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Early-Phase Data Show Prasugrel Demonstrates More Consistent Platelet Inhibition Compared to Clopidogrel

Posted on: Monday, 17 October 2005, 09:00 CDT

INDIANAPOLIS, Ind., and TOKYO, Japan, Oct. 17 /PRNewswire-FirstCall/ -- Eli Lilly and Company and Sankyo Co., Ltd. announced today data results from three early-phase, cross-over studies demonstrating that all subjects responded to prasugrel, an investigational antiplatelet agent, while 22 to 43 percent of the same subjects did not respond to clopidogrel (Plavix(R)), as measured by objectively defined parameters for inhibition of platelet aggregation. The data were presented at the Cardiovascular Research Foundation's (CRF) 17th Annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium, in Washington, D.C.

"We are very encouraged by the consistent response rate seen with prasugrel across these three studies," said Govinda Weerakkody, Ph.D., Principal Research Scientist at Eli Lilly and Company. "We are studying whether more reliable inhibition of platelet aggregation could have an important effect on patient outcomes." Eli Lilly and Sankyo Co., Ltd. are developing prasugrel as a potential treatment for patients who have suffered a heart attack or unstable angina (heart-related chest pain).

Antiplatelet agents are used both acutely and as maintenance therapy to inhibit platelet activation and aggregation that occurs in diseased arteries and in response to invasive procedures such as percutaneous coronary intervention (PCI), a procedure to open blockages in heart arteries, and includes the use of coronary stents. Antiplatelet agents prevent platelets from clumping or sticking together, which can cause formation of blood clots and lead to heart attack or stroke. Recent studies suggest that a relationship may exist between a poor platelet response to antiplatelet agents in individual patients and poor clinical outcomes, which manifest as major adverse cardiovascular events, including heart attacks.(1,2,3)

About the Data

The pooled analysis, "Clopidogrel Nonresponders: A Comparison With Prasugrel (CS-747, LY640315), a Novel Thienopyridine P2Y12 Receptor Antagonist," is based on the results of three, single-center, two-way cross- over clinical pharmacology studies.(4,5,6) One hundred and twelve healthy volunteers aged 18-65 years old were randomized to receive either a 60 mg loading dose of prasugrel or the approved 300 mg loading dose of clopidogrel in a 2-way cross-over design. Adenosine diphosphate (ADP) was used to induce platelet aggregation in samples of subjects' blood. Inhibition of platelet aggregation (IPA) and the change in maximum platelet aggregation (MPA) from baseline were evaluated at both 4-5 and 24 hours after the medication was administered.

Nonresponders were objectively defined as subjects achieving less than 25 percent IPA or a difference of less than 20 percent in MPA in response to 5 micromolar adenosine diphosphate (ADP), and less than 20 percent IPA or a difference of less than 15 percent in MPA in response to 20 micromolar ADP. These thresholds represent levels of platelet inhibition that are more consistent with a placebo than that of an active antiplatelet agent.

All subjects responded effectively to a loading dose of prasugrel 60 mg. However, when the same subjects were administered 300 mg of clopidogrel, 22 percent were nonresponders based on IPA in response to 5 micromolar ADP (p < .001) and 43 percent were nonresponders based on IPA in response to 20 micromolar ADP (p < .001).

Current Clinical Research with Prasugrel

A Phase III clinical study with prasugrel -- TRITON-TIMI 38 -- is under way. This head-to-head study will compare the effects of prasugrel with clopidogrel in up to 13,000 patients with acute coronary syndrome who suffer a heart attack or have unstable angina and are to undergo PCI. The primary focus of the study is to compare the two agents' ability to prevent heart attack, stroke and death in patients who undergo PCI. The secondary focus is to look at the impact on bleeding, hospitalization for recurrent heart-related chest pain (ischemia) or the need for additional procedures to restore blood flow (urgent target revascularization). It is anticipated that the TRITON TIMI-38 study should be completed in early 2007 with regulatory submissions to follow in the second half of 2007.

"Early studies have revealed the promise of prasugrel as an antiplatelet therapy," said Jeffrey Warmke, Ph.D., Sankyo's Senior Director of Global Project Management. "We look forward to receiving the results of the current Phase III trial to determine whether prasugrel provides additional clinical benefits for patients with acute coronary syndrome."

