Since 2000, Pfizer's statin Lipitor (atorvastatin) has been the world's top-selling pharmaceutical product, with global sales of $13 billion in 2006: more than double the $5.4 billion recorded when it overtook AstraZeneca's ulcer drug Prilosec/Losec (omeprazole) as the no.1 in 2000.
Lipitor was the prime reason for Pfizer's $90 billion acquisition of developer Warner-Lambert in 2000, and thanks to its marketing power, steadily increased revenues and market share, aided by the granting of new indications, and its perceived safety and efficacy. Older, less powerful statins, such as Merck & Co's Mevacor (lovastatin) and Novartis' Lescol (fluvastatin) began to see their sales slump, and by the turn of the century, the market was dominated by Lipitor, Merck & Co's Zocor (simvastatin), and Bristol-Myers Squibb's Pravachol (pravastatin); the latter is licensed from Daiichi Sankyo, which markets it in Japan as Mevalotin.
Top 10 statins - USA
12 months to March 2007
Source: IMS MIDAS Quantum
In 2006, however, the US statin market faced a paradigm shift, as first Pravachol (April) and then Zocor (June) lost exclusivity. After seeing healthy growth for many years, the total C10A (cholesterol and triglyceride reduction preparations) therapy class, which also includes fibrates and cholesterol-lowering compounds such as Zetia (ezetimibe) and Niaspan (extended-release niacin), saw sales fall by 1% in the US in the 12 months to March 2007 - though it was still an impressive $18.7 billion; statins accounted for 80% of the US C10A market by revenue, down by 4%.
Teva and Ranbaxy both launched generic simvastatin products in June 2006, and they are now ranked fourth and tenth in the US statin arena respectively. At the same time, Dr Reddy's launched an authorised generic version through an agreement with Merck & Co, which is ranked fifth. Pravastatin products from Teva and Watson take eighth and ninth place respectively, though Zocor and Pravachol have maintained their positions in the top 10, ranking second and sixth respectively, with Lescol in seventh position.
The other notable statin product in the US market is AstraZeneca's Crestor (rosuvastatin), which is licensed from Shionogi. It has sometimes been dubbed a 'superstatin', but has only relatively recently seen its sales ramp up, as the product was somewhat dogged by safety concerns at the time of its launch, particularly at higher doses. Indeed, when it was first introduced in the US in 2003, the large health insurer Wellpoint initially wouldn't reimburse the use of Crestor, citing safety issues. As cholesterol-lowering guidelines have become more aggressive, however, Crestor's utilisation has increased, and it saw 61% growth in the US in the year to March 2007, according to IMS' sales data.
Fighting for market share
Unlike in the UK, where Zocor Heart-Pro launched in 2004, in the US statins are not available without a prescription: the FDA again turned down Merck & Co's application to sell Mevacor over-the-counter in 2005. Generics are therefore the main source of competition to the branded products; overall, in the 12 months to March 2007, the top five generic statins accounted for more than 11% of the total US cholesterol-lowering market - exceeding Zocor's 10.6% share, but still considerably less than Lipitor's 44.1%. Lipitor's growth, however, has slowed considerably, to just 1% in the US in the year to March 2007, according to IMS.
Pfizer has fought back with strong promotional and advertising campaigns for Lipitor, and like other brand manufacturers, is trying to differentiate its product by demonstrating extra safety and/or efficacy - in a situation one company executive described as a "dog fight". In March 2007, it received new approvals from the FDA to market Lipitor to reduce the risk of non-fatal heart attacks, fatal and non-fatal strokes, certain types of heart surgery, hospitalisation for heart failure (becoming the first statin to win this indication), and chest pain in patients with heart disease.
Overall, however, Pfizer has had mixed success in providing concrete proof of Lipitor's superiority. In November 2005, the 8,888-patient IDEAL trial failed to show that 80mg Lipitor (an aggressive, high dose) offered a statistically significant benefit over 20mg simvastatin in patients with a history of acute myocardial infarction, leading to just an 11% relative reduction in major coronary events despite being more effective at lowering LDL-cholesterol; however, it did lead to a significantly lower rate of non-fatal MIs and secondary endpoints such as hospitalisation for unstable angina. But, patients on the high dose of Lipitor were more than twice as likely (9.6% versus 4.2%) to discontinue treatment because of adverse events than those on 20mg Zocor.
To switch or not to switch?
