Atherosclerotic vascular diseases are the leading cause of mortality and morbidity in the Western world. The most important modifiable risk factor, partly influenced by genetics and partly by lifestyle factors, is dyslipidemia.
Since their introduction around 20 years ago, statins, which inhibit a key enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), have become the mainstay of medical treatment to lower LDL cholesterol. Although they produce only a 30% risk reduction, most statins have historically experienced blockbuster sales (>$1 billion). During 2006, however, revenues from two leading statin products—Zocor (simvastatin, Merck) and Pravachol (pravastatin, Bristol Meyers Squibb)—declined by 69% and 63%, respectively, as these drugs lost marketing exclusivity in the U.S. The resulting influx of low-cost generics adversely impacted the remaining patented statins.
New lipid-modifying products would ideally have become available to replace the aging statins, but this process has not been smooth sailing. In 2002, Merck introduced Zetia (ezetimibe), which targets the intestinal Niemann-Pick C1 Like 1 protein and inhibits cholesterol absorption. Ezetimibe is now available as a combination tablet with simvastatin—Vytorin (Inegy, outside the U.S.)—and has become a blockbuster product with world sales in 2007 exceeding $5 billion (70% in the U.S.). Unfortunately, ezetimibe encountered a couple of setbacks this year, and its midyear U.S. sales were down 16% in 2007.
The dyslipidemia market now faces flat or slowly growing sales until the next convulsion sometime after 2010, when Pfizer's Lipitor, the world’s best-selling drug, loses market exclusivity. Still, the market is basically healthy. It is nowhere near saturation, and prescription volumes are continuing to increase at a steady rate.
What can pharmaceutical companies do to safeguard revenues? Litigation against future generic competitors is clearly an option, and one which Pfizer is already exploring, with some success. Another option, for manufacturers of branded statins retaining marketing exclusivity but experiencing competition from other generic statins, is to promote their particular benefits—through postmarketing trials. For example, the most reliable way to protect revenues in the medium and long term is to introduce novel branded products. The most straightforward of these include combination therapies. Unlike statins, the agent niacin (vitamin B3, given in gram doses) is effective in raising HDL cholesterol as well as lowering triglycerides. Niacin/statin combinations are currently receiving close scrutiny, since several small studies have suggested that they could reduce cardiovascular event rates by 70–90%. Other companies are targeting the GPR109A niacin receptor, which appears to mediate its most prominent lipid-related effects.
More Effective NCEs for Treatment
In the long term, the industry needs to develop more new chemical entitities (NCEs) to treat dyslipidemia more effectively. In our survey of the dyslipidemia drug landscape, we identified over 178 products (including successful launched products) aimed at 45 molecular targets. Those targets managed to attract two or more drugs (Figure).
Launched agents target mainly HMGCR (statins) and PPARs (fibrates). PPARs are numerically the most popular targets overall. Agents aimed at them include PPAR alpha, PPAR gamma, PPAR delta, PPAR alpha/gamma, PPAR delta, and PPAR pan agonists. These are intended to influence various aspects of the metabolic syndrome, but are being hindered by their toxicity.
The most advanced drug class with no launched members inhibit the plasma cholesteryl ester transfer protein (CETP). Pfizer’s torcetrapib was an early contender, but the agent proved toxic and was discontinued in 2006. Roche and Merck have recently advanced their CETP product candidates into Phase III trials.
Several RNA interference (RNAi) agents are still at the preclinical phase, but may take a shorter than average time to reach the clinic.