Posts Tagged ‘Lipitor’
Disease Creep or Good Medical Practice?
The American Heart Association has been monitoring deaths due to cardiovascular disease (CVD) in the U.S. for over a century. While the CVD death rate grew steadily for most of the 20th century, it leveled off and then began to drop somewhat over the past 25 years. Nevertheless, CVD is still the leading cause of death in the U.S. with 600,000 people dying annually, which accounts for more than 25% of all deaths in the country. The direct costs associated with treating heart disease amount to over $80 billion/year and indirect costs attributed to loss of productivity exceed $60 billion/year.
Despite the progress made in moderating the CVD death rate, it is still a major disease. Furthermore, as the obesity epidemic continues in the U.S., recent headway is liable to be counteracted by the increase in obesity, which is already resulting into a concomitant increase in type 2 diabetes, a precursor to heart disease. Even with improvements in diagnosis and treatment, better understanding of risk factors, reductions in smoking, etc., CVD is going to remain a major health problem for decades.
Diet and exercise are keys to staying healthy, not just to ward off heart disease and diabetes but other diseases as well. Yet, there are times when medical treatment becomes a necessary add-on to preventing heart attacks and strokes. It is not a coincidence that the lowering of CVD deaths occured at the advent of statins such as Zocor (simvastatin) and Lipitor (atorvastatin), drugs that lower LDL cholesterol which is a key factor in the formation of atherosclerosis. These medicines have been shown to be both effective and safe for long-term use.
Thus, it is stunning to see an essay like Jeanne Lenzer’s “Disease Creep: How we’re fooled into using more medicine than we need” (December 22, 2011). Lenzer’s views can be summarized in her quote below:
“Elevated cholesterol is not a disease. It doesn’t cause symptoms. It is a risk factor. People with high cholesterol levels are somewhat more likely to develop a heart attack or stroke, but they are at far less risk than individuals who already have cardiovascular disease. This is the definition of disease creep: when pre-conditions or risk-factors are treated as if they are the same as the actual disease state.”
In Lenzer’s utopia, you wouldn’t get a statin until AFTER you have already had a heart attack. The problem is that many first heart attacks are fatal – you don’t get a second chance to go on statin therapy then. She is correct in saying that just having high cholesterol alone does not justify taking a statin to prevent a heart attack or stroke. But CVD risk factors also include male sex, older age, family history of heart disease, post-menopause, smoking, obesity, high blood pressure, diabetes and stress. If a patient presents to a physician with multiple risk factors and if diet and exercise have not been effective in lowering cholesterol levels to those recommended by the American Heart Association, that physician would be remiss if the patient wasn’t prescribed a statin. Waiting for a patient to first have a heart attack or stroke before providing such treatment would be irresponsible.
Lenzen implies in her article that the prophylactic use of statins may only prevent 1 in 50 heart attacks. I don’t necessarily agree with that number, but let’s say that is correct. There are 785,000 first heart attacks/year in the U.S. Even employing Lenzen’s assumptions, the use of statins in the overall treatment paradigm of patients with multiple CVD risk factors would prevent thousands of heart attacks or strokes annually. Now that the most-studied statins like simvastatin and atorvastatin are generic, it would seem like the cost-benefit of statin use to prevent first heart attacks is non-controversial. This isn’t “Disease Creep” – it is simply good medical practice.
Is the Road to Big Pharma Success Slimming Down R&D and Focusing on Mini-Blockbusters?
Today’s long awaited launch of the generic form of Lipitor, atorvastatin, has been the inspiration for a number of recent news stories. One that particularly caught my eye is by Bloomberg’s Drew Armstrong entitled “Pfizer After Lipitor Slims Down to Push Mini-Blockbusters.” The gist of the article is contained in the following line: “The next step will be rebuilding the world’s biggest drugmaker into a smaller, faster-moving company that focuses on development of biologic drugs and specialty medicines….” The implication of this statement is that Pfizer previously had a strategy that was based on discovering compounds like Lipitor that would each generate annual sales of $12 billion and that Pfizer now realizes that this is a flawed plan and is going to get leaner and smarter.
