Today, the U.S. patent expires on the Pfizer’s Lipitor, the best-selling drug of all time. The first generic versions will go for sale, marking the end of a brand that has dominated the drug industry, lowered the cholesterol of tens of millions of patients, and generated more in annual sales than Major League Baseball or the entire box office of U.S. movies.
There may never be another medicine like it. That’s because of fundamental shifts in our understanding of biology, because of the demands made by patients, doctors, and society on new drugs, and because new drugs now have to compete with the super-cheap, generic versions of every medicine ever invented. Already, eight of ten prescriptions are for generics, and the drug industry is focusing on higher priced, specialty products for patients who are not helped by existing options. Good luck creating a new cholesterol drug as potent, safe for most people, and widely tested as Lipitor.
Thanks to aggressive marketing and pricing tactics by Pfizer, Lipitor will remain a big seller for years even as sales drop. Les Funtleyder, a fund manager at Miller, Tabak, says that the the stock, which his fund holds, could perform well partly because Lipitor sales may decline more slowly than investors expect, allowing Pfizer to beat earnings expectations. In fact, Pfizer probably has more to gain in the short term by controlling Lipitor’s descent than it does from any of several experimental drug programs, including a pill for rheumatoid arthritis and the use of its Prevnar 13 pneumonia vaccine in adults, that could show results in the next year. Because Lipitor is that big.
It’s hard to remember now, but Lipitor was introduced at a time before big drug safety scandals such as Merck‘s Vioxx being linked to heart attacks or worries that antidepressants like Paxil and Zoloft might increase the risk of suicide in some patients. It was a time when Jay Leno routinely joked about Viagra – not a terribly big seller, but one of the biggest drug launches in history – and writer Elizabeth Wurtzel made the talk show rounds talking about her Prozac. It really did seem there would soon be a pill for everything and anything, and cholesterol drugs were the era’s biggest success.
A 1994 study with Merck’s cholesterol drug Zocor proved cholesterol-lowering meds could prevent death – to be specific, four deaths and seven non-fatal heart attacks were prevented for every 100 patients who took the medicine for six years. A study of Pravachol, from Bristol-Myers Squibb, showed similar benefits. When it was introduced in 1996, Lipitor didn’t have any such study proving its worth, but it was way more powerful than those drugs. It instantly grabbed market share, and then Pfizer followed up by running a series of giant clinical trials, some of the biggest ever, in order to get more patients on cholesterol drugs and prove that Lipitor was the best option. Pfizer also got a big boost from a backfiring Bristol study that showed high-dose Lipitor was better than Pravachol in some of the sickest heart patients.
Something like 20 million Americans take cholesterol-lowering drugs, and before Zocor went generic in 2006 more than half of them were on Lipitor. But all those huge, market-expanding clinical trials came with a cost. As heart patients got healthier because of better treatment, and Pfizer sought to expand the cholesterol market by testing patients who were healthier still, the absolute benefit that needed to be shown got smaller. For instance, in one big clinical trial, 100 patients had to be treated to prevent one heart attack. It’s not that the drugs stopped working, but that patients got healthier.
You can argue that it’s still worth taking Lipitor, especially at cheap generic prices, because heart attacks, the leading killer in the developed world, are a lifelong problem and clinical trials only last for a few years. But there’s no arguing that doctors are starting to rebel against the idea of treating everybody with the same pill for years in order to get a small benefit for the average patient. Why not, many say, insist that drug companies find the patients who do great on a medicine, so people who don’t benefit don’t have to take it?
One prominent voice in this changeover is Eric J. Topol of the Scripps Research Institute, who helped establish the one-pill-for-everyone ethos a decade ago by running some of the biggest clinical trials ever, including one of Plavix, a blood thinner that, like Lipitor, prevents heart attacks. It is the second-best-selling drug in the world, with sales of $9 billion, and its U.S. patent expires in 2012, posing Lipitor-like problems to makers Sanofi-Aventis and partner Bristol-Myers.
