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Issue dated - 1st April. 2004

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Stained statins

Rosuvastatin is the only statin that has shown life-threatening rhabdomyolysis in pre-approval stage of clinical trials, says Dr Krishan Maggon in the first part of the article

Rosuvastatin (Crestor, Astra Zeneca) was hailed as a ‘superstatin,’ expected to be more effective and safer than atorvastatin (Lipitor) during its development and at one time had peak projected sales of $5 billion. The drug was expected to make up for the lost sales and profits after patent expiry of omeprazole (Losec, Prilosec) for AstraZeneca.

Current market projections by analysts were scaled back to peak sales of $3 billion due to slow market uptake, lack of long term safety and outcome data and strong competition from existing and other combination products in development. Worldwide sales were $129 million (USA $62 million) in 2003. In comparison, another lipid lowering product ezetimib (Zetia) introduced in 2003 had much faster uptake with sales of $600 million.

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 only approved to be used along with a low-cholesterol diet and an exercise programme to lower cholesterol.

Cerivastatin (Baycol, Lipobay) was introduced in the USA market by Bayer in 1997 and was withdrawn in August 2001. Cerivastatin was removed from the market because of at least 31 reports of fatal rhabdomyolysis, an adverse reaction involving the destruction of muscle tissue that can lead to kidney failure. In September 2003, Bayer announced 100 deaths linked to the use of Baycol and settlement of 1342 lawsuits for $442 million.

Rosuvastatin was initially discovered and developed by the Japanese pharmaceutical company Shionogi, Osaka and in-licensed to AstraZeneca in April 1998. AstraZeneca originally filed its application with the FDA to market rosuvastatin in June 2001. The application was delayed when the company halted clinical trials worldwide after reports of kidney damage and muscle weakness (an early signal for rhabdomyolysis) in clinical trials in patients taking 80 milligrams of the drug per day.

The FDA asked AstraZeneca to generate and submit additional clinical trial data at 20 and 40mg doses in June 2002. The company terminated development of the 80mg dose because of the safety problems and FDA refusal. The Netherlands was the first country to grant approval for rosuvastatin in November 2002 and the drug has now been approved in 51 countries. It was first marketed in Canada in February 2003, and over one million patients have now been treated with the drug with over two million prescriptions dispensed worldwide.

The FDA Advisory Committee unanimously recommended for rosuvastatin approval in July 2003. The regulatory authorities of some European countries withdrew from the EMEA mutual recognition procedure to grant market authorisation. The drug is now approved in Ireland, Finland, Denmark, Sweden, Iceland and the UK. The FDA approved rosuvastatin on August 12, 2003, (5, 10, 20, and 40 mg tablets) based on multiple trials of at least 6 weeks’ duration in which rosuvastatin treatment was compared to placebo and other marketed statins.

In these trials, rosuvastatin reduced total-cholesterol, LDL-C, and TG and increased HDL-C with therapeutic response occurring within one week and maximum response seen at four weeks. ICH guidelines require, for long-term treatment of non-life-threatening conditions, 1,500 patients treated with the drug for safety, 300-600 treated for at least six months for efficacy and at least 100 for 12 months. FDA has required 200 patients treated for one year.

AstraZeneca total patient exposure in clinical trials submitted for approval for rosuvastatin (12,500) was considerably greater than the 2,000 to 3,000 patients submitted for most of the currently approved statins. Galaxy is the umbrella name for at least 16 clinical trials designed to investigate the efficacy of rosuvastatin in various clinical settings.

Rosuvastatin clinical data in the treatment of primary hypercholesterolemia was published in Annals of Pharmacotherapy (January 2002). The pooled data suggested that at dosages of 1-40 mg/day, rosuvastatin significantly reduced total cholesterol and low-density-lipoprotein cholesterol (LDL-C) and produced treatment benefits on other lipid parameters as well. The LDL—C reduction ranged from -33 per cent at 1mg and -62 per cent at 40 mg. Increases in HDL-C were most notable in those patients with HDL-C, 34 mg/dL at entry. Similarly, reductions in TGs were more pronounced in patients whose baseline TG levels exceeded 200 mg/dL.

The drug was found to be well tolerated and superior to other statins on the mg to mg basis and other cholesterol-lowering agents. Rosuvastatin clinical data was published in the American Heart Journal, American Journal of Cardiology, and the Journal of Cardiovascular Risk (Olsson AG. Statin therapy and reductions in low-density lipoprotein cholesterol: initial clinical data on the potent new statin Rosuvastatin. Am J Cardiol 2001; 87: 33B-36B).

The entire dose range studied, down to 1mg, effectively lowered cholesterol and produced favourable changes on other lipid parameters. The Stellar six-week, parallel group, open-label, randomised, multicentre trial compared rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of low density lipoprotein (LDL) cholesterol.

Patients (2,431) with hypercholesterolemia, were randomised to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At six weeks, across-dose analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean of 8.2 per cent more than atorvastatin 10 to 80 mg, 26 per cent more than pravastatin 10 to 40 mg, and 12 per cent to 18 per cent more than simvastatin 10 to 80 mg (all p ,0.001).

Across dose ranges, rosuvastatin reduced total cholesterol more significantly than all comparators and triglycerides more than simvastatin and pravastatin and more patients achieved LDL goals. Rosuvastatin was, dose for dose, more effective at achieving national guideline targets for lipid concentrations than its competitors. Drug tolerability was similar across treatments (Jones et al. Am J Cardiol 2003;92:152-160 and Current Medical Research and Opinions 2003; 19: P1-P10).