If it was only so simple.
First of all, the original peak sales predictions for Lipitor were on the order of $700 – 800 million, as it was the fifth statin to reach the marketplace. As discussed in this blog previously, the fact that it evolved into the biggest selling drug of all time was due to a “perfect storm” of great efficacy, excellent safety and the growing realization of needing to lower bad cholesterol (LDL) more than had been previously recognized. Lipitor is a once in a generation product. To base a company’s strategy on this luck is foolish – and it’s not what happened at Pfizer.
What is a mini-blockbuster? Is it a compound that has sales of $750 – $1 billion? Pfizer generated a number of these internally in the last decade: Chantix, Vfend, Geodon, Sutent, etc. Interestingly, most analysts paid little heed to these compounds. The general refrain was: “These are nice compounds, but none of them are Lipitor.” Yet, many of these same analysts are now advocating this as the direction that Pfizer should take.
Will focusing on these biologics and specialty drugs make Pfizer “a smaller, faster-moving company” as the author suggests? These drugs should be quicker to develop after all, right? Not exactly. A recent issue of the New England Journal of Medicine published an editorial titled “Therapy for Cystic Fibrosis (CF) – The End of the Beginning?” (NEJM, 365;18, November 3, 2011) which discusses the truly outstanding research that led to the CF drug ivacaftor. This is an important new medicine that will meet an important medical need. It is also a specialty drug. And this research STARTED in 1989. A focus on specialty drugs doesn’t ensure rapid R&D programs – nor robust revenues.
Analysts give high grades to compounds in the company’s late stage pipeline, including tofacitinib for rheumatoid arthritis, criizotinib (Xalkori) for lung cancer and apixiban (Eliquis) for heart disease (which was co-developed with BMS). All of these drugs are traditional small molecules and all resulted from extensive R&D programs. In fact, the tofacitinib program began in 1993. The predictions for peak sales of these compounds range from $1.5 billion for crizotinib to over $4 billion for tofacitinib and apixiban – not exactly “mini-blockbuster” numbers. Pfizer also has important biologics in its pipeline, including the vaccine Prevnar, which is also on its way to being a blockbuster. Pfizer’s portfolio is diverse; its problem is that with top line revenues of over $60 billion, it needs more of these great compounds.
There are a few lessons in all of this. First of all, predicting commercial success for a new medicine is always tenuous. The biopharmaceutical industry has always been surprised, both positively and negatively, by the performance of new drugs. That is not going to change. As I’ve written before, to say that you are going to focus on niche or specialty products is a prescription for disaster. Such compounds can play a role in a company’s portfolio of products, but this shouldn’t be a driver for companies with sales of $25 – 60 billion.
Second, from a discovery research standpoint, the resources needed to come up with a new compound for clinical development differ little for a niche product or a projected blockbuster. Admittedly, the development costs for a specialty products can be less, particularly for a so-called orphan disease for which there is no treatment and relatively few patients worldwide with the disease. But a big pharmaceutical company’s portfolio should have a very limited number of such approaches if it is to thrive.
Finally, there is a view that there are fewer and fewer opportunities for major blockbusters. I beg to differ. A truly effective and safe drug to cause weight loss would likely have sales in excess of Lipitor’s. The challenge in this field is clearing the high regulatory hurdle that exists for such a compound. A new drug that can slow or reverse Alzheimer’s Disease would also have tremendous commercial potential as the incidence of this disease will surge over the coming years with the increasing life spans of people globally. Heart disease continues to be a problem, and the obesity/diabetes epidemic will likely reverse the progress made in this arena over the past decade. Will an agent that raises the good cholesterol, HDL, be a new breakthrough for treating cardiovascular disease? If yes, major blockbuster status will be achieved here as well. There also other major medical needs awaiting new, effective treatments.
