Requiem for a Heavyweight: Big Brand Statin Era Comes to a Close as Crestor Heads Off-Patent

This month marks the end of an era: Crestor, once dubbed the “Super Statin” and the “Gorilla,” has lost its market exclusivity in the United States. As of May 2, 2016, a generic rosuvastatin is available for US patients in need of LDL-cholesterol lowering, and later this summer, more than a half dozen generic competitors will flood the market, altering the economic landscape for treating patients with dyslipidemia.

Approved for more than 12 years, rosuvastatin (Crestor, AstraZeneca) has been one of the most widely prescribed branded drugs in the US, with one research firm reporting that more than 22 million prescriptions were written over a 12-month period in 2013 and 2014, translating into nearly $6 billion in sales. The drug has consistently had annual sales in the $5 to $6 billion range for the last several years.

While there remains one, albiet infrequently prescribed, brand-name statin available in the US, the shift from Crestor to generic rosuvastatin marks the end of aggressively marketed statins competing for space in a crowded field. Rosuvastatin, considered the most potent statin available, now joins atorvastatin, another heavyweight, and others as a cheaper generic alternative to the branded statins that added billions of dollars to the bottom line of big pharma.   

“Over time, millions of patients were successfully treated with the drug,” Steven Nissen, MD (Cleveland Clinic, OH), told TCTMD. “The JUPITER trial was indeed a landmark study, and I think we’ve all come to believe that like all the statins, rosuvastatin is very safe and it happens to be very effective. It belongs in our armamentarium. I use it, others use it, and it’s done very well. It was never as big a product as atorvastatin, but it’s done very well.”

For Amit Khera, MD (University of Texas Southwestern Medical Center, Dallas), rosuvastatin was and will remain part of his arsenal of statins to lower LDL cholesterol levels. In recent years, however, Khera has relied more heavily on generic atorvastatin and simvastatin because these drugs were cheaper and provide similar potency.

While rosuvastatin 40 mg and atorvastatin 80 mg are very similar in terms of LDL-cholesterol lowering, Khera said, there are select patients where a generic rosuvastatin will be a boon to patients. These include high-risk patients, such as those with familial hypocholesteremia or profound dyslipidemia, where every little bit of LDL-cholesterol lowering counts. “It’s not like it’s markedly better if you look at the percent lowering, but it is a bit better,” he told TCTMD.

Success of Crestor Wasn’t Guaranteed

Despite the role rosuvastatin eventually carved out in the physician’s toolbox, the outlook wasn’t always so rosy, particularly when the drug was approved in 2003 on the basis of LDL-cholesterol lowering, not hard endpoints. At the time, the US Food and Drug Administration (FDA) was somewhat concerned over the potential side effects with the statin drug class, particularly since Bayer was forced to withdraw cerivastatin (Baycol/Lipobay) in 2001 after reports of increased fatal rhabdomyolysis. AstraZeneca had applied for approval of rosuvastatin in doses ranging from 5 mg to 80 mg, but the FDA worried about safety concerns at the 80-mg dose. The company was ultimately forced to resubmit data in 2002 supporting dosages ranging from 5 mg to 40 mg, which delayed the drug’s launch.

Even when it was approved, rosuvastatin faced large challenges, namely that it looked like yet another “me-too” drug, one following in the footsteps of brand-name atorvastatin (Lipitor, Pfizer) and simvastatin (Zocor, Merck), among others, and that it might be too late to the party. The year before Crestor was approved, Lipitor, which is the best-selling drug of all time, had annual sales of $8 billion. After the approval of Crestor in 2003, sales of Lipitor continued to grow, with annual sales north of $12 billion from 2005 to 2008. When it finally came off-patent in November 2011, Pfizer had made more than $125 billion from Lipitor.

Howard Weintraub, MD (NYU Langone Medical Center, New York, NY), a preventive cardiologist, said Crestor faced a pitched battle against Lipitor in those early days, primarily because it hadn’t been proven to cut clinical events. “Atorvastatin had all the data,” he said. “They were dealing with a drug that had event data in every population you could imagine: primary prevention, secondary prevention, acute coronary syndromes, everything. What AstraZeneca was hoping on was the ‘build it and they will come’ attitude. They figured Lipitor sold early without event data so why can’t we?”

And sell they did. Rosuvastatin was, many times over, a “blockbuster” in every sense of the word.

