Crestor/fenofibrate combination moves into Phase III trials
AstraZeneca and Abbott Laboratories have announced that a project to develop the first statin/fibrate combination in a single pill is to move into late-stage trials.
The firms are starting Phase III trials of AstraZeneca's blockbuster Crestor (rosuvastatin) with the US group's investigational new compound ABT-335 (fenofibrate) in a fixed-dose combination treatment into Phase III clinical trials. The single pill will target "all three major blood lipids," the firms say, namely the lowering of 'bad' low-density lipoprotein cholesterol and triglyceride levels, and also increased cardioprotective 'good' high-density lipoprotein cholesterol levels.
The partnership dates back to a deal signed by the two companies in July 2006 under which they would jointly develop a product combining Crestor with either Abbott's older fenofibrate drug Tricor or ABT-335, which is due to be filed with the US Food and Drug Administration as a monotherapy (as an adjunct to diet) by the end of 2007. That they have plumped for the latter suggests considerable confidence in the new compound.
Abbott will continue to be responsible for the clinical trial programme and be responsible for regulatory registration of the new combination therapy, while AstraZeneca will hold the New Drug Application. A regulatory application is pencilled in for submission in 2009.
Crestor patent challenges looming?
The news came as analysts at Citigroup noted that five generic firms have submitted 'drug master files' with the FDA to make a generic version of Crestor, suggesting a patent challenge could be on the cards. The main US patent on the drug does not expire until 2016 and it was recently extended by four years, but a challenge can happen well before then.
Citigroup said in a research note that there is typically a delay of a month or two after a drug master file is submitted before the notification of a patent challenge is published. The companies looking to challenge Crestor, which had second-quarter sales of $1.3 billion, up 47%, are Teva of Israel, China's Changzhou Pharmaceutical and the Indian trio Glenmark, Aurobindo and MSN Laboratories.
Abbott and AstraZeneca Announce Collaboration to Develop and Commercialize CRESTOR and Next-Generation TriCor (ABT-335) Fixed-dose Combination
First Statin and Fibrate Combination in a Single Pill Would Help Patients Manage Lipids
Abbott Park, Illinois, July 5, 2006 - Abbott and AstraZeneca announced today a collaboration to co-develop and market a combination treatment that will target all three important blood lipids - LDL-C "bad" cholesterol, HDL-C "good" cholesterol, and triglycerides - in one single pill as part of a comprehensive treatment regimen. Under the agreement, the companies will initiate two parallel programs: a CRESTOR (rosuvastatin calcium)/TriCor (fenofibrate tablets) fixed-dose combination and a CRESTOR/ABT-335 combination. ABT-335 is Abbott's proprietary next-generation fenofibrate currently in Phase III clinical trials.
One of the two programs will be selected for final development and commercialization based upon data generated from the initial studies.
According to the American Heart Association (AHA), more than 38 million Americans have complex lipid disease and may benefit from this new combination. The cholesterol market is currently valued at $17 billion. Combination therapy makes up 15 percent and represents the fastest-growing segment of the overall cholesterol management market.
"Treatment guidelines emphasize the need to manage three important lipids by lowering bad cholesterol and triglycerides and raising good cholesterol. Increasing evidence shows that addressing these three key lipid targets helps to protect patients from heart disease," said Eugene Sun, M.D., vice president, Global Pharmaceutical Clinical Development, Abbott. "This collaboration has the potential to provide physicians and patients with the first statin and fibrate combination in a single pill to comprehensively manage lipids."
"We're excited by the opportunity this deal presents to serve an important area of patient need," said Tony Zook, executive vice president, North America, AstraZeneca. "This represents an important further step in broadening the full, long-term potential of CRESTOR for the treatment of lipid disorders."
