SNY » Topics » Plavix / Iscover

This excerpt taken from the SNY 20-F filed Mar 4, 2009.

Plavix® / Iscover®

 

Plavix® (clopidogrel bisulfate), a platelet adenosine diphosphate (ADP) receptor antagonist with a rapid onset of action that selectively inhibits platelet aggregation induced by ADP, is indicated for long-term prevention of atherothrombotic events in patients with a history of recent myocardial infarction, recent ischemic stroke or established peripheral arterial disease. Plavix® is currently the only drug indicated for the secondary prevention of atherothrombosis regardless of the location of the arteries initially affected (heart, brain, lower limbs). This indication is supported by the results of the landmark CAPRIE trial, including almost 20,000 patients. CAPRIE demonstrated the superior efficacy of Plavix® over acetylsalicylic acid (ASA, the active ingredient of Aspirin®), with a comparable safety profile.

 

Following the significant results of the CURE, CLARITY and COMMIT clinical trials, Plavix® is now also indicated for the treatment of acute coronary syndrome with and without ST segment elevation (ACS; Q-wave and non-Q-wave myocardial infarction and unstable angina) in combination with ASA. These indications are incorporated into the guidelines of the American Heart Association, the American College of Cardiology and the European Society of Cardiology.

 

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In addition to the 75mg tablet, a new Plavix® 300mg tablet was launched in over 15 countries during 2008. This new 300mg tablet reinforces Plavix® early use by simplifying its approved loading dose administration in patients with acute coronary syndrome (unstable angina, myocardial infraction). The 300mg tablet is bioequivalent to four 75 mg tablets of Plavix®.

 

The extensive clinical program for Plavix® including all completed, ongoing and planned studies, is one of the largest of its kind and has involved more than 100,000 patients overall. In addition, over 92 million patients worldwide are estimated to have been treated with Plavix® since its launch, providing significant evidence of real-life efficacy and safety experience with this product.

 

The ongoing clinical trials that are designed to support the long-term value of Plavix® by providing complementary clinical data include:

 

 

 

The ACTIVE study, which is intended to assess the value of Plavix® on top of ASA compared with ASA alone in patients with atrial fibrillation (who cannot take an oral anticoagulant) for the reduction of cardio-embolic and atherothrombotic events. This study has completed recruitment (14,000 patients included, currently in the follow-up phase). While one arm of the study — ACTIVE-W — was terminated early, the other two arms, ACTIVE-A and ACTIVE-I, are ongoing. The results of both ACTIVE-A and ACTIVE-I are expected in 2009;

 

   

The CURRENT study, which aims to optimize the dosing regimen of clopidogrel bisulfate in 25,000 patients with ACS scheduled for percutaneous coronary intervention. A loading dose of 600 mg followed by 150 mg daily for 6 days then followed by 75 mg daily up to the end of the study (30 days) is compared to the currently approved regimen (300 mg loading dose followed by 75 mg daily). The recruitment started in 2006 and results are expected in 2009; and

 

 

 

Following an FDA written request for pediatric data, the development of a pediatric indication for Plavix® in the United States is ongoing. The dose ranging Phase II (PICOLO study) has helped determine the right dose to be studied in Phase III (CLARINET). CLARINET is ongoing and results are expected in 2010. A pediatric investigational plan was approved in 2008 by the European Medicines Agency.

 

Plavix® is marketed in over 115 countries, including the United States, through our alliance with Bristol-Myers Squibb (BMS).

 

Sales of Plavix® in Japan are consolidated by sanofi-aventis and are outside the scope of our alliance with BMS. In Japan, a New Drug Application (NDA) for marketing authorization was approved in January 2006 for the reduction of recurrence after ischemic cerebrovascular disorder and launch took place in May 2006. In October 2007, the Japanese Health Authorities approved a new indication in cardiology for patients with Acute Coronary Syndrome for whom percutaneous coronary intervention is being planned.

 

Plavix® is the leading antiplatelet in the European and the U.S. markets (source: IMS 2008 sales, all available channels). Germany has been affected by competition from clopidogrel besylates since August 2008 in the monotherapy segment. The share of the German market by volume retained by Plavix®/Iscover® in December 2008 remains approximately 75% (source: IMS Pharmatrend, week of December 22, 2008).