‘AstraZeneca Must Retreat’

To cut into a market dominated by Pfizer, a company legendary for its fleet of sales reps and high-profile advertising campaign (Pfizer’s campaign, “Know Your Number,” appeared during a commercial break for the popular primetime television drama ER), an equally aggressive sales strategy was needed for rosuvastatin.

But the launch of rosuvastatin and AstraZeneca’s subsequent marketing and advertising strategy drew heavy criticism from the venerable Lancet, however, particularly from the journal’s editor-in-chief, Richard Horton, MD, who penned a 2003 editorial calling on AstraZeneca to “retreat.” The editorial was particularly hostile toward the quality of clinical trials testing rosuvastatin, calling some of those studies “blatant marketing dressed up as research” and stating there were no reliable data regarding the safety and efficacy of Crestor.

In the kicker, Horton said physicians should pause before prescribing rosuvastatin and called on AstraZeneca to stop its unprincipled marketing campaign.

The company responded, of course, writing a letter to the editor, but the Lancet editorial stands out to this day. Many experts were puzzled by the scathing attack, with some suggesting the regulatory bodies, particularly the FDA, would have made a better target for having taken the decision to approve rosuvastatin on the basis of surrogate endpoints. After all, the other statins had also been approved before clinical outcome trials showed a reduction in cardiovascular events.

“I thought the criticism was misguided,” said Nissen, noting that Public Citizen, a health watchdog, urged the FDA to withdraw rosuvastatin not long after it was approved because of concerns about rhabdomyolysis and kidney damage. He said that while JUPITER—the large cardiovascular morbidity and mortality trial that followed approval—was a well-conducted study, his proof that Crestor was as good as the other available statins came from the ASTEROID trial. “We showed rather convincing regression of atherosclerosis with 40 mg of rosuvastatin, and I think that as more time went by the putative safety issues that were raised early on didn’t pan out,” said Nissen.

Khera pointed out that while rosuvastatin and AstraZeneca were criticized in the early days because of the lack of hard clinical outcomes data, other companies faced similar criticisms. Pfizer took heat when atorvastatin was approved, with critics saying there was no data showing that treatment reduced the risk of MI and other cardiovascular events. Ezetimibe (Zetia, Merck/Schering-Plough) received a similar pummeling, and in fact, was nearly derailed by the ENHANCE study showing that despite lowering LDL cholesterol, the drug didn’t reduce subclinical coronary atherosclerosis as measured on carotid ultrasound. 

The new PCSK9 inhibitors are also facing similar challenges in that they have not yet shown they reduce clinical events, he noted.

Good Tolerability With Rosuvastatin

When rosuvastatin was first approved by the FDA, Weintraub said he was not an immediate convert, namely because he did not see the benefit of further lowering LDL cholesterol levels with rosuvastatin. For certain patients, switching to rosuvastatin would translate into an additional reduction of just 3 or 4 mg/dL, depending on their starting point, compared with what could be achieved with high-dose atorvastatin, a drug with proven clinical benefit.

“It didn’t really knock me out of my socks,” he said. Moreover, even among his patients that had been started on rosuvastatin, Weintraub switched many back to generic atorvastatin once it became available in late 2011 because it was significantly cheaper.

That said, though, Weintraub says he uses “a lot” of rosuvastatin in his practice.

“The reason being is that it’s better tolerated,” he told TCTMD. In managed care, patients are typically started on a generic statin, such as atorvastatin, but if myalgia develops, the next step is to switch to rosuvastatin. “If you fail atorvastatin, in my hands as a prevention guy, my bent is to use the next most potent statin, which would be Crestor. There are a lot of people on Crestor who are there because they did not tolerate Lipitor,” he said.

Another advantage rosuvastatin has is that it has fewer drug-drug interactions, because the metabolism differs from atorvastatin’s. The antihypertensive medications verapamil and diltiazem, as well as the antiarrhythmic amiodarone, are to be avoided with atorvastatin, as are colchicine, cyclosporine, and various antiviral agents.

“There are a fair number of drugs that can react in a much more serious manner with atorvastatin,” said Weintraub. “These are what I call designer drugs. [After] simvastatin came out, they made a better version of simvastatin with atorvastatin. It was more potent and had fewer drug-drug interactions. Now they go from atorvastatin to Crestor where there is a little more potency and fewer drug-drug-interactions. So, the drug has a place.”

