AstraZeneca Crestor NDA Includes Rhabdomyolysis Reports At Highest Dose

AstraZeneca's discussions with FDA about the safety profile of the experimental cholesterol drug Crestor (rosuvastatin) are focusing on the potential for the highest dose to cause rhabdomyolysis, the company indicated during analysts meetings the week of Dec. 3.

"Within the Phase III database, a couple of the investigators reported cases of possible rhabdomyolysis side effects" at the 80 mg dose, VP-Cardiovascular Therapy Hamish Cameron, MD, told a Dec. 3 meeting in London. The patients' condition improved after they were taken off Crestor.

The lower doses of Crestor are free of any incidences of rhabdomyolysis, Cameron maintained. "There's absolutely no safety concerns at the lower end of the dose range," he declared. "Any debate that we have is about 80 mg."

Following the withdrawal of Bayer's Baycol (cerivastatin) in August, FDA is likely to take a careful look at any safety signals in the Crestor database.

The profile of a potential rhabdomyolysis risk at the highest dose appears to parallel the experience with Baycol. Bayer withdrew the drug after reports of severe and fatal rhabdomyolysis associated with the highest doses ( (Also see "Baycol Withdrawal Gives Boost To Pravachol; Will Crestor NDA Be Affected?" - Pink Sheet, 13 Aug, 2001.), p. 4).

Cameron declined to provide firm numbers of rhabdomyolysis cases, because "there isn't always a very clear definition [of the condition] that everybody accepts."

The overall myopathy rate in Phase III was .2%, Cameron noted. AstraZeneca maintained that the myopathy incidence is comparable to other statins.

"Pharmacologically, if you get enough of any of these products into the muscle tissue, they do inhibit the enzyme in the muscle tissue, and they will cause muscle damage," CEO Tom McKillop said at a Dec. 5 meeting in New York City.

AstraZeneca expects the statin will be approved in either a 5 mg or 10 mg starting dose. The company said it saw no sign of rhabdomyolysis in patients on those doses.

One challenge for AstraZeneca in its discussions with FDA may be convincing the agency that recommendations to initiate therapy at low doses will be followed in practice. One apparent contributing factor to the Baycol adverse events was that the high-doses (.4 mg and .8 mg) were being used as starting therapy, despite labeling instructions to begin at lower doses and monitor for safety signals.

AstraZeneca emphasized that Crestor remains "on track" for FDA approval next year. The NDA was submitted June 26 ( (Also see "AstraZeneca To "Go It Alone" For Crestor, Cites Large Market Opportunity" - Pink Sheet, 30 Jul, 2001.), p. 16).

AstraZeneca is hoping to receive a 10-month review for Crestor, in time for a launch by early fall.

"History says that more and more you can expect a 10-month response from the FDA," McKillop said. "The question is what happens after that." FDA is required to complete 90% of reviews in 10 months by FY 2002.

The agency recently acknowledged that, at least in some cases, 10-month reviews may be more likely to end in an "approvable" letter, which then puts final labeling discussions on a slower track ( (Also see "FDA “Approvable” Actions Increasing Under PDUFA, Agency Acknowledges" - Pink Sheet, 19 Nov, 2001.), p. 5).

McKillop suggested that AstraZeneca is faring better at FDA than its competitors. The average approval time for recent AstraZeneca products is 15 months, he said, versus the 18-month industry average.

"We seem to be continuing to have a very constructive dialogue with the FDA and getting pretty quick approvals," McKillop said.

AstraZeneca believes it can demonstrate to FDA's satisfaction that there are pharmacological differences between Crestor and Baycol that should make safety less of a concern.

"When you look at the clinical profile...of all the currently marketed statins alongside Crestor, you have a clinically relatively benign pattern," Cameron maintained.

"What we saw with Baycol was something fundamentally different, with a more malignant course," he declared. "We can explain that on the basis of the pharmacology and chemistry of these drugs, and obviously, we're making those full submissions to the regulatory authorities."

To further support the safety and efficacy data submitted to FDA, AstraZeneca is compiling a "scientific package" twice the size of the Crestor NDA, Exec VP-Product Strategy & Licensing John Patterson said. The program involves 8,500 patients at 400 centers worldwide.

The efficacy at 80 mg was presumably intended to be an important feature of AstraZeneca's marketing plans for Crestor. Bayer and co-marketing partner GlaxoSmithKline did not initially launch Baycol at the .1 mg and .2 mg doses, opting to wait for approval at higher doses with greater efficacy.

Cameron reported that the Phase III program was designed to "stress-test" the statin with an overload of patients on the 80 mg dose.

"Whereas in the clinical practice setting we would expect about one in 100 or two in 100 patients to receive the top dose for clinical use, in the clinical trial program for Crestor, we had about one in three," he said. AstraZeneca tested the 80 mg dose in older patients and in those with renal impairment.

"We really stress-tested this product, to really take it out and show what it could do, and to give the regulatory authorities real assurance that there was a good benefit-risk case," Cameron maintained. "We've tried to give all regulatory authorities a very sound basis on which to base an assessment of risk."

Addressing the medical community's reaction to the Baycol withdrawal, McKillop acknowledged that "there may have been initial reaction with some physicians of, 'Is this the beginning of a problem with the class?' but it seems to have moved on very, very quickly."

The market share data following the withdrawal of Baycol appears to back up McKillop's analysis. Bristol's Pravachol (pravastatin) picked up a disproportionate share of the former Baycol users, perhaps because of pravastatin's reputation as the safest (least-potent) member in the statin class.

However, in recent weeks, market share numbers have trended back toward the pre-Baycol levels, with Lipitor and Zocor holding higher shares than Pravachol (, p. 21).