 

This excerpt taken from the SNY 20-F filed Mar 7, 2008.

Plavix® / Iscover®

 

Plavix® (clopidogrel bisulfate), a platelet adenosine diphosphate (ADP) receptor antagonist with a rapid onset of action that selectively inhibits platelet aggregation induced by ADP, is indicated for long-term prevention of atherothrombotic events in patients with a history of recent myocardial infarction, recent ischemic stroke or established peripheral arterial disease. Plavix® is currently the only drug indicated for the secondary prevention of atherothrombosis regardless of the location of the arteries initially affected (heart, brain, lower limbs). This indication is supported by the results of the landmark CAPRIE trial, including almost 20,000 patients. CAPRIE demonstrated the superior efficacy of Plavix® over acetylsalicylic acid (ASA, the active ingredient of Aspirin®), with a comparable safety profile.

 

Plavix® was launched in 1998, and is now marketed in over 80 countries, including the United States, through our alliance with Bristol-Myers Squibb (BMS). In Japan a New Drug Application (NDA) for marketing authorization was approved in January 2006 and launch took place in May 2006. In October 2007 the Japanese Health Authorities approved a new indication in cardiology for patients with Acute Coronary Syndrome for whom percutaneous coronary intervention is being planned. Sales of Plavix® in Japan are consolidated by sanofi-aventis and are outside the scope of our alliance with BMS.

 

Since 2002, Plavix® has also been indicated for the treatment of non ST segment elevation acute coronary syndrome (ACS; non-Q-wave myocardial infarction and unstable angina) in combination with ASA following the very significant results of the CURE trial. This indication was rapidly incorporated into the guidelines of the American Heart Association, the American College of Cardiology and the European Society of Cardiology. The CURE trial demonstrated that Plavix® provided significant early- and long-term benefits in patients with Non ST segment elevation Acute Coronary Syndrome (ACS). Plavix® reduced the relative risk of atherothrombotic events (myocardial infarction, stroke and death from a cardiovascular cause) by 20% when added to standard therapy including ASA, with a 1% increase in the rate of major bleeding. With more than 12,000 patients enrolled, CURE is the largest clinical trial ever conducted in patients presenting unstable angina or non-Q-wave myocardial infarction. Based on its broad clinical evidence base in this population, Plavix® has gained the highest grade of recommendation in recent guidelines issued by medical societies for the management of ACS and percutaneous coronary intervention (PCI).

 

Also in the cardiology field, the results of the CLARITY and COMMIT clinical trials have led to the approval of a new indication in ST-segment elevation ACS (Q-wave myocardial infarction). This approval was granted by the U.S. Food and Drug Administration (FDA) in August 2006 and by the European Medicines Agency (EMEA) in September 2006.

 

The CLARITY trial, which enrolled nearly 3,500 patients, demonstrated that Plavix®, added to standard therapy including fibrinolytics and ASA, significantly reduced the odds of acute myocardial infarction patients having another occluded artery, a second heart attack or dying after one week of hospitalization, as well as the odds of clinical events such as cardiovascular death, recurrent myocardial infarction and certain recurrent ischemias at 30 days.

 

The COMMIT trial, which enrolled nearly 46,000 patients, demonstrated that Plavix®, added to standard therapy including ASA, significantly reduced mortality in acute myocardial infarction patients at day 28 in an in-hospital setting.

 

The indications resulting from the results of the CURE, CLARITY and COMMIT trials make Plavix® a cornerstone therapy in management of ACS patients.

 

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Other studies have also further explored the role of clopidogrel bisulfate in various patients’ profiles (mostly atherothrombotic patients):

 

 

 

The results of the CREDO clinical trial, published in November 2002, confirmed the therapeutic value of Plavix® in the early- and long-term prevention of atherothrombotic events in patients having undergone coronary angioplasty, either with or without stenting. The CREDO trial, conducted in over 2,000 patients, demonstrated the efficacy of Plavix®, which reduces the relative risk of atherothrombotic events by 27% after one year;

 

 

 

The MATCH trial results released in May 2004 showed that ASA did not provide additional clinical value (benefit/risk ratio) in specific patients who have recently experienced a stroke or transient ischemic attack when added to Plavix® and other standard therapies.

