The statin war

As with all medicines, reports of rhabdomyolysis have been very rare (less than 0.01 per cent), often associated with confounding factors, and have occurred with a similar frequency to other currently marketed statins, says Dr Krishan Maggon

Rosuvastatin was the new statin approved in 2003 after the withdrawal of Bayer’s cerivastatin in 2001. The drug has been under intense scrutiny from regulatory, medical journals and media during its approval, marketing and for its adverse event profile. The ‘headline effect’ has slowed sales and market uptake and reduced the market value of AstraZeneca.

The company has responded by posting a list of completed and ongoing clinical trials and updates of adverse event reporting. The reported adverse event rate for muscle, renal and hepatic systems with rosuvastatin is similar to that of other marketed statins like atorvastatin and simvastatin. The current clinical and marketed doses are 10, 20 and 40 mg in USA and Europe.

In Japan, lower doses of 2.5, 5, 19 and 20 mg are marketed. Data filed with FDA for approval show efficacy of lower doses at 1, 2.5 and 5 mg, increased bioavailability and AUC in Asians and patients with renal and hepatic insufficiency. Ongoing trials with lower doses and Asians may lead to the use of lower doses in routine clinical practice.

The drug has been approved in 68 countries. It was first marketed in Canada in February 2003, and over four million patients have now been treated with the drug, with 16 million prescriptions dispensed worldwide. The drug is approved in 19 European countries like Ireland, Finland, Denmark, Sweden, Iceland and UK besides Japan.

Rosuvastatin (Crestor) is the sixth cholesterol lowering ‘statin’ drug on the US market. The other members of the statin family are atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor). These drugs are approved for use with a low-cholesterol diet and an exercise programme to lower cholesterol.

Recent controversies

The market value of AstraZeneca was recently down by 10 per cent ($7 billion) due to safety concerns about rosuvastatin (Crestor), during the last months of 2004. The European Medicines Agency (EMEA) investigated whether all patients taking rosuvastatin should start on the lowest five mg dose following a referral from the UK sparked by public health concerns. Many European countries showed their preference for the 10 mg starting dose.

Dr Graham, an FDA reviewer and a crusader for safe drugs, named rosuvastatin as one of five medicines needing closer scrutiny for drug safety. Dr Graham said rosuvastatin was the only cholesterol-lowering drug in the market that caused acute kidney failure. And the drug is more likely to cause a serious muscle-weakening disease than similar drugs. His comments are not the official policy of the FDA.

Dr Wolfe of Public Citizen, Dr Graham of FDA drug safety expert, editorials in Lancet and JAMA and Health Canada safety alert and UK referral to EMEA for five mg starting dose have raised safety concerns about the drug. AstraZeneca has provided data about the drug, list of ongoing trials, publications and adverse event monitoring update at its website.

AstraZeneca has termed Dr Wolfe’s claims as “misleading” and based on inappropriate interpretation of data and that Dr Wolfe had failed to compare the number of cases with side-effects with the rate of the drug used. The rate of side-effects with Crestor is in line with other statins (table 4). Ten milligrammes of all marketed statins have been associated with some cases of rhabdomyolysis. To date, there has been only one fatal rhabdomyolysis case, which may be linked to Crestor.

As with all medicines, reports of rhabdomyolysis have been very rare (less than 0.01 per cent), often associated with confounding factors, and have occurred with a similar frequency to other currently marketed statins. FDA is closely monitoring the data and believes that many patients had other associated risks for the muscle problems.

AstraZeneca’s analysis of the 40,000 patients in clinical trials and post-marketing safety data, involving an estimated four million patients and 16 million prescriptions, show rosuvastatin to have a similar safety profile to that of other marketed statins. The banned statin cerivastatin was associated with 31 fatal reports of rhabdomyolysis on a background of nearly 10 million prescriptions. Over 80 per cent of the patients can reach their target LDL cholesterol with the 10 mg dose of rosuvastatin.

Sales and marketing of statins

Rosuvastatin (Crestor, Astra Zeneca) is hailed as a superstatin, expected to be more effective and safer then atorvastatin (Lipitor) and had peak projected sales of $5 billion. Current market projections by analysts were scaled back due to slow market uptake, lack of long term safety and outcome data and strong competition from existing and other combination products in development.

Rosuvastatin was launched in selected European countries, USA and Canada in 2003. Worldwide sales were $129 million (USA $62 million) in 2003 and $900 million instead of its projections of $1.3 billion (Table 1). Another lipid lowering product ezetimib (Zetia) introduced in 2003 had much faster uptake with sales of $600 million and $1 billion in 2004.

AstraZeneca hopes to capture 20 per cent of the $26 billion (2003 sales) a year statin market with Crestor. In the USA, it was the second best selling statin after atorvastatin and had 18 per cent of the market share. In the UK and the Netherlands, it had 10 per cent of the statin market. Rosuvastatin has suffered due to Headline Curse as safety concerns issues were raised by Dr Wolfe of Public Citizen, Dr Graham of FDA drug safety expert, editorials in Lancet and JAMA and Health Canada safety alert and UK referral to EMEA for 5 mg starting dose.

AstraZeneca has provided data about the drug, list of ongoing trials, publications and adverse event monitoring update at its web site.

The writer is pharma biotech R&D advisor. E-mail: maggonk@yahoo.com