Molecule of the Month (2008)

Is Zetia™ a A ‘Do Nothing’ Drug? After months of delays and on the eve of meetings with congressional investigators, results from the much anticpated ENHANCE clinical trial for Vytorin™ were finally disclosed (January 15, 2008) to the dismay of pharmacuetical giants Merck and Schering- Plough, with the announcement that VytorinTM conferred no medical benefit over Zocor™ alone [1-4]. The ENHANCE trial was launched to demomstrate superior cardiovascular protection (fewer heart attacks and strokes) with Vytorin™ versus Zocor™ and enrolled 720 patients with heterozygous familiar hypercholesterolemia, a rare condition that predisposes them to abnormally high blood cholesterol. The two year study measured the amount of artery-clogging plagues in three areas and compared patients taking Vytorin ™ versus high dose Zocor™ [1-4]. Vytroin™, approved by the FDA in 2004, is a combination drug consisting of Mercks Zocor™, an HMG-CoA reductase inhibitor (statin) that inhibits cholesterol production in the liver, and Zetia™, the first cholesterol absorption inhibitor (works in digestive track). These complimentary cholesterol lowering strategies in a single pill where touted to treat the two sources of cholesterol - heredity and diet and provide superior protection from heart attack and stroke versus stain alone therapy. Zocor™ has proven to be a safe and effective statin which lowers cholesterol and decreases the risk of adverse cardiovascular events. Zetia™, was shown to lower LDL (bad cholesterol) 15-20% in a surrogate goal trial, with no clinical support that its effects on LDL confer cardioprotection - the chief concern of patients [1-4]. These data raised questions about aggressive marketing tactics, the delays to announce negative clinical data and the issue of Brand versus cheaper Generic medications with Vytorin™ [2-4]. Many physicians and clinicians voiced their displeasure and referred to Zetia™ and Vytorin™ as ‘Do Nothing’ drugs [2-4]. Moreover, both Vytroin™ and Zetia™ had achieved blockbuster status with billions in sales/year and provided additional sales for Mercks Zocor™, which is now facing billion dollar generic competition, and a major component of Schering-Ploughs annual revenue. Mercks Zocor™ is an excellent example of the impact of the loss of patent protection and generic competition. In 2005, the statins LipitorTM and ZocorTM were ranked No.1 ($7.6 billion) and No.2 ($4.5 billion) in sales, and No. 1 and No. 11 in prescriptions dispensed, respectively. After generic variants of Zocor™ entered the market mid-year 2006, Pfizers Lipitor™ remained No. 1 in terms of both sales ($ 8.6 billion) and prescriptions dispensed (74,020) while Zocor™ slid to No.7 in sales ($3.2 billion) and No. 25 in prescriptions dispensed [5-7]. With an increasing market share in each quarter of 2007, Vytorin™ was poised to recoupe much of Zocors™ lost revenues for Merck, but the ENHANCE trial may derail this rally and drive more patients to request cheaper, generic simvastatin [1-7]. However, three larger clinical trials are underway, including the 10,000 patient IMPROVE IT trial, which Merck and Schering-Plough hope will conclusively demonstrate that Vytorin™ can reduce the number of detahs and major, adverse cardiac events versus Zocor™ alone [1-4]. Unfortunately, data from these trials will not be available for ∼ three years and the moniker of ‘Do Nothing’ drug may linger until conclusive data proves otherwise. REFERENCES [1] For information on the ENHANCE trial see: www.merck.com, www.sherng-plough.com [2] For information on the ENHANCE trial in the popular media see: www.cnn.com, keyword Vytorin and www. Healthrevolution.com, search Vytorin. [3] Sternberg, S. ‘Drug Trials Under Pressure’ USA Today, D1, January 17, 2008. [4] Rubin, R. ‘Surrogtae goals can defuddle patients’ USA Today, D2, January 17, 2008. [5] Lamb, E. Top 200 prescription drugs of 2006. Pharmacy Times, May 2007, pp.1-4, and reference therein. [6] IMS Health. Press release. March 8, 2007, www.imshealth.com. [7] For more information on generic drug approvals and impact on sales see the US Food and Drug [8] Adminstration: www.fda.gov.