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<?xml version="1.0" ?> <tei> <teiHeader> <fileDesc xml:id="0"/> </teiHeader> <text xml:lang="en"> <p>Epidemiological studies and large-scale clini-<lb/>cal trials with the statin class of cholesterol-<lb/>lowering drugs have conclusively shown the<lb/> association between reduced levels of low-<lb/>density-lipoprotein cholesterol (LDL-C) and<lb/> decreased morbidity and mortality from coro-<lb/>nary heart disease (CHD) <ref type="biblio" >1–3</ref> . But despite these<lb/> demonstrated benefits of lowering LDL-C<lb/> levels, many patients receiving cholesterol-<lb/>lowering therapies fail to reach the LDL-C levels<lb/> recommended by current guidelines <ref type="biblio">4</ref> . The<lb/> need for more effective cholesterol-lowering<lb/> has encouraged the greater use of higher doses<lb/> of established statins, and also prompted<lb/> efforts to develop more potent statins and<lb/> drugs with novel modes of action that can be<lb/> used to achieve greater reductions in LDL-C<lb/> levels in a broad spectrum of patients.<lb/></p> <head>Therapeutic hypothesis<lb/></head> <p>Statins inhibit the enzyme 3-hydroxy-3-<lb/>methylglutaryl CoA (HMG-CoA) reductase,<lb/> which catalyses the conversion of HMG-CoA to<lb/> mevalonate, an early and rate-limiting step in<lb/> cholesterol biosynthesis <ref type="biblio">1</ref> . This inhibition leads<lb/> to reductions in LDL-C levels through two<lb/> mechanisms: first, through reduction in<lb/> mevalonate levels, which leads to a reduction<lb/> in the regulatory sterol pool, resulting in<lb/> upregulation of the hepatic LDL receptors<lb/> that mediate the clearance of LDL-C from<lb/> plasma; and second, through inhibition of<lb/> hepatic synthesis of very-low-density lipo-<lb/>protein (VLDL), the precursor of LDL-C.<lb/> Statins also reduce levels of triglycerides<lb/> (increased levels of which are a risk factor for<lb/> CHD) and increase levels of high-density-<lb/>lipoprotein cholesterol (HDL-C, decreased<lb/> levels of which are a risk factor for CHD).<lb/></p> <p>The first statin, lovastatin (Mevacor; Merck),<lb/> was marketed in 1987, and by 1998 had been<lb/> joined by simvastatin (Zocor; Merck), pravas-<lb/>tatin (Pravachol; Bristol-Myers Squibb), fluvas-<lb/>tatin (Lescol; Novartis), atorvastatin (Lipitor;<lb/> Pfizer), and cerivastatin (Baycol; Bayer),<lb/> although cerivastatin was withdrawn from<lb/> the market in 2001 because of a large number<lb/> of reported cases of rhabdomyolysis (severe<lb/> muscular toxicity), some of which were fatal.<lb/></p> <head>Drug properties<lb/></head> <p>Rosuvastatin calcium <ref type="figure">(FIG. 1)</ref> was discovered<lb/> through the synthesis and screening of a series<lb/> of pyrimidine-substituted 3,5-dihydroxy-6-<lb/>heptenoates containing a sulphonyl moiety<lb/> introduced to lower lipophilicity and thereby<lb/> improve selectivity for the liver <ref type="biblio" >5</ref> . In addition,<lb/> lower lipophilicity might be associated with<lb/> reduced metabolism by cytochrome P450s.<lb/> Unlike a number of other statins, rosuvastatin<lb/> calcium is not metabolized significantly by<lb/> cytochrome P450 3A4, the major cytochrome<lb/> P450 involved in drug metabolism, and so has<lb/> less potential for drug–drug interactions.<lb/></p> <p>Rosuvastatin calcium was found to be more<lb/> potent than lovastatin, fluvastatin and pravas-<lb/>tatin in inhibiting HMG-CoA reductase in vitro,<lb/> and more potent than pravastatin in reducing<lb/> plasma LDL-levels in vivo, and was therefore<lb/> chosen for clinical testing <ref type="biblio">5</ref> .<lb/></p> <head>Clinical data<lb/></head> <p>In a six-week, double-blind, placebo-controlled,<lb/> study in patients with hypercholesterolaemia, a<lb/> single daily dose (5 mg, 10 mg, 20 mg or 40 mg)<lb/> of rosuvastatin calcium significantly reduced<lb/> levels of total-C, LDL-C, non-HDL-C and<lb/> apolipoprotein B (Apo B, the major protein<lb/> consituent of LDL) across the dose range <ref type="biblio">6</ref> .