You don’t build a business strategy on the hope of discovering $10 billion/year products. You DO base it on having the most robust R&D organization possible. And this leads to my final point. Slimming down R&D isn’t the answer. Rather focus, stability and resources are required for an R&D organization to thrive.
Does Niacin Still Have a Role in Cardioprotection?
A number of years ago, I needed to address my rising cholesterol levels. Despite being an avid runner with a Body Mass Index well within normal limits, my total cholesterol was 250 mg/dL and my LDL (“bad cholesterol”) was 140 mg/dL – both above recommended healthy levels. Given that I have a family history of heart disease, I decided to seek medical treatment and, being a Pfizer employee, I visited my personal physician with the intent of getting a prescription for Lipitor.
Interestingly, my doctor was reluctant to do this. This was the 1990s and Lipitor was new to the market. He was not comfortable prescribing a drug that I potentially would take for the rest of my life without having seen more long term safety data. Instead, he recommended that I take long-acting niacin, which is available over-the-counter at any pharmacy.
Niacin, also known as vitamin B3, is known to raise HDL, the so-called good cholesterol, by about 25% as well as modestly lower both LDL and triglycerides. It has been used for decades to treat dyslipidemia based on results from the Coronary Drug Project (CDP). Carried out in the late 1960s, the CDP study tested niacin vs. placebo in men who’d had a previous heart attack, over a period of five years. Interestingly, niacin showed no difference from placebo in the death rate of the men in this study, but fewer patients on niacin had a non-fatal heart attack or stroke, by 26% and 24% respectively. This study is the basis of the use of niacin in cardiovascular (CV) disease.
My experience with niacin was pretty typical. There were modest reductions of both total cholesterol and LDL (~15%), but these changes weren’t maintained over time. But I also experienced the major niacin side-effect, flushing. This irritation wasn’t minor. The flushing was intense and was accompanied by itching and heat sensations. Because of this side-effect, many patients refuse to stay on this medication despite its potential benefits. After about a year, my physician took me off niacin and I started on Lipitor which was far more effective for me than niacin and which I tolerated very well.
So, why am I taking you on this stroll down memory lane? A recent study reported in The New England Journal of Medicine (NEJM.org, 11/15/11), along with an accompanying editorial, call into question the value of using niacin to treat CV disease. The AIM-HIGH trial, co-sponsored by the NIH and Abbott, looked at patients with established CV disease who were already on intensive statin therapy. The goal of this study was to see whether adding niacin therapy provided any extra benefit. The rationale for this was pretty sound. Unlike statins, niacin can significantly raise HDL and further lower LDL. Shouldn’t combining both modalities work better? Surprisingly, it didn’t. While the expected beneficial changes in terms of raising HDL did occur, adding niacin to intensive statin therapy was no different from adding a placebo in terms of preventing heart attacks, strokes or other adverse CV events.
The NEJM editorial accompanying the AIM-HIGH study results entitled, “Niacin at 56 Years of Age – Time for an Early Retirement?,” basically questions further use for niacin given the copious data with statins showing the superiority of these drugs in CV disease therapy. This is causing some intense debate amongst cardiologists, who are unwilling to give up on niacin after this one study. The defenders of niacin correctly point out that there are other long-term studies with niacin currently underway that will provide a more definitive answer to the value of niacin for treating heart disease.
Niacin is a medicine that has been used by physicians for 56 years. Physicians take comfort in the fact that it has been around for so long and it has been taken by millions of people, so they know what the side-effects are. Yet, niacin hasn’t been as intensively studied as newer classes of lipid modulating drugs. It is now being subjected to the same type of scrutiny demanded by the FDA of new drugs. I, for one, am looking forward to the completion of these studies.
As I have often written in this blog, decades of use does not ensure that a medicine is automatically safe and/or effective. Industry detractors seem to forget that pharmaceutical companies are full of people that also need medicine. I was my own case study in the effectiveness and risk-benefit profile of Lipitor versus niacin. For me, Lipitor was the answer. Whether or not that is also the case for others is a decision that a patient must make in consultation with his physician. However, one thing is for certain: only long-term, well-controlled studies can provide assurance that a medicine is both safe and effective.