TriCor and CRESTOR are both lipid-regulating agents available within the cholesterol management market. TriCor and ABT-335 are part of a class of medications called fibrates. TriCor has been shown to predominantly raise HDL-C and reduce triglycerides, a form of fat or lipid obtained through food sources. It also is effective at reducing elevated LDL-C. CRESTOR is part of a class of medications called statins, which have been shown to predominantly reduce LDL-C. This combination would potentially address LDL-C, HDL-C and triglycerides simultaneously with a combined fibrate and statin medication in a single pill, and is thus expected to lead to improved compliance and outcomes.
The overall intention of the agreement is for the two companies broadly to share development costs and profits over the duration of the collaboration. Abbott will execute the clinical trial program and be responsible for regulatory registration of the new combination therapy. AstraZeneca will hold the New Drug Application (NDA). Following successful completion of the clinical program, a regulatory application for the new combination therapy is targeted for submission in 2009.
"Rigorous clinical study of these two drugs in combination to document their safety and efficacy is important for patients and could produce an important new comprehensive lipid treatment tool for physicians," said Peter H. Jones, M.D., associate professor of medicine, Baylor College of Medicine, Houston.
Presently, health care professionals are advised to carefully weigh the risks and benefits of using fibrates and statin drugs in combination.
The effectiveness of the agreement is subject to satisfying certain conditions, including obtaining customary Hart-Scott-Rodino antitrust clearance.
Abbott is currently evaluating ABT-335 as a co-administered therapy with three other on-market statins, including CRESTOR.
Cardiovascular disease is the leading cause of death in the United States. More than 100 million Americans have dyslipidemia. More than 38 million American adults have LDL-C, HDL-C and triglycerides at levels that represent a major risk factor for coronary artery disease and stroke. Recently, treatment guidelines endorsed by the National Cholesterol Education Panel (NCEP), the American College of Cardiology (ACC), AHA and others have called for more aggressive treatment of lipids, including a lower LDL-C goal for many patients, as well as more aggressive treatment of HDL-C and triglycerides. In addition to healthy lifestyle changes, a certain percentage of patients will require more than one medication to meet these goals, which the proposed combination could address.
About Cholesterol and Triglycerides
Cholesterol is a natural, waxy, fat-like substance found in the body. There are two sources of cholesterol in the body. Some cholesterol is made in the liver, and the rest comes primarily from animal products that are eaten, such as meats, poultry and cheese.
Elevated cholesterol can lead to heart attacks and other cardiovascular-related problems. Unlike high LDL-C, which has been directly linked to increased heart disease risk, a high HDL-C level is considered "good" because HDL-C can often help reduce risk of heart disease. Triglycerides are another type of fat in the bloodstream. The NCEP guidelines say that elevated triglycerides also are an independent risk factor for heart disease.
CRESTOR (rosuvastatin calcium) is a once-daily, lipid-lowering agent prescription medication for use as an adjunct to diet in the treatment of various lipid disorders including primary hypercholesterolemia, mixed dyslipidemia and isolated hypertriglyceridemia. It is a member of the statin (HMG-CoA reductase inhibitors) class of drug therapy. CRESTOR has not been determined to prevent heart disease, heart attacks, or strokes. For patients with hypercholesterolemia and mixed dyslipidemia, the usual recommended starting dose of CRESTOR is 10 mg. However, initiation of therapy with 5 mg once daily should be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy, and for special populations such as patients taking cyclosporine, Asian patients, and patients with severe renal insufficiency. For patients with marked hypercholesterolemia (LDL-C>190 mg/dL) and aggressive lipid targets, a 20-mg starting dose may be considered. AstraZeneca licensed worldwide rights to CRESTOR from the Japanese pharmaceutical company Shionogi & Co., Ltd.
