Statins have become the gold standard in the treatment of dyslipidemia, accounting for approximately 60% of treatments prescribed to patients with coronary heart disease in the late 1990s. However, with these drugs limited in their ability to lower LDL cholesterol to the target recommended by the National Institutes of Health an opportunity awaits for a therapy able to achieve this goal.
In the Market Brief 'Statin Adjunct Therapy: Zetia, Revenue Protection For Zocor?' Datamonitor examines Zetia, the first in a new class of cholesterol-lowering agents to reach the market in the past 15 years. Datamonitor then analyses the drug's potential to reshape the cholesterol drug market, as well as safeguard cardiovascular revenues at parent company Merck & Co.
Dyslipidemia is a disorder of lipid metabolism. The term is often used as a blanket to describe any imbalance in the level of blood lipids: thus, it is often used to describe a variety of conditions characterized by either excessively high or excessively low levels of certain lipids in the bloodstream.
Statin drugs have demonstrated strong efficacy in the treatment of dyslipidemia and represent the standard of care for this disease. Indeed, the statin class is amongst the most widely prescribed of all drug families. Merck & Co's blockbusting anti-cholesterol drug Zocor, for example, generated staggering full-year sales figures of $5.6 billion in 2002.
However, in spite of the success of these drugs, there remain a significant number of patients who are deemed ‘difficult-to-treat’, and who achieve only a limited response to statin therapy. An opening therefore exists for novel anti-dyslipidemic therapies, and companies such as Schering-Plough
and Merck have been busy developing therapies in order to address this patient need.
One of the more promising anti-cholesterol therapies to be developed in recent years is Zetia (ezetimibe), an intestinal cholesterol absorption inhibitor originated by Schering-Plough. In May 2000, Schering-Plough entered into an agreement with Merck & Co to jointly develop and commercialize Zetia. Although an alliance between two competing big pharma players may at first seem strange, this partnership is in fact ideally suited to both companies' needs.
On the one hand, Schering-Plough gains access to Merck’s experience of the anti-dyslipidemic market, as well as to significant marketing resources. For Merck, the motivation is more to protect and extend its highly lucrative Zocor franchise as the loss of patent protection approaches. Indeed, generic Zocor (simvastatin) is already available in certain European countries such as Spain, with a US arrival expected in 2006.
At the time of the agreement, it was clear that Zetia, although potentially more efficacious than other non-statin monotherapies, was not potent enough as a lipid-lowering agent to compete effectively against the statins for market share. In clinical trials, the drug has been shown to reduce LDL cholesterol by around 18%, with a modest increase in HDL of some 3.5% over a 12 week period.
Although these figures are considerably lower than those that are achieved with statin monotherapy, Zetia may prove to be a helpful adjunct in patients who have reached a treatment plateau with existing therapy, offering increased cholesterol lowering at lower statin doses. With its completely novel mechanism of action, Zetia demonstrates efficacy in the 5-8% of the population who are intolerant (contraindicated, non-responsive, or develop serious side effects) towards statins.
Not only will this furnish Merck and Schering-Plough with a niche population, but more importantly doctors will be more likely to prescribe Zetia in combination with statins to achieve improved lipid control, given that the two drugs target different sources of cholesterol.
This is a particularly strong advantage given the current and growing concerns in the medical world concerning the potential adverse effects of statin therapy, which came to the fore in 2001 with the withdrawal of Bayer's
Baycol (cerivastatin). And indeed, clinical studies examining Zetia as a monotherapy or in combination with a statin have shown it to be safe, exhibiting side-effect profiles similar to placebo.
Awaiting the third generation
But perhaps the greatest single factor in favor of Zetia is Merck's extensive experience of selling drugs in the cardiovascular class. Amid rigorous competition from Pfizer's
Lipitor, the third-generation statins, and even generic simvastatin, the best strategy to extend the Zocor franchise would be to encourage combined Zetia/simvastatin use, not only to improve Zocor's immediate revenue prospects, but also extend its life span to better compete with later-generation statins, which will be patent protected well into the second decade of the 21st century.
Merck and Schering-Plough are already developing a single-pill combination of the two drugs to drive uptake, while also providing physicians with plenty of clinical trial data on the use of Zetia and Zocor to convince them of the safety and efficacy benefits.
Zetia's success could be compromised however. In addition to a restrictive pricing plan the drug will also be threatened by the launch of the third-generation statins such as Crestor and pitavastatin, which achieve increased LDL cholesterol reduction at lower statin doses, thereby negating the need for an add-on therapy such as Zetia.
There are also a number of novel compounds in development which provide added anti-atherosclerotic benefits on top of their lipid-modifying properties. Datamonitor believes that many of these compounds will be more advantageous than Zetia, potentially limiting the drug's commercial success.
Zetia is nevertheless expected to have reasonable potential within the anti-dislipidemic market, although much of this may be due more to the commercial power of the marketing companies involved than the intrinsic benefit of the drug.
While the drug poses little threat to the currently marketed statins as a monotherpy, it is an effective, novel and safe lipid-lowering drug with convenient, once-a-day oral dosing that may be ideally suited for adjunctive therapy.
However, sales of the drug may be limited by a number of factors, including its inferior LDL cholesterol lowering profile; the increased pill burden and cost associated with an add-on therapy, and finally the fact that other novel anti-dislipidemics are under development. For these reasons, Datamonitor's global sales forecasts for Zetia are lower than is the general consensus amongst the investor community.
If you found this week's Expert View useful, you may be interested in Datamonitor's reports:
· Statin Adjunct Therapy - Zetia, Revenue Protection for Zocor? priced $1,600
· Market Dynamics: Anti-dyslipidemics - Third Generation Statins Superfluous to Market Requirements? $6,100
· Antithrombotics in Acute Ischemic Stroke - The Clot Thickens priced $1,600
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