What Really Drove Lipitor’s Success?
This month, Lipitor loses its patent exclusivity in the US. This event has prompted a number of articles in the press and elsewhere. An excellent piece was done earlier this week by Shannon Pettypiece on Bloomberg television. She actually went to the former Warner-Lambert Parke-Davis (WL) labs in Ann Arbor, Michigan and interviewed Dr. David Canter, who led the clinical trials program for what proved to be the biggest selling drug of all time.
At the time Lipitor was launched, however, it wasn’t envisioned to be a $13 billion per year product. In fact, as Dr. Canter pointed out, the former WL executives estimated that the initial annual sales projections would be about $600 – 800 million. Given that Lipitor was being launched into a statin market already dominated by Merck (Mevacor and Zocor) and BMS (Pravacol), WL felt it needed a marketing partner who could help them compete. Thus, they signed a co-marketing deal with Pfizer in 1997.
The Pfizer sales force has always been known to be among the best in the industry. Furthermore, Lipitor was known to be able to lower LDL cholesterol more than the competitive agents, so the sales force had actual data to share with prescribing physicians to show that Lipitor was different from the other marketed statins. But in the late 1990s, the significance of greater LDL lowering was unappreciated. Many felt that an LDL cholesterol level under 120 mg/dL was good enough. Furthermore, why would a physician who had been happily prescribing Zocor for years (and getting good results with patients) suddenly switch to the newest entry?
The answer lies in the studies that Pfizer carried out with Lipitor AFTER it had already been approved and on the market. Pfizer invested over $800 million to show the importance of driving LDL cholesterol as low as possible. One such study was “Treating to New Targets” (also known as TNT). Conceptually, it was a simple study. Ten thousand patients with stable coronary artery disease and a baseline level of 130 mg/dL of LDL (which was considered reasonable 15 years ago) were randomly assigned to get either 10 mg or 80 mg of Lipitor and followed for nearly 5 years. At the end of the study, those on 10 mg of Lipitor had a median LDL level of 101 mg/dL and those on 80 mg had a median LDL cholesterol of 77 mg/dL. More importantly, those on 80 mg of Lipitor had 22% fewer heart attacks and 25% fewer strokes.
This proved to be a landmark study. For the first time, it was shown that lower LDL is better and that for people with a high risk of cardiac events, driving LDL levels down can be life-saving. Suddenly, Lipitor’s potency advantage proved to have a major clinical benefit. Pfizer also performed another major study known as CARDS (Collaborative Atorvastatin Diabetes Study) which for the first time showed that diabetics can reduce their risk of heart attacks and strokes by lowering their LDL levels with Lipitor. Similarly, in the lipid lowering arm of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) lowering LDL cholesterol in patients with high blood pressure was shown to lower the risk of adverse cardiac events over hypertension therapy alone.
These studies and others helped to change medical practice. The importance of lowering LDL cholesterol as much as possible in patients at risk of a heart attack or stroke was unquestionable. In addition, these studies greatly expanded the patient population for those who would benefit from Lipitor therapy. With these data in hand, it was easy for the Pfizer sales force to drive the Lipitor sales from $5 billion to almost $13 billion six years later. But there is no doubt that the results from these studies proved to be crucial in recognizing the full potential of this important medicine.
Loss of Exclusivity of Pfizer’s Lipitor Will Also Impact AstraZeneca (AZ)
Rightfully, much has been made of the expiration of Pfizer’s US patent for Lipitor (generic name: atorvastatin), which will occur by the end of this year. Lipitor is the most notable of the statin class of lipid-lowering drugs, compounds that have helped to lower the rates of heart disease-related deaths around the world. Lipitor’s commercial success was unprecedented. At its peak, it had worldwide sales in excess of $13 billion dollars annually. Even with its patent expirations in recent years in various parts of the world, it still rang up $10.7 billion in 2010 keeping it the world’s number one selling drug.