<lb/></p> <p>Rosuvastatin calcium was compared with<lb/> three other statins in an open-label study involv-<lb/>ing 2,240 patients with type IIa and IIb hyper-<lb/>cholesterolaemia. After randomization, patients<lb/> were treated for six weeks with a single daily dose<lb/> of either rosuvastatin calcium (10 mg, 20 mg or<lb/> 40 mg), atorvastatin (10 mg, 20 mg, 40 mg or 80<lb/> mg), pravastatin (10 mg, 20 mg or 40 mg) or<lb/> simvastatin (10 mg, 20 mg, 40 mg or 80 mg); the<lb/> size of each treatment group ranged from<lb/> 156–167 patients <ref type="biblio">6</ref> . At the 10-mg dose, rosuvas-<lb/>tatin calcium reduced LDL-C levels by 46%, sig-<lb/>nificantly more than atorvastatin 10 mg (37%),<lb/> simvastatin 10–40 mg (28–39%) and pravas-<lb/>tatin 10–40 mg (20–30%). At the highest doses,<lb/> rosuvastatin calcium 40 mg reduced LDL-C<lb/> levels by 55%, compared to 51% for atorvastatin<lb/> 80 mg and 46% for simvastatin 80 mg.<lb/></p> <head>Indications<lb/></head> <p>Rosuvastatin calcium is indicated as an adjunct<lb/> to diet to reduce elevated total-C, LDL-C, Apo<lb/> B, non-HDL-C and triglyceride levels, and to<lb/> increase levels of HDL-C in patients with<lb/> primary hypercholesterolaemia (heterozygous<lb/> familial and non-familial) and mixed dyslipi-<lb/>daemia (Frederickson type IIa and IIb) <ref type="biblio">6</ref> .<lb/></p> <p>On the basis of small-scale trials, rosuvas-<lb/>tatin calcium is also indicated as an adjunct to<lb/> diet for the treatment of patients with elevated<lb/> serum triglyceride levels (Frederickson type<lb/> IV) and to reduce levels of LDL-C, total-C and<lb/> Apo B in patients with homozygous familial<lb/> hypercholesterolaemia as an adjunct to other<lb/> lipid-lowering treatments or if such treatments<lb/> are unavailable <ref type="biblio">6</ref> .<lb/> ▲<lb/></p> <figure>N<lb/> N<lb/> F<lb/> N<lb/> CH 3<lb/> S<lb/> O<lb/> O<lb/> H 3 C<lb/> OH<lb/> OH<lb/> Ca 2+<lb/> O<lb/> O<lb/> b<lb/> OH<lb/> O<lb/> OH<lb/> OH<lb/> O<lb/> O<lb/> O<lb/> S<lb/> CoA<lb/> HMG-CoA reductase<lb/> HMG-CoA<lb/> O<lb/> Mevalonate<lb/> 2<lb/> –<lb/> –<lb/> –<lb/> Rosuvastatin calcium<lb/> Bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-<lb/>2-[methyl(methylsulphonyl)amino] pyrimidin-5-yl]<lb/> (3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt;<lb/> (C 22 H 27 FN 3 O 6 S) 2 Ca; M r = 1001.14;<lb/> CAS registry number: 147098-20-2<lb/> a<lb/> Figure 1 | Rosuvastatin calcium. a | The molecule contains the characteristic statin pharmacophore, a<lb/> dihydroxy heptenoic acid moiety that binds to the active site of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)<lb/> reductase (the structures of the substrate and product of the reaction catalysed by HMG-CoA reductase<lb/> are shown in b for comparison). The remainder of the molecule, which is structurally distinct from the corres-<lb/>ponding portions of other statins, contains a polar sulphonyl moiety that confers relatively low lipophilicity.<lb/></figure> <p>The market for cholesterol-lowering drugs is<lb/> the largest in the pharmaceutical sector.<lb/> Driven by a prevalent patient population in<lb/> excess of 295 million and valued at more<lb/> than US $17 billion, this market is dominated<lb/> by the statins <ref type="figure">(FIG. 2)</ref>. Competition in this<lb/> crowded segment is fierce, but the rewards for<lb/> successful market entry are substantial. In<lb/> 2002, atorvastatin and simvastatin recorded<lb/> revenues for the treatment of dyslipidaemia in<lb/> the seven major markets of ~US $7 billion<lb/> and ~US $5.3 billion, respectively <ref type="figure">(FIG. 2)</ref>.<lb/></p> <p>New entrants in the dyslipidaemia market<lb/> face considerable barriers to success. Prescrip-<lb/>tions for atorvastatin and simvastatin, the most<lb/> potent of the established statins, are both<lb/> supported by compelling long-term safety and<lb/> mortality data. Moreover, generic simvastatin<lb/> will soon be available in many markets<lb/> (including the massive US market), promoting<lb/> its greater use in primary prevention of CHD.<lb/></p> <p>We predict that the dyslipidaemia market<lb/> will grow to US $32 billion by 2012 <ref type="figure">(FIG. 2)</ref>. The<lb/> adoption of 'lower is better' treatment goals for<lb/> LDL-C, together with recommendations <ref type="biblio" >4</ref><lb/> from the US National Cholesterol Education<lb/> Program Adult Treatment Panel III encourag-<lb/>ing more aggressive prescription of lipid-<lb/>modifying therapies, will favour the use of<lb/> potent statins. If emerging agents such as rosu-<lb/>vastatin are to succeed in this market, they<lb/> must offer improved efficacy, morbidity and<lb/> mortality benefits relative to established<lb/> agents, without compromising patient safety.