AstraZeneca Crestor Post-NDA Studies Focusing On 40 Mg Dose

AstraZeneca's ongoing trials of Crestor are focusing on 40 mg as the maximum dose of the cholesterol-lowering drug.

The company has amended the protocols for the studies to down-titrate patients on 80 mg Crestor (rosuvastatin) to 40 mg. AstraZeneca has 10 ongoing rosuvastatin studies that include more than 10,000 patients. The Crestor NDA is "approvable" at FDA as of May 31 (¹ 'The Pink Sheet' June 10, In Brief).

"Our published data showed that only a very small percentage of patients derived a further benefit in going from 40 mg to 80 mg, and that it is only in 80 mg that a small incidence of myopathy is seen," CEO Tom McKillop said during a conference call July 25.

"In view of this information, we amended the protocol of our studies to down-titrate patients on 80 mg to 40 mg," McKillop said.

The studies would help AstraZeneca position the lower dose of Crestor if the product were approved with labeling that discourages treatment at 80 mg. Alternatively, the trials readily provide supplemental data if FDA determines that the current NDA database cannot support approval.

McKillop noted that the data from down-titrated patients would likely be considered supportive rather than primary data in the event that FDA has questions about the efficacy of the 40 mg dose.

FDA "normally" applies an intent-to-treat analysis, so the down-titration "would not normally be captured in that. But any exposure data is of course important in a safety database," McKillop said. "Clearly the exposure data you get at 40 mg is going to be very supportive, very important wherever it comes from."

McKillop stressed that his remarks should not be taken as a description of any conversations with the agency. "That's just my personal observation from a fair bit of experience." AstraZeneca plans to meet with FDA shortly to discuss the "approvable" letter.

AstraZeneca says it is still pursuing 80 mg as an approved strength for Crestor, but has repeatedly downplayed the commercial importance of the higher dose (² (Also see "AstraZeneca Crestor 80 Mg Dose Would Have Low Demand, CEO Suggests" - Pink Sheet, 4 Feb, 2002.), p. 25).

"While 80 mg may be important to that small percentage of difficult-to-treat patients, we have stated consistently that it is of little commercial significance," McKillop said.

The AstraZeneca CEO emphasized that the ongoing Crestor studies were initiated for marketing and supplemental labeling purposes, not in response to any FDA concerns.

"Following the submission for marketing approval, a large program of more than ten...clinical trials was implemented in preparation for launch, a normal part of the commercialization and further development of a major new chemical entity," McKillop said.

With more than 10,000 patients participating, the trials would give AstraZeneca a good jump-start into the cholesterol category.

Only one of the ten ongoing Crestor trials was requested by FDA, McKillop said: a study of potential interactions between Crestor and gemfibrozil.

The company believes the same request was made of all statin sponsors in October. Bayer's cholesterol drug Baycol (cerivastatin) was withdrawn in August 2001 due to reports of rhabdomyolysis. Bayer said at the time that the problem was particularly acute when Baycol was taken in combination with gemfibrozil (³ (Also see "Baycol Withdrawal Gives Boost To Pravachol; Will Crestor NDA Be Affected?" - Pink Sheet, 13 Aug, 2001.), p. 4).

McKillop acknowledged that the data generated in the post-NDA Crestor trials has confirmed the incidence of rhabdomyolysis associated with 80 mg rosuvastatin suggested in the NDA dataset.

"The incidence of myopathy in all trials remains at the level observed in our submission, and we have no cases of Crestor-related myopathy at 40 mg or below."

McKillop reported that in addition to rhabdomyolysis in patients on Crestor 80 mg, the company has seen two cases of renal impairment.

"Several months ago, we notified trialists of two cases of renal impairment in patients on 80 mg Crestor with many confounding factors," McKillop said. "We don't know that Crestor was the cause of this ailment, nor can we rule it out."