Lipitor’s success can be attributed to a number of factors, but most notably the large (and expensive!) clinical trials Pfizer carried out over a number of years that showed how the treatment of patients at risk of heart attacks and strokes have greatly reduced incidents of adverse events when treated with Lipitor when compared to placebo. Its efficacy, coupled with its remarkable long-term safety profile, have made Lipitor a household name.
In November, when the US patent expires, generic drug makers will be able to begin selling atorvastatin (the active ingredient in Lipitor) and they will do so at greatly reduced prices. It is not unusual for the costs of generic drugs to be 10 – 20% of what the branded drug costs. Thus, Pfizer’s sales of Lipitor will drop dramatically, as pharmaceutical industry analysts have noted for the past few years.
What does this have to do with AstraZeneca? Well, AZ sells its own statin, Crestor (generic name: rosuvastatin), and with 2010 sales of $5.6 billion, it is a major product for the company. AZ has always touted Crestor as the superior compound with slightly better lowering of LDL (“bad cholesterol”) and slightly better elevation of HDL (“good cholesterol”). Unfortunately for AZ, Lipitor had been on the market for a number of years before Crestor made it, and the differences in cholesterol modulation between the two drugs was not significant enough for physicians, who were already very familiar with Lipitor, to switch their patients to the newer drug. Thus, Crestor, while still an important and heavily prescribed drug, trailed Lipitor.
But with Lipitor going generic, AZ has a major problem – one that is a reflection of the cost-consciousness of health care systems. The generic price of atorvastatin will likely be one-tenth of the cost of Crestor. Thus, payers–insurance companies, Medicare, etc.–will insist that patients newly diagnosed as needing a cholesterol lowering agent be prescribed the less expensive atorvastatin rather than Crestor. Even more concerning will be those health care plans that will try to have their Crestor patients switched to atorvastatin in an attempt to reduce their costs. The arrival of generic atorvastatin, therefore, not only impacts Pfizer, but might also cause a drop in Crestor sales as well.
AZ has been acutely aware of this issue for years and has tried to take steps to differentiate its drug from atorvastatin. Interestingly, Crestor has a biologic property that differentiates it from atorvastatin – it lowers an inflammatory marker call C-Reactive Protein (CRP). CRP is associated with a variety of inflammatory conditions, including inflammation of the arteries. Scientifically, it is thought that high levels of cholesterol damage arterial walls and the process of repairing the artery wall results in the beginning of atherosclerosis. High CRP levels could therefore be a signal of early atherosclerosis.
For unknown reasons, Crestor lowers CRP levels and this distinguishes it from other statins. Is this medically significant? AZ thought so and to prove it thecompany ran the SATURN trial. This study compared Crestor directly with Lipitor in measuring the build-up of plaque in the arteries of patients with heart disease. AZ’s thinking, and hope, was that the differences in the biochemical profile of Crestor vs. Lipitor would translate into a meaningful clinical difference in slowing the progression of atherosclerosis. If the theory held up, it would be a great result as AZ would be able to clearly show that Crestor was the superior agent.
The Lipitor patent expiration won’t just impact Pfizer’s net sales in 2012; AZ’s Crestor sales are also going to feel the impact.
The Death of the Blockbuster Has Been Greatly Exaggerated
Over the past few years, a number of critics of biopharmaceutical companies have predicted the demise of the industry because of its dependence on blockbusters. A blockbuster is defined as a branded prescription drug that generates annual revenues of $1 billion or more. Discovering a blockbuster should be a good thing as it is a medicine that is prescribed to millions of people because of its beneficial effects on disease and suffering. However, many major blockbusters, like Zoloft, Lipitor and Fosamax, have already lost or are about to lose their patent protection and it is thought that there is a dearth of new compounds in the drug makers’ pipelines with blockbuster potential to take the place of older products.