New drugs in development

Pfizer is spending $1 billion to buy Esperion and develop one of its drugs to raise HDL. Torcetrapib, a partial cholesterol ester transfer protein blocker, is in phase III trials in combination with atorvastatin (Lipitor). If effective, torcetrapib will produce enough HDL to remove plaque from arteries, and decrease the risk of heart attack and stroke. Recent study published in JAMA raises some questions about the benefits of raising HDL levels. Torcetrapib is will be sold in combination with Lipitor.

Pfizer is also developing a combination product that combines atorvastatin and amlodipine. The combination pills are going to be blockbusters and could preserve the Lipitor franchise for another decade after the drug loses patent protection in 2010. The current perception is that combination of agents with different modes of action to reduce lipids, cholesterol, free fatty acids and triglycerides like ACAT inhibitors, bile acid sequestrants and lipid absorption inhibitors will provide marketing blockbusters and prolong the life of statin patents.

Agents used to treat hyperlipidemia and hypertension have dominated the cardiovascular market. The lipid lowering drugs account for approximately $22 billion of the $60 billion cardiovascular market. Three blockbuster drugs dominate this segment: atorvastatin (Pfizer’s Lipitor $9.2 billion), simvastatin (Merck’s Zocor, $5 billion), and pravastatin (Bristol-Myers Squibb’s Pravachol $2.8 billion, Sankyo’s Mevalotin).

In 2003, atorvastatin and simvastatin were the world’s second and third best-selling drugs after erythropoietin. By 2008, the hyperlipidemia market will be valued at more than $40 billion. Generics have already entered the European market as Merck’s Mevacor and Zocor have lost patent protection in different EU countries since 2002. Pravachol will lose protection in Europe by 2004, and US patent expiry of all three statins will take place in 2006.

The superstatins — rosuvastatin (Crestor, AstraZeneca) and pitavastatin (Sankyo) — have proved superior to the first-generation agents. Rosuvastatin was launched in selected European countries, USA and Canada in 2003. Sankyo has filed for approval of pitavastatin in Japan (expected 2004), and in the United States and Europe (expected 2005). Novartis will market pitavastatin in Europe, while the marketing partner in USA is not decided.

Other cholesterol reducers that has generated substantial revenues include ezetimibe (Merck/Schering-Plough’s Zetia), avasimibe and torcetrapib (Pfizer), and combinations of new and existing products. Ezetimibe is a selective intestinal cholesterol absorption inhibitor that was launched in late 2002 in the United States and Europe and had sales of $600 million in 2003 making it one of the most successful market launch. Wall street analysts forecast for Zetia range from $2 billion to 10 billion.

In clinical trials of ezetimibe co-administered with simvastatin, there was no increased incidence of myopathy or rhabdomyolysis associated with ezetimibe/simvastatin. Ezetimibe is expected to make up for revenues loss due to patent expiry of simvastatin by 2006.

Avasimibe is an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor that could receive approval in 2004. Ezetimibe is the more significant product: the Merck/Schering-Plough joint venture is also developing a combination of ezetimibe and simvastatin that produces enhanced lipid-lowering effects. The combination product will be launched in 2005.

Rosuvastatin adverse reactions

The most frequent side effects seen in patients treated with rosuvastatin included muscle aches, stomach pain, constipation, nausea, and weakness. In rare instances, severe muscle pain and muscle weakness resulting in kidney damage have been associated with statin drugs. Patients should be monitored for abnormalities of liver function before treatment, at 12 weeks following initial therapy and with any elevation of dose. Monitoring is recommended periodically thereafter.

Rosuvastatin causes abnormal elevations in urine protein and blood that are signals for serious kidney toxicity; other statins are not associated with this risk of kidney toxicity. Rosuvastatin is the only statin that has shown life-threatening rhabdomyolysis in pre-approval clinical trials. Development of severe myopathy or rhabdomyolysis requiring hospitalisation for IV hydration occurred only at the 80 mg dose.

The incidences of CK elevations and myopathy in clinical trials of rosuvastatin 5 to 40 mg were between 0.2 to 0.4 per cent and 0.1 to 0.2 per cent, respectively, which are similar to rates seen with other currently approved statins. Patients receiving rosuvastatin had an increased rate of developing proteinuria with and without hematuria, and in a small percentage of these cases the findings were persistent and associated with an increase in serum creatinine. Proteinuria was most pronounced at the 80 mg dose and the rate decreased in patients back-titrated from 80 to 40 mg suggesting reversibility.

There were two cases of renal failure and one case of renal insufficiency in patients receiving rosuvastatin 80 mg associated with proteinuria and hematuria. Renal biopsies in two of these cases suggested tubular inflammation and necrosis. The risks of muscle and renal toxicity appear dose-related and are clearly evident at the 80 mg dose. No patients treated with rosuvastatin 20 mg daily had drug levels in the range observed with clinical toxicity.

A few patients treated with rosuvastatin 40 mg (2 per cent) had drug levels within this range and a greater proportion of patients treated with 80 mg (33 per cent) achieved drug levels 50 ng/mL. This analysis suggests a potential threshold in the drug level at which risks of muscle and renal toxicity are increased. Treatment at the 20 mg and lower doses does not appear to raise drug levels into this ‘range of concern.’ However, clinical situations (e.g. drug-drug interactions, special populations, Asians) which may increase drug levels require careful consideration as patients in these settings may be exposed to drug levels beyond what is typical for the 20 and 40 mg doses.(To be concluded)The writer is can be contacted at

Pharma Research
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