As high stakes battles go, the 20-year competition between the various marketed statins in the cholesterol-lowering indication has been one of the most fascinating, and commercially important, in the history of the pharmaceutical industry. The prize is the largest annual sales of any drug ever, thanks in no small part to the controversial decision of the FDA to allow cholesterol-lowering, rather than cardiovascular outcomes, as a regulatory end-point. This, together with a raft of data demonstrating that lowering LDL-cholesterol protects against major cardiovascular events irrespective of your lipid profile at baseline means that the population who can potentially benefit from statin therapy is essentially the entire population of the world. Statins therefore joined coca cola, Big Macs and more recently the Apple iPad in the shopping baskets of anyone rich enough to afford them.
The status quo is about to be shaken again: November 2011 sees the expiry of the atorvastatin patent protection
As with cola, burgers and tablet computers, success breeds competition. There are currently seven different statins on the market. The early leader in the race was simvastatin, launched by Merck as Zocor™. Zocor™ achieved peak sales in excess of $4billion in 2005, the year before its US patent expiry.
But in preparation for the simvastatin patent expiry, the industry had already developed a cadre of new-generation “super statins” – compounds which lowered LDL cholesterol considerably more aggressively than the first-to-market statins, but with similar or improved risk profiles, particularly with respect to rhabdomyolysis, the rare but severe side effect that stalks the statin class.
The clear winner among the super-statins was the first to market: Pfizer’s Lipitor™ atorvastatin. The legendary dominance it has achieved, as the biggest selling pharmaceutical in history, racking up about $100billion in total worldwide sales since its launch in 1997, owed as much to its early launch date as its superior properties compared to other super-statins. To an impartial observer there is little to choose between Lipitor™ and the silver medalist, Crestor™ rosuvastatin from AstraZeneca in terms of clinical profile, yet annual sales of Lipitor™ have run at around 3-times those of Crestor™ for the last few years.
But the status quo is about to be shaken again: November 2011 sees the expiry of the atorvastatin patent protection. The spectre of atorvastatin selling for $2 a month (the price, today, for simvastatin) obviously threatens to decimate sales of branded Lipitor™, but also to take a huge bite out of the market for Crestor™ – worth a healthy $6billion a year or so to AstraZeneca. Patent protection for rosuvastatin lasts until 2016, but it has long been clear that the day of reckoning will come much sooner than that.
“Attempts to position Crestor™ as materially superior to Lipitor™ are doomed to fail, and as a consequence the markets have already priced in the impact of generic atorvastatin on Crestor™ sales”
Like all good students of history, the owners of Crestor™ have tried to repeat the trick that won the lottery for atorvastatin even in the face of generic simvastatin: to position rosuvastatin as an “ultra statin” – clearly superior to atorvastatin. If the necessary data could be assembled, Crestor™ would be in pole position to assume the mantle of world’s best selling pharmaceutical for the next five years. Unfortunately (at least for AstraZeneca) that is a massive “if”.
Three months ahead of the atorvastatin patent expiry, the announcement of the top-line data from the Phase IIIb SATURN trial on Friday 2 September, looks like the last roll of the dice. The full dataset will be presented at the American Heart Association gathering in Miami in November, but we already know that the primary end-point (reducing percent plaque volume versus Lipitor™) was missed. Even with 1,385 patients enrolled, the small numerical superiority of Crestor™ was not statistically significant, confirming what many of us expected: across an “average” patient population there is little to chose between to the two products.
It was always going to be a bigger, and more expensive, challenge to determine whether Crestor™ really is superior to Lipitor™. Ten years ago, Pfizer had been able to use cholesterol reduction, a central component of the Zocor™ label, to demonstrate the clear superiority of atorvastatin, without the need to resort to comparative hard end-point data. But rosuvastatin and atorvastatin are too similar as lipid lowering agents to allow this strategy to work again.
The SATURN trial therefore used measurement of plaque volume measured by intravascular ultrasound. This isn’t a clinical outcome measure, but perhaps something of an “intermediate phenotype” between lipid profile and cardiovascular events. Objectively, a clear demonstration of superiority on this end-point would have been an important building block in the construction of the argument that Crestor™ deserved to retain (or gain) market share versus generic atorvatstain even at a substantial premium price point.
This failure isn’t the end of the road. There was a statistically significant improvement in total plaque volume (a secondary end-point of the study, and arguably a more powerful end-point from a statistical perspective, that would have been DrugBaron’s recommendation for the primary end-point of such a study in the first place). There is also much more data still to come, both from SATURN when we see data on lipid and inflammatory biomarkers at the AHA meeting in November, and from other trials comparing the two statins. But there is a growing feeling of inevitability about the final outcome, with the owners of Crestor™ looking increasingly like King Canute attempting to hold back the tide.
In a world increasingly focused on value for money in pharmaceutical prescribing, it needs a clear and unambiguous demonstration of superiority to maintain the very large differential in price between proprietary options (such as Lipitor™ and Crestor™ today) and generic options (such as simvastatin today) – a differential that is in excess of 5-fold. Last week we compared proprietary anti-coagulants with warfarin, where the same question applies, and concluded that a small but significant improvement in safety may be sufficient to maintain a market share with such a price differential. But maintaining market share on the basis of a small improvement in efficacy will be a far greater challenge. The SATURN data suggests that even if an argument for the superiority of Crestor™ can eventually be assembled when all the data is in, it will be of too small a magnitude to maintain significant sales against generic atorvastatin.
“King Canute will still try to hold back this particular tide, but the markets have already priced in his eventual, inevitable failure.”
As a clinician or healthcare provider, the equation looks pretty simple: can I do more good by putting five patients on generic atorvastatin or one patient on branded Crestor™? The outcome of SATURN doesn’t leave much room for doubt as to the answer to such a question.
The share price of AstraZeneca fell ‘only’ 3.4% on 2 September, on a day when the equity markets lost more than 2% of their value across the board. This muted response to the deteriorating prospects of the company’s biggest selling drug is surely in line with expectations. Most industry-watchers, like DrugBaron, already felt that the attempts to position Crestor™ as materially superior to Lipitor™ were doomed to fail, and as a consequence the markets have already priced in the impact of generic atorvastatin on Crestor™ sales. The SATURN data, therefore, represents more of a lost opportunity for an unexpected win than a surprisingly negative outcome. Canute will sit for several more years trying to hold back this particular tide, but the markets have, or should have, already priced in his eventual, inevitable failure.
RxCelerate Ltd is an outsourced drug development platform based near Cambridge, UK. We specialize in delivering an entire road map of drug development services from discovery and medicinal chemistry through to formal preclinical development and clinical up to Phase IIa. In the last five years, we have witnessed dramatic changes in the drug development …