<lb/></p> <head>Impact of rosuvastatin<lb/></head> <p>Dose-for-dose, rosuvastatin is more effective<lb/> in lowering LDL-C levels and raising HDL-C<lb/> levels than atorvastatin, simvastatin or<lb/> pravastatin <ref type="biblio" >7</ref> . Furthermore, rosuvastatin is<lb/> reported to have a side-effect profile similar<lb/> to its competitors. Ultimately, this greater<lb/> efficacy should drive the widespread use of<lb/> rosuvastatin.<lb/></p> <p>However, the withdrawal of cerivastatin<lb/> and the concerns of the US FDA about rhab-<lb/>domyolysis associated with statin treatment,<lb/> in particular with high doses, culminated in<lb/> the voluntary withdrawal by AstraZeneca of<lb/> the NDA for the 80-mg rosuvastatin dose and<lb/> a request for further data supporting the<lb/> safety of other doses. In the light of these con-<lb/>cerns, considerations about the relevance of<lb/> proteinurea associated with the 40-mg dose<lb/> of rosuvastatin (included as a warning on the<lb/> label) could temper the success of this agent.<lb/> Until positive long-term safety and mortality<lb/> data are available, rosuvastatin is expected to<lb/> be restricted to high-risk patients, or those<lb/> unable to achieve target lipid levels with other<lb/> treatments; nevertheless, sales in 2007 are still<lb/> forecast to exceed US $1.7 billion <ref type="figure">(FIG. 2)</ref>.<lb/></p> <p>AstraZeneca's pricing policy will promote<lb/> the use of rosuvastatin in severely affected<lb/> patients. In the United States, rosuvastatin is<lb/> flat-priced at US $2.10 per dose, making it<lb/> more expensive than the 10-mg dose of ator-<lb/>vastatin, but substantially less expensive than<lb/> the 20-, 40-or 80-mg doses.<lb/></p> <p>In moderately affected or normo-choles-<lb/>terolaemic people, strong support for the use<lb/> of rosuvastatin could be provided by data from<lb/> the 15,000-patient JUPITER (Justification<lb/> for the Use of statins in Primary prevention:<lb/> an Intervention Trial Evaluating Rosuvastatin)<lb/> study, which is expected to report in 2006.<lb/></p> <p>Additionally, this study will examine the effect<lb/> of rosuvastatin on emerging cardiovascular<lb/> risk factors such as the inflammatory marker<lb/> C-reactive protein (CRP). Assuming that the<lb/> results from this and other trials are positive,<lb/> sales of rosuvastatin could grow to US $4.3<lb/> billion in 2012 <ref type="figure" >(FIG. 2)</ref>.<lb/></p> <p>The main threats to rosuvastatin's success<lb/> will be the simvastatin and atorvastatin com-<lb/>bination therapies in development by Merck<lb/> and Pfizer, respectively. Merck are developing<lb/> a fixed pill combination of simvastatin and<lb/> the cholesterol absorption inhibitor ezetimibe<lb/> (Zetia; Schering-Plough/Merck) <ref type="biblio">8</ref> . Pfizer are<lb/> developing a fixed pill combination of ator-<lb/>vastatin and the cholesteryl ester transferase<lb/> protein (CETP) inhibitor torcetrapib. Both of<lb/> these combinations offer improved LDL-C,<lb/> triglyceride and HDL-C modifying efficacy<lb/> relative to their respective monotherapies.<lb/> Ultimately, we expect that the combination of<lb/> price, safety and ability to modify non-LDL<lb/> lipids such as HDL-C and triglycerides, as<lb/> well as the action of these agents on emerging<lb/> risk factors such as markers for oxidative<lb/> stress, will prove decisive in the battle for<lb/> market dominance.<lb/></p> <figure>9 (29%)<lb/> 3.5<lb/> (11%)<lb/> 4.3<lb/> (14%)<lb/> 3 (9%)<lb/> 1.9 (5%)<lb/> 6.6 (21%)<lb/> 3.4<lb/> (11%)<lb/> 5.3 (32%)<lb/> 3.6 (20%)<lb/> 1.2<lb/> (7%)<lb/> 7 (41%)<lb/> 5 (21%)<lb/> 1.7<lb/> (7%)<lb/> 2.7 (9%)<lb/> 1.2 (6%)<lb/> 3.1<lb/> (13%)<lb/> 1.2 (5%)<lb/> 2007<lb/> 9.5 (39%)<lb/> Atorvastatin<lb/> Simvastatin<lb/> Other statins<lb/> Rosuvastatin<lb/> Other lipid-modifying treatments<lb/> Ezetimibe/simvastatin+ezetimibe<lb/> CETP inhibitors<lb/> 2012<lb/> 2002<lb/> Figure 2 | Market for drugs to treat dyslipidaemia in US $ billion. Other lipid-modifying treatments<lb/> include fibrates and bile-acid sequestrants. Data are for the seven major markets (United States, France,<lb/> Germany, Italy, Spain, United Kingdom, Japan). CETP, cholesteryl ester transferase protein.</figure> </text> </tei>