Dyslipidemia Market in 2008: The Way Forward
by Sreten Bogdanovic, PhD
(A version of this article will appear in the 1 October 2008 issue of Genetic Engineering News)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 (gene symbol 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). However, during 2006, revenues from two leading statin products - Zocor (simvastatin, Merck & Co) and Pravachol (pravastatin, BM Squibb) - declined by 69% and 63% respectively as these drugs lost marketing exclusivity in the US. The resulting influx of low-cost generics adversely impacted the remaining patented statins. The effects are apparent in Figure 1, which shows US sales of lipid-modifying agents between 2002 and 2007, together with our projections for 2008.
New lipid-modifying products would ideally have become available to replace the aging statins, but this process has not been plain sailing. In 2002, Merck & Co introduced Zetia (ezetimibe), which targets the intestinal Niemann-Pick C1 Like 1 (NPC1L1) protein and inhibits cholesterol absorption. Ezetimibe is now also available as a combination tablet with simvastatin called Vytorin (Inegy outside the US), and has become a blockbuster product with world sales in 2007 exceeding $5 billion (70% in the US). Unfortunately, ezetimibe encountered a couple of clinical trial setbacks during 2008, and its mid-year US sales were 16% down on 2007.
The dyslipidemia market now faces flat or slowly growing sales until the next convulsion sometime after 2010, when Pfizer's Lipitor, the dominant statin and the world's best-selling drug, loses market exclusivity. Yet the market is basically healthy. It is nowhere near saturation, and prescription volumes are continuing to increase at a steady rate (Figure 1). As levels of obesity and type 2 diabetes surge worldwide and the dyslipidemia market adjusts to accomodate changing needs there will also be new opportunities for manufacturers of diagnostic and risk assessment tests (opens in a new window).
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, e.g. through postmarketing trials. However, 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, and also lowers 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.These agents should be effective in much lower doses, and have far fewer side effects than niacin.
In the long term, the industry needs to develop more NCEs to treat dyslipidemia more effectively. In our survey of the dyslipidemia drug landscape, we identified 178 drugs (including successful launched products) aimed at 45 molecular targets. Those targets which have managed to attract two or more drugs are shown in Figure 2. Hover over a gene symbol to see its name (in a tooltip). Click to read the gene record in the US NCBI's OMIM database. If you are reading this in Internet Explorer, you can also double-click to read the Entrez GENE entry. 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. Only one - Metabolex's metaglidasen, a selective PPARG modulator - is in Phase 3 trials (in diabetes).
The most advanced drug class with no launched members all 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. However, Roche and Merck & Co have recently further advanced their lead CETP product candidates. Other agents in advanced development which could reach the market by 2012 include Alizyme's cetilistat (a pancreatic lipase [PNLIP] inhibitor), GlaxoSmithKline's darapladib, deCODE Genetics' veliflapon (a FLAP [ALOX5AP] inhibitor), and AtheroGenics' AGI-1067 (an antioxidant). Cetilistat reduces fat absorbtion, and is expected to have a better side effect profile than Xenical. Darapladib inhibits phospholipase A2 (PLA2G7), believed to play a key role in the inflammatory reactions of atherosclerosis. Veliflapon (on hold since 2006 owing to manufacturing problems) and AGI-1067 target the oxidative stress involved in plaque progression, a risky strategy given the previous performance of antioxidants in cardiovascular trials.
Isis Pharmaceuticals' mipomersen, an antisense inhibitor of apoB-100 (APOB) may also reach the market by 2011, but will initially only be targeted at familial hypercholesterolemia, although broader applications are likely to follow. Several RNA interference (RNAi) agents are still at the preclinical phase, but may take a shorter than average time to reach the clinic. Alnylam Pharmaceuticals is targeting Apo-B100 and PCSK9, a protease which breaks down the LDL receptor. The liver MIRN122 (microRNA-122) gene is being targeted by both antisense and RNAi agents.
Sreten Bogdanovic is Managing Director of Biophoenix Limited (73 Highland Road, Coventry, CV5 6GS, UK), and a co-author (with Beata Langlands, PhD) of Dyslipidemia: Opportunities in Cardiovascular Risk Reduction, published in August 2008. Biophoenix' website is at www.biophoenix.com.
Copyright © Biophoenix Limited (August 2008).