A few years ago, no less than the former head of the FDA, Dr. David Kessler, slammed the blockbuster mentality saying: “The model that we’ve based pharmaceutical development on the past ten years is simply not sustainable. The notion that there are going to be drugs that millions of people can take safely, the whole notion of the blockbuster, is what has gotten us into trouble.” Melody Petersen was even more strident in an opinion piece titled “A Bitter Pill” that appeared in The Los Angeles Times in 2008: “For 25 years, the drug industry has imitated the basic business model of Hollywood. Pharmaceutical executives, like movie moguls, have focused on creating blockbusters. They introduce products that they hope will appeal to the masses, and then they promote them like mad.”
Sorry. It’s hard for me to envision my old boss, former Pfizer CEO, Hank McKinnell “taking a lunch” to discuss strategy with the heads of Paramount and Twentieth Century Fox.
First, it must be pointed out that a company doesn’t set its research priorities based on whether or not a program can eventually yield a blockbuster. Such predictions are difficult, if not impossible. For a new medicine to be successful, it must be safe, effective and meet a major medical need. Assuming that 15 years after starting a new R&D program, the new compound finally gets approved, it then needs to get a favorable label from the FDA, reasonable pricing from those who reimburse drug costs, and acceptance by physicians and patients. A great example in the difficulty of predicting blockbusters, interestingly enough, is Lipitor. When Warner-Lambert was seeking a partner to help sell and market what proved to be the biggest selling drug of all time, the company approached Pfizer. The Pfizer marketing team’s analysis said that the peak sales potential of this medicine would be $800 million – a significant amount, but not exactly blockbuster territory. However, the actual peak in worldwide sales for Lipitor was in excess of $13 billion. What the marketing team did not anticipate were the results of the long-term studies with Lipitor, completed some years later, which showed the importance of the value of this compound in preventing heart attacks and strokes.
Nevertheless, one might think this point is moot. Based on the pronouncements of the doomsayers, one would think that the industry has lost the capability to produce major new products. However, two reports that appeared last week indicate that this is not the case and further, suggest that the strategy of working on projects meant to discover compounds that meet major medical needs can still lead to blockbusters. This was evident in two reports last week. The first came from Jonathan Rockoff and Ron Winslow in The Wall Street Journal, an article highlighted in this blog last week. Although Rockoff and Winslow focused on the increase in FDA approvals likely to occur over the coming years, they had a table which highlighted a dozen exciting new medicines that have either been recently approved or are in late-stage development. They also included predicted peak sales of these compounds, which ranged from $1.1 – $4.3 billion, annually – blockbusters all.
A second paper, “The New Face of Blockbuster Drugs” by Elizabeth Schwarzbach, Ilan Oren and Pierre Jacquet in “IN VIVO: The Business and Medicine Report” more than affirms the views in The Wall Street Journal article. Their detailed analysis shows that there will be more blockbusters in 2015 than there had been 10 years earlier (132 vs. 101). Furthermore, these will bring in on average 15% more revenue apiece.
This is very encouraging news. Yet, when many of these programs started, it wasn’t clear if the compounds that were discovered would even work in the clinic, much less emerge as blockbusters. So what has happened to create these potential blockbusters? In the late 90s, industry leaders realized that for new products to be successful in the future, they had to address major medical needs or at least be highly improved over existing therapy. R&D priorities were altered to reflect the needs of the future and
the products now emerging from R&D pipelines meet these needs. Dr. Janet Woodcock, the FDA’s drug
division director, recently celebrated this revamped strategy: “ We’re seeing a lot of innovation, much more than in recent memory.”
There are still many diseases where new treatments are needed: obesity, Alzheimer’s disease, antibiotic resistant infections, etc. The number of people affected by these diseases is so great that any new medicines that are shown to be safe and effective in the treatment of these diseases won’t just be a great benefit to patients around the world, they will also be blockbusters.
Drug Truths 