CRESTOR Important Safety Information
CRESTOR is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases, in women who are pregnant or may become pregnant, and in nursing mothers. It is recommended that liver function tests be performed before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically (e.g., semiannually) thereafter. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with CRESTOR and with other drugs in this class. The 40-mg dose of CRESTOR is reserved only for those patients who have not achieved their LDL-C goal utilizing the 20 mg dose of CRESTOR once daily. When initiating statin therapy or switching from another statin therapy, the appropriate CRESTOR starting dose should first be utilized, and only then titrated according to the patient's individualized goal of therapy. The benefit of further alterations in lipid levels by the combined use of rosuvastatin with fibrates or niacin should be carefully weighed against the potential risks of this combination. Combination therapy with rosuvastatin and gemfibrozil should generally be avoided. CRESTOR should be prescribed with caution in patients with predisposing factors for myopathy, such as renal impairment, advanced age, and inadequately treated hypothyroidism. Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. CRESTOR is generally well-tolerated. Adverse reactions have usually been mild and transient. The most frequent adverse events thought to be related to CRESTOR were myalgia (3.3 percent), constipation (1.4 percent), asthenia (1.3 percent), abdominal pain (1.3 percent) and nausea (1.3 percent). A full copy of the prescribing information for CRESTOR is available at www.astrazeneca-us.com/pi/CRESTOR.pdf, or by calling 1-877-420-7249.
TriCor (fenofibrate tablets) is a lipid-lowering agent used to treat abnormal lipid levels in the bloodstream, including cholesterol and triglycerides. TriCor is a once-daily treatment available in 145 mg and 48 mg tablets that can be taken with or without food.
TriCor, in addition to appropriate diet, is used to treat adults with high cholesterol, with or without elevated triglycerides (Fredrickson types IIa, IIb). TriCor reduces elevated LDL-C ("bad" cholesterol), total cholesterol, triglycerides and apolipoprotein B, and increases HDL-C ("good" cholesterol). The effect of TriCor on cardiovascular morbidity and mortality and noncardiovascular mortality has not been established. Abbott markets TriCor in the U.S. through an agreement with Solvay Pharmaceuticals. ABT-335 development is co-funded by Solvay Pharmaceuticals.
TriCor, in addition to appropriate diet, is also used to treat adults with high triglycerides (Fredrickson types IV and V). Excessive body weight, drinking alcohol, diseases such as diabetes and hypothyroidism, and various drugs can contribute to high triglyceride levels, and these should be assessed before a patient is prescribed TriCor tablets. TriCor should only be prescribed after reasonable attempts to modify lipid profile with diet modification, exercise and decreased alcohol consumption have failed. It is important for patients to stay on a diet restricted in saturated fat and cholesterol while taking TriCor.
TriCor Important Safety Information
TriCor tablets are not for everyone. TriCor should not be taken by people with serious liver, kidney or gallbladder disease, or by those who may be allergic or sensitive to the drug.
The combined use of TriCor and HMG-CoA reductase inhibitors (statins) has not been advised because of a potential for serious side effects that could lead to acute renal failure. The benefit of further alterations in lipid levels needs to be weighed against the increased risks of this drug combination.
TriCor tablets may cause changes in laboratory reports, especially in liver chemistry results. Regular periodic liver tests should be performed while patients are taking TriCor. Patients should contact their doctors if they feel pain in the stomach area while taking TriCor, as this can be a sign of gallstones or inflammation of the pancreas. TriCor may cause muscle pain or serious muscle disease, allergic-type reactions and possible changes in blood chemistry. If patients experience unexpected muscle pain, tenderness or weakness while taking TriCor, a health-care provider should be contacted immediately.
Patients should notify their doctor if they are taking any other drugs while taking TriCor including any other cholesterol-lowering medications. TriCor may have an effect on drugs that help prevent blood clotting, such as the blood thinner Coumadin (warfarin sodium tablets, USP), and doctors should monitor blood-clotting tests more frequently.
Patients should tell their doctors about any side effects they experience, including breathing problems, back pain and headaches.
For more information about TriCor (fenofibrate) tablets, including full prescribing information, please visit www.tricortablets.com.
Coumadin is a registered trademark of Bristol-Myers Squibb Company
Abbott is a global, broad-based health care company devoted to the discovery, development, manufacture and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs 65,000 people and markets its products in more than 130 countries.