Gazing Back at JUPITER

Although Crestor initially made a big splash because of its potency, with data from clinical trials showing the drug reduced LDL cholesterol levels by 43% and 62% across the approved dose range, true credibility for rosuvastatin did not emerge until 5 years after its approval with the completion of JUPITER study. Until then, studies testing rosuvastatin had only shown the drug reduced LDL cholesterol levels, not hard endpoints.In contrast, major morbidity and mortality trials with Lipitor, Zocor, Mevacor (lovastatin), and Pravachol (pravastatin), all showed these other statins significantly reduced the risk of mortality, MI, stroke, and other cardiovascular endpoints.

In JUPITER, which was a randomized clinical trial with 17,802 men and women who had normal LDL cholesterol levels but elevated C-reactive protein levels, investigators showed that treatment with rosuvastatin did in fact reduce the risk of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes compared with placebo (absolute risk reduction 1.2%). Overall, there was a 55% relative reduction in nonfatal MI, a 48% reduction in the risk of nonfatal stroke, and a 47% reduction in the risk of MI, stroke, and death from cardiovascular causes.

In January 2010, on the basis of JUPITER, AstraZeneca received the modified indication for rosuvastatin, with the drug now approved for use in the prevention of hard cardiovascular events. Today, rosuvastatin 40 mg, along with atorvastatin 80 mg, has a solid position in the clinical guidelines for the treatment of patients with atherosclerotic cardiovascular disease—and those with a baseline LDL cholesterol level > 190 mg/dL—who need to achieve at least a 50% reduction in LDL cholesterol levels.  

“It’s really interesting to look back retrospectively,” said Khera, referring to early days when Crestor emerged and its early competition against statins with proven cardiovascular risk reduction. “As an academic, you always say, we need data, so having that data was important, particularly when there was a significant cost differential.”

For their part, AstraZeneca said the fact that Crestor went on to become the most prescribed brand-name drug in the US despite the availability of generic statins is a “testament to its science and the value it has brought to patients.” In a statement to TCTMD, Steven Zelenkofske, vice president of US Medical Affairs (Cardiovascular) at AstraZeneca, said the company followed a clinical pathway set out in the GALAXY development program to test the drug in a diverse set of patients, answering “some of the most important unanswered questions in statin research.”

AstraZeneca Not Giving Up Entirely

The first generic rosuvastatin will be made by Actavis, a company which has market exclusivity until July 2016 when a number of other companies will be allowed to produce and market their generic versions of Crestor. 

“The funny thing is that it’s probably going to be more expensive once it goes off patent,” said Weintraub, referring to the decision to allow just one generic manufacturer exclusivity for three months. He added that AstraZeneca representatives have already called at his office to drop off $3 copayment cards in an attempt to drive patients away from generic rosuvastatin to the branded drug. The previous copay card for Crestor was $18. For Weintraub, the copayment reduction shows just how cheap the drug is to make.

Khera said there is a wait-and-see approach for generic pricing with rosuvastatin, but if the price comes down to where it is comparable to atorvastatin, he’d welcome the chance to use it, particularly in patients who develop statin-induced myalgia. Finding a tolerated statin can be undone if the drug is financially unsustainable, he noted.

For Nissen, the ability for physicians and patients to choose a potent statin, “and to give it in full doses at very low costs should be able to help us get more people, particularly people at high LDL cholesterol levels, to reasonable goals.”

Despite the end of the era for Crestor, one branded statin remains available in the United States. Pitavastatin (Livalo, Kowa Pharmaceuticals), available in Japan since 2003 and in the US since 2009, is approved for the treatment of elevated cholesterol levels and is considered a “modest” LDL lowering drug. It does not have an indication for the reduction of clinical events as such a trial has never been done. Covered only by a select number of managed care companies, Livalo is a good option for statin-intolerant patients as it is well tolerated, said Weintraub. In addition, Livalo has the cleanest drug-drug interaction profile, making a good option for HIV positive patients taking multiple antiviral medications, he said.

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Related Stories:

• JUPITER: Rosuvastatin Cuts Heart Risk, Even in LDL-Normal Patients
• ASTEROID: Rosuvastatin Produces Coronary Plaque Regression
• PCSK9 Inhibitors: Good Early Responses With Pricey Drugs, but Doctors Still Waiting on Real Data