Thursday, Aug 23, 2001
South San Francisco, Calif. -- August 23, 2001 --Genentech, Inc. (NYSE: DNA) today announced that heart attack patients who received a new investigational therapy regimen consisting of the single-bolus thrombolytic agent TNKase™ (Tenecteplase) and the low-molecular-weight heparin Lovenox® (enoxaparin sodium) Injection experienced improved clinical efficacy and safety benefits in the ASSENT 3 (ASsessment of the Safety and Efficacy of New Thrombolytic regimens) trial. The treatment regimen also yielded a very low 30-day mortality rate (5.35 percent), one of the lowest reported to date in a large-scale clinical trial of acute myocardial infarction (AMI). Results of