In a forthcoming book, The Creative Destruction of Medicine, Topol remembers being in the room in an extravagant Paris hotel when he first saw the results of a study comparing Plavix, a $4 a day drug, with aspirin. “The answer was, to my mind, quite disappointing,” he writes. Two patients out of every 100 benefited. That helped launch Plavix to success, but Topol has lately been pushing new work in genetics to help figure out which patients are helped most by a particular drug and electronic health records to track how well medicines are working in the real world. The current, one-size-for-all system just cannot hold, he says.
To see how big this change is for drug companies, you only have to look at the reception to a new drug that was just found to be better when added to Plavix than Plavix alone. The medicine, Xarelto, is expected to become a multi-billion dollar seller for Bayer and marketing partner Johnson & Johnson. It’s one of a class of new blood thinners, called Factor X inhibitors, that are expected to replace the old blood thinner warfarin for many patients with heart valve problems.
But Xarelto is the only one of these drugs that succeeded in a clinical trial to best Plavix in heart patients, and you’d be forgiven for thinking that would mean it would be a Plavix-like success. The drug actually managed to save lives in its large trial, reducing the risk of death by an impressive 30%, despite increasing the risk of major bleeding. One of several Harvard-based physicians who ran the study, C. Michael Gibson, compared the findings for Xarelto to the findings with aspirin. Another, Eugene Braunwald, compared it to Lipitor beating out Bristol’s Pravachol, a study which his research group had also run.
A more revealing statement, though, came from Jessica Mega, another Harvard Medical School-based researcher who helped run the trial. She too argued that the mortality benefit was “hard to ignore,” but also said that part of the reason Xarelto is important is because it provides a new option as we start to better understand how the blood-clotting process goes wrong to cause heart attacks.
“Patients probably have heart attacks for a lot of different reasons,” Mega says. “The more we understand about the biology, the more we’re going to be able to give the patient options.” This is actually the flip side of the main argument against Xarelto, as made by Paul Gurbel of the Sinai Center for Thrombosis Research: that the bleeding rate is too high, and that doctors need a way to test which patients need their blood thinned more and which don’t. Whoever you side with, one-size-fits-all is on its way out.
Analyst Larry Biegelsen of Wells Fargo Securities estimates that there if every patient who could got Xarelto, it would be worth $2.1 billion a year to Bayer and J&J, essentially doubling the drug’s market opportunity. But he thinks that only 10% to 20% of those patients will get the drug – about $300 million of extra sales. Not a Lipitor. Not a Plavix.
That’s why the drugs with the biggest sales forecasts – medicines like Abbott’s Humira for rheumatoid arthritis or Roche’s Rituxan for cancer – are expensive, targeted at less common diseases. Without more Lipitors, the best hope for more progress against common diseases is that new technologies for understanding biology and genetics also make it easier, faster, and cheaper to develop new medicines.
Given the stakes, it should be no surprise that Pfizer is doing everything it can to slow Lipitor’s decline. The efforts started a yaer ago with a new coupon card that brings the patient’s share of Lipitor costs down to $4, less than a generic. (See: How Bargain Lipitor Could Raise Health Costs) Pfizer has also cut deals with the pharmacy-benefit managers to decrease cost to health plans, and even set up its own retail outfits. A web site called LipitorForYou will help patients stay on the brand. Pfizer says its research says a third of people don’t want to switch to generics, even though generics have an excellent track record for safety and efficacy thanks to the FDA’s regulation.
These steps work because only two companies – India’s Ranbaxy and Watson Pharmaceuticals – can make generics for the first six months after the patent expires. Ranbaxy challenged Pfizer’s patent and reached a deal with the drug giant, and Watson has a license from Pfizer. Ranbaxy does not yet have FDA approval for its copy. Watson will pay a 70% royalty to Pfizer, according to Sanford C. Bernstein. This three-way competition will drop Lipitor’s price 20% to 30%. After that, dozens of generic companies will make copies in the U.S., and competition could push Lipitor’s $5-per-pill price well below $1.
Even after cheap generics abound in the U.S., Lipitor will persist, selling more than $1 billion a year in countries where there is not an arbiter like the FDA to make sure generics are safe enough to substitute for brand names. For instance, in South Korea, the price of Lipitor dropped 20% when generics were introduced, but sales are already recovering because more Lipitor is being sold there. So Lipitor will hang around a bit, even though the economic and scientific environment that created it is gone – perhaps forever.
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