 

The results of the CHARISMA trial were released at the 55th Annual Scientific Session of the American College of Cardiology in March 2006. The CHARISMA trial enrolled over 15,600 patients and aimed to demonstrate the clinical value of Plavix® on top of standard therapy including ASA in patients at high risk of future cardiovascular events. The study findings did not demonstrate an improvement of the risk/benefit ratio but significant differences by sub-group:

 

 

 

on the one hand, in patients with established atherothrombotic diseases (also referred to as secondary prevention), clopidogrel bisulfate in addition to ASA reduced the relative risk of recurrent heart attack, stroke or cardiovascular death by a statistically significant 12.5%, compared to patients receiving placebo and ASA. These patients accounted for almost 80% of the total CHARISMA study population;

 

 

 

on the other hand, patients with multiple risk factors but no clearly established vascular disease did not benefit from the addition of clopidogrel bisulfate to ASA, with a 20% relative risk increase. These patients represented approximately 20% of the overall study population. In this patient subgroup, there was an excess in cardiovascular mortality as well as a non-statistically significant increase in bleeding observed in patients treated with clopidogrel bisulfate and ASA.

 

Other planned or ongoing clinical trials that are designed to support the long-term value of Plavix® by providing complementary clinical data include:

 

 

 

ACTIVE, which is intended to assess the value of Plavix® in patients with atrial fibrillation for the prophylaxis of cardio-embolic events. This study has completed recruitment (14,000 patients included, currently in the follow-up phase). While one arm of the study — ACTIVE-W — was terminated early, the other two arms, ACTIVE-A and ACTIVE-I, are ongoing. Results are expected in the third quarter of 2008;

 

   

the CURRENT study aims to optimize the dosing regimen of clopidogrel bisulfate in 12,000 patients with non ST elevation ACS, and planned to receive a stent. A loading dose of 600 mg followed by 150 mg daily for two weeks then followed by 75 mg daily is compared to the currently approved regimen (300 mg loading dose followed by 75 mg daily). The recruitment started in 2006 and results are expected in the fourth quarter of 2008.

 

Since 2003, following an FDA written request for pediatric data, the development of a pediatric indication for Plavix® in the United States is ongoing. The dose ranging Phase II (PICOLO study) has helped determine the right dose to be studied in Phase III (CLARINET).

 

In addition to randomized controlled trials, one of the largest observational studies was initiated in 2003 to evaluate the real-life risk of patients with atherothrombosis. This registry, called REACH (Reduction of Atherothrombosis for Continued Health) includes 63,000 patients in more than 44 countries. The one-year results published in the landmark journal JAMA show a considerable rate of events, although in a population receiving the contemporary standard of care. This illustrates the high burden of atherothrombotic disease and the need to evolve pharmacological management more aggressively.

 

In the United States, the FDA approved a new dosage in October 2007: the 300 mg tablet, indicated in the setting of the loading dose for patients with Acute Coronary Syndromes.

 

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The extensive clinical program for Plavix®, including all completed, ongoing and planned studies, is one of the largest of its kind and will enroll more than 100,000 patients overall. In addition, over 70 million patients worldwide are estimated to have been treated with Plavix® since its launch, providing significant evidence of real-life efficacy and safety experience with this product.

 

Plavix® sales in the United States were negatively impacted in 2006 and early 2007 following the launch of an at-risk generic of 75-mg clopidogrel bisulfate in August 2006. In June 2007, the U.S. District Court for the Southern District of New-York confirmed the validity of the Plavix® patent in the United States and forbade the generic company from marketing generic clopidogrel bisulfate in the United States until the patent expires in 2011. The generic company appealed this decision to the Court of Appeals for the Federal Circuit, and oral argument took place March 3, 2008. See Note D.22 to our consolidated financial statements at Item 18.

 

Plavix® remains the leading product in the European and the U.S. markets for anti-platelet agents (source: IMS/GERS for France, 2007 sales, all available channels).

 

EXCERPTS ON THIS PAGE:

20-F
Mar 4, 2009
20-F
Mar 7, 2008

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