Cardiovascular disease is the leading cause of death in the U.S. and worldwide, killing 17 million people each year.(7) Acute heart attacks and unstable angina, called acute coronary syndrome (ACS), affect more than 942,000 Americans each year. Despite current medical interventions, 300,000 people experience recurrent heart attacks and 500,000 people die from heart attacks annually in the U.S.(8)

About Prasugrel

Prasugrel is an investigational antiplatelet agent designed to prevent platelet activation and aggregation by blocking adenosine diphosphate receptors on the platelet surface. This novel oral compound was discovered by Sankyo and Ube Industries, Ltd. . It is being investigated as a potential treatment for higher risk patients with acute coronary syndrome who undergo percutaneous coronary intervention (PCI).

About Lilly

Lilly, a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers -- through medicines and information -- for some of the world's most urgent medical needs. Building on the strong foundation of ReoPro, Lilly is in the process of building a robust cardiovascular pipeline. Lilly has multiple cardiovascular drugs in that pipeline -- in every stage from pre-clinical and Phase I to the Phase III trials for prasugrel.

Additional information is available at http://www.lilly.com/ . P-LLY About Sankyo

Sankyo Co., Ltd. of Tokyo, one of Japan's largest pharmaceutical companies, has a long history of discovering new classes of drugs, including the statin class of lipid-lowering drugs. Beginning with the discovery of the first statin, mevastatin, and the co-discovery of lovastatin, the first statin to be marketed, Sankyo has been a pioneer in the cardiovascular disease arena. Additionally, Sankyo discovered, developed, manufactures and markets pravastatin sodium and olmesartan medoxomil, an angiotensin II receptor blocker (ARB). Sankyo Co., Ltd. and Daiichi Pharmaceutical Co., Ltd., recently announced the integration of the organizations, creating the second- largest drug company in Japan. For further information about Sankyo and its products, log on to http://www.sankyo.co.jp/english/ .

This press release contains certain forward-looking statements about the potential of the investigational compound prasugrel (CS-747, LY640315) and reflects Lilly's current beliefs. However, as with any pharmaceutical product under development, there are substantial risks and uncertainties in the process of development and regulatory review. There is no guarantee that the product will receive regulatory approvals, or that the regulatory approval will be for the indication(s) anticipated by the company. There is also no guarantee that the product will prove to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filing with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

Plavix(R) is a registered trademark of Sanofi-Synthelabo Inc.

(1) Barragan, P., Bouvier, J. L., Roquebert, P. O., Macaluso, G., Commeau, P., Comet, B., Lafont, A., Camoin, L., Walter, U., and Eigenthaler, M. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003; 59: 295-302

(2) Muller, I., Besta, F., Schulz, C., Massberg, S., Schonig, A., and Gawaz, M. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783-787

(3) Matetzky, S., Shenkman, B., Guetta, V., Shechter, M., Bienart, R., Goldenberg, I., Novikov, I., Pres, H., Savion, N., Varon, D., and Hod, H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.

(4) A Comparison of Prasugrel (CS-747, LY640315) With Clopidogrel on Platelet Function in Healthy Male Volunteers; Fumitoshi Asai, Joseph A. Jakubowski et al. Presented at American College of Cardiology March 9, 2005

(5) Inhibition of Platelet Aggregation With Prasugrel (CS-747, LY640315), A Novel Thienopyridine P2Y12 Receptor Antagonist, Compared With Clopidogrel in Aspirin-Treated Patients With Atherosclerotic Vascular Disease; Lars Wallentin, John T. Brandt et al. Presented at American College of Cardiology March 8, 2005.

(6) Superior Responder Rate for Inhibition of Platelet Aggregation With a 60 mg Loading Dose of Prasugrel (CS-747, LY640315) Compared With a 300 mg Loading Dose of Clopidogrel; John T. Brandt, Christopher D. Payne et al, Presented at American College of Cardiology March 9, 2005.

(7) World Health Organization. The Atlas of Heart Disease and Stroke - Types of Cardiovascular Disease 2005.

(8) American Heart Association. Heart Disease and Stroke Statistics 2005. (Logo: http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGO http://www.newscom.com/cgi-bin/prnh/20040827/SANKYO )

Photo: NewsCom: http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGOhttp://www.newscom.com/cgi-bin/prnh/20040827/SANKYOPRN Photo Desk, photodesk@prnewswire.com

Eli Lilly and Company; Sankyo Co., Ltd.

CONTACT: Janice M. Chavers of Eli Lilly and Company, +1-317-651-6253(office), +1-888-422-3853 (pager); Jo-ann Straat of Sankyo (New Jersey),+1-973-359-2602 (office); or Shigemichi Kondo of Daiichi Sankyo (Tokyo),81-3-6225-1126 (office)

Source: PRNewswire-FirstCall

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