AstraZeneca’s blockbuster statin Crestor (rosuvastatin) got a huge boost on Sunday with news that the treatment helped decrease risk of major cardiovascular events by 44 percent in a clinical trial of nearly 18,000 men and women. 

The study-dubbed Jupiter-was designed to determine the impact of Crestor on cardiovascular events in a population of patients that do not have elevated cholesterol, but have elevated C-reactive protein or CRP. Before a packed audience at Sunday’s meeting of the American Heart Association, investigators released their findings, which include:

A 47 percent drop in deaths due to heart attacks, strokes, and other major CV deaths 

A 54 percent drop in risk of heart attack 

A 48 percent reduction in risk of stroke 

A reduction in total mortality of 20 percent 

Decision Resources senior analyst Nikhil Mehta told 

 that this was a huge study for AZ because it should yield Crestor’s first approval for preventing cardiovascular outcomes. “That was a major weakness for the drug before Jupiter,” Mehta said. “All the other statins that are available in the Western market have outcomes data. The trial itself answers important questions of Crestor’s safety and efficacy, but it also poses new questions that need to be followed up in future research.”

Those questions include reports of a small spike in diabetes cases found in patients taking Crestor. But Mehta noted that the diagnosis has been seen in other statin trials.

“I think the data and the media response to the data is going to be positive," Mehta said. “Because the CRP test is commercially available, some clinicians might be tempted to start using it a lot more and prescribing Crestor or another statin therapy to their patients.”


Other statins that lower CRP include Zocor (simvastatin ) and Lipitor (atorvastatin), which is losing exclusivity in 2011. AstraZeneca made it clear, however, that this trial was for Crestor alone. “The Jupiter trial was with Crestor therapy; other drugs were not studied in this category of patients, and it cannot be extrapolated to other statins as a result,” said James Blasetto, VP strategic development at AZ. “We can only speak to the results demonstrated for Crestor.”

AstraZeneca CEO David Brennan downplayed the potential boost in sales, telling 

, “We’ve seen a flurry of estimates from analysts about the commercial impact of [the study], some of them pretty bullish. I would urge caution when forecasting the speed of such changes.”

AZ plans to file a regulatory submission in hope of having a labeling change by the first half of 2009.

Articles

News Analysis

AstraZeneca caused a ruckus at the American Heart Association's annual meeting as data was released proving that its statin not only works for its target indication, but also reduced major CV events in patients who don?t have high cholesterol.

Jupiter Study Gives Huge Boost to Crestor

FDA, last week, announced that it seized 11 lots of the blood-thinner heparin from Cincinnati-based Celsus Laboratories due to possible contamination.

According to the FDA release, US Marshals seized five lots of heparin sodium active pharmaceutical ingredient and six lots of heparin lithium that the agency deemed tainted with over-sulfated chondroitin sulfate-the same foreign substance found in Chinese labs earlier this year. According to Celsus, the lots had been held under quarantine in its facility since spring, when the company instituted new tests recommended by FDA in the wake of the Chinese heparin incident, and identified problems in the lots, which were reportedly imported before the new testing standards took effect.

“This action will help prevent this contaminated heparin from finding its way into the marketplace," stated Mike Chappell, acting associate commissioner for regulatory affairs, FDA.

In a statement, Celsus said that its heparin is not sold directly to patients, and is intended only for research, purchase by a drugmaker as a component for further manufacturing, or for use in medical devices such as blood collection tubes. Celsus notified its customers about the contamination, but FDA said that the company did not do an adequate job getting the heparin back from customers. In the release, FDA noted that “the company's actions to notify customers about a contaminant in its heparin were insufficient to assure an effective recall.”

“They were old lots identified back in March, and FDA was notified by us…voluntarily,” a Celsus employee told 

 on Monday. When pressed as to why FDA felt the Celsus’s recall was not good enough, the employee refused to comment further. 

In the statement, Celsus noted that FDA had checked the suspect lots in May, June, and September before finally seizing them on November 6. FDA did not return calls requesting an explanation as to why the lots weren’t seized in the first place.  

