AstraZeneca's updated Crestor NDA will focus on doses of 40 mg and lower following a decision not to seek approval for the 80 mg strength of the cholesterol drug.

After a meeting with FDA that clarified what would be required for approval, AstraZeneca said it will submit more data on patients taking Crestor (rosuvastatin) doses of 20 mg and 40 mg for longer periods of time. The submission will take place in the first quarter.

The Crestor NDA, filed in June 2001, includes data on the 10 mg through 80 mg strengths, and has been "approvable" since May 31. AstraZeneca expects the additional data will be adequate to support FDA approval for Crestor 10 mg, 20 mg and 40 mg.

Although AstraZeneca will not pursue 80 mg at this time, it may revisit that dose in the future. Crestor 80 mg has been associated with reports of rhabdomyolysis and two cases of renal impairment.

The additional data will come from 10 ongoing trials initiated after submission of the NDA. The ongoing studies all focus on Crestor doses of 40 mg and lower. Although the studies initially also looked at 80 mg rosuvastatin, AstraZeneca has since amended the protocols to titrate patients down to the 40 mg dose (¹ Also see "AstraZeneca Crestor Post-NDA Studies Focusing On 40 Mg Dose" - Pink Sheet, 29 July, 2002., p. 28).

Since reporting in December that some patients on Crestor 80 mg experienced rhabdomyolysis, AstraZeneca has downplayed the commercial importance of the highest strength, maintaining that the 80 mg dose would have a niche market of very difficult-to-treat patients (² Also see "AstraZeneca Crestor 80 Mg Dose Would Have Low Demand, CEO Suggests" - Pink Sheet, 4 February, 2002., p. 25).

FDA recently cleared a higher strength 80 mg dose of Bristol-Myers Squibb's Pravachol (pravastatin) and approved a higher starting dose for Pfizer's Lipitor (atorvastatin).

AstraZeneca's difficulties with the Crestor review may suggest a new pattern at FDA for late entrants into crowded therapeutic classes that are looking to distinguish themselves based on potency.

Pfizer has had similar difficulties with the highest dose (80 mg) of its migraine therapy Relpax (eletriptan). The drug received its second "approvable" letter in December 2000, in which FDA requested a cardiovascular physiology study to promote reassurance about the margin of safety (³ Also see "Pfizer Neurontin Neuropathic Pain NDA Planned; Relpax Awaits New Study" - Pink Sheet, 18 December, 2000., p. 12).

AstraZeneca Crestor Plan: Drop 80 Mg, Submit Lower-Dose Data In Q1

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