with the major opinion leaders on board all doing those studies," said the London analyst. "That is all going to help it in the longer term."