Over the past year, feds have initiated 13 recalls of tainted medical products found to contain bad heparin. In February, Baxter Healthcare temporarily halted manufacturing on multi-dose vials of its heparin after severe side effects-including allergic reactions and death-were reported by patients using large quantities of the anticoagulant. 

The investigation eventually led to a Chinese manufacturing plant, where it was discovered that a key ingredient in heparin had been replaced with over-sulfated chrondroitin sulfate-a man-made chemical used in place of the anti-clotting ingredient. When taken by patients, the modified drug can cause major side effects, including seizures and death.

US heparin manufacturer ordered to turn over contaminated batches of heparin. Just how much of the tainted chemical is on the market?

Federal Marshals Seize Celsus Heparin

In 2005, Sanofi-Aventis’s obesity drug Acomplia (rimonabant) topped 

 list of blockbusters with potential annual earnings of $2 billion. Three years later, Acomplia, along with treatments from Merck and Pfizer with the same mechanism of action, have been canned. 

Last week, Pfizer and Sanofi-Aventis announced that they had ended all clinical trials for their CB-1 antagonist obesity treatments. The drugs target the cannabinoid type 1 receptor in the brain, basically turning off the pleasure center that causes people to crave food. Both Pfizer’s Phase III drug CP-945,598 and Sanofi-Aventis’s Acomplia (rimonabant) had been universally criticized for causing psychiatric adverse reactions in patients using the drugs.

“While confident in the safety of the compound, we believe that this is the appropriate decision based on all available information regarding this class of agents, as well as recent discussions with regulatory authorities,” stated Martin Mackay, president, Pfizer global research and development. “As part of our ongoing portfolio prioritization, we will refocus research and development resources on high-priority therapeutic areas that address an unmet medical need and have a high probability for success.”

The once-promising obesity treatment hit a huge stumbling block in 2007, when FDA refused to approve Acomplia in the United States. The European Medical Agency approved the drug in 2006, but with the caveat that doctors had to screen out patients with psychiatric disorders, and closely monitor patients taking the drug. In October, a year after Acomplia launched, EMEA declared that the drug’s risks outweighed its benefits, and recommended withdrawal. Merck also had a recent obesity drug failure in taranabant, which was stopped in Phase III in the beginning of October. 

Decision Resource analyst Donny Wong told 

 that he had spoken to many doctors who prescribed the drug and they said it drug worked fairly well when given to the right patients. Some of the primary care trusts (localized health authorities in the EU) reimbursed for rimonabant, and as recently as four months ago some of the trusts actively recommended the treatment for some obese patients.

“We very clearly saw both Merck and Pfizer’s compounds following Acomplia’s path,” Wong said. “We were thinking that since the EU had approved Acomplia originally, that the other drugs would have a chance in Europe. But I think this reflects the growing concern over long term safety for any drug.”

Daniel Ruppar, Industry Manager for Frost & Sullivan's Pharmaceuticals & Biotechnology team told 

 that the writing had been on the wall for some time. “Anything in this drug class targeting an obesity indication at this point will have some higher safety hurdles from the FDA-pretty much guaranteed,” Ruppar said “Pfizer refocusing/restructuring, their canceling of their Phase III product also makes good sense, as they are probably trying to focus on the best possible compounds in the clinic to invest in.”

Rupar compares the obesity drug debacle to the failure of most of the pulmonary insulin pipeline. “Once a couple of big drugs fall in trials, or the first-to-market drug gets pulled, companies who are following the same pathway get nervous, often get hit with similar problems, or re-evaluate and move on for the good of their overall portfolio,” he said.

So what does the future hold for cannabinoid receptor antagonists? The compound had been being considered for smoking cessation and drug rehabilitation treatments, but those indications also seem to have been put aside. 

“This particular drug class is done now,” Wong said. “With three late-stage, high-profile failures, I don’t think anyone is going to try to get into this space now. I think the hurdles are just too high.”

Once considered the future of weight loss drugs, CB-1 antagonists have now been shelved globally. With failures from Pfizer, Merck, and Sanofi-Aventis, analysts say that this is the end of a potential blockbuster therapy.

Pharmaceutical Executive-11-12-2008

Jupiter Study Gives Huge Boost to Crestor

Federal Marshals Seize Celsus Heparin

CB-1 Antagonists for Obesity: R.I.P.