In March 2007, Pfizer then publicised a retrospective analysis of 80,000 patients from a US managed care database, which it said demonstrated that Lipitor led to a significant 14% reduction in the risk of cardiovascular events, including heart attacks and strokes, compared with patients who took simvastatin. In a secondary analysis, which looked at event reduction from day one, Lipitor achieved a 26% cardiovascular risk reduction compared with simvastatin. "This study is significant because it calls into question whether statins should be prescribed interchangeably through simple dose adjustments," said Michael Berelowitz, Senior Vice President of Pfizer's global medical division.
In June 2007, however, Pfizer backtracked on these claims in an SEC filing, stating: "A subsequent review by the company shows that the additional reduction in the risk of cardiovascular events in Lipitor patients compared to simvastatin patients was 10% in the primary analysis, which is not a statistically significant difference, and the additional risk reduction in the secondary analysis was 22%, which is a statistically significant difference." The mistake was due to a "programming error" and came to light after the manuscript was submitted for publication to an undisclosed medical journal, a Pfizer spokeswoman told the Wall Street Journal. Berelowitz then told the paper that the initial analysis had incorrectly included some data from 2005, when it should have been just 2002-2004. He declined to say whether Pfizer was funding additional head-to-head studies.
Nevertheless, in September 2007, at the European Society of Cardiology Congress in Vienna, Pfizer presented an observational study based on the analysis of a British primary care database (1997-2005), comparing outcomes from 2,511 patients who took Lipitor for six months and then switched to simvastatin with data from 9,009 who continued taking Lipitor. According to the company, switching was associated with a 30% increase in the relative risk of major cardiovascular events. Switched patients were also more likely to discontinue treatment (20.5% versus 7.6%). Berelowitz commented: "Today, many health care payors including governments and managed care companies are encouraging patients who are well-established on one therapy to switch to a different statin therapy. This study raises concerns about those policies.
Money counts...
While some patients might be unhappy about being switched from Lipitor to a generic statin, evidence from the US so far suggests that they are more willing to oblige if it means significantly lower healthcare costs. Pfizer has tried to protect its revenues, raising Lipitor's price by 5% in January 2007. Then, in a change of tactic, it signed an agreement with pharmacy benefits manager Express Scripts: it had dropped Lipitor from its preferred formulary at the end of 2005 in order to encourage the take-up of the upcoming generic simvastatin. As of June 1 2007, Lipitor was reinstated - after Pfizer offered Express Scripts a rebate. The PBM said the switch to generic statins saved its patients $230 million from January 2006 to April 2007, with their share of prescriptions increasing from 8% to 44%. For those patients who needed a more potent anticholesterol drug, the lower-cost Crestor and Vytorin had had preferred status: Vytorin is Merck & Co and Schering-Plough's fixed-dose combination of Zetia and simvastatin.
In March 2007, Wellpoint added generic simvastatin to its GenericSelect programme in a number of additional US states, meaning patients could receive up to four months of the drug for free as an incentive to switch from a branded cholesterol treatment. Then, in July 2007, the large retailer Kmart added generic simvastatin to its discount drug programme, allowing consumers to buy a 90-day supply for $15.
...as Pfizer feels the pinch
Pfizer certainly has its work cut out: as well as trying to defend Lipitor's market share, Indian generics manufacturer Ranbaxy is also forcing it to prove the validity of the patents protecting its cash cow in courts around the world. In the latest decision in the US, in August 2007, Ranbaxy was successful in shaving more than a year off Lipitor's protection, from June 2011 to March 2010: this could cost Pfizer $6 billion in lost sales.
It is difficult to under-estimate the importance of the world's top-selling drug to the world's no.1 pharmaceutical manufacturer, which like many of its peers has been slow to find potential replacements for Lipitor within its R&D laboratories. In the nine months to September 2007, Pfizer reported total revenues of $35.5 billion, down 1% from 2006, with Lipitor revenues dropping 3% to $9.2 billion: 26% of its total corporate revenues. For the third quarter, Lipitor's US revenues declined by 13% to $1.8 billion. Pfizer commented: "The US statin market in particular continues to be highly competitive, with both branded and generic competition in an increasingly cost-sensitive environment. We continue to respond to this competition with an integrated multi-channel effort." For the full year, the company forecasts that worldwide Lipitor sales will drop by 3-5% from 2006's $12.9 billion.
This article was written by Selena Class, Deputy Executive Editor of IMS Company Profiles. Covering more than 80 of the top pharmaceutical and biotechnology companies, including many of the leading generics manufacturers, the profiles offer authoritative insight into company strategy, finances, portfolio management, R&D and history and also contain top-line IMS sales data. For more information, please contact Stephanie Earle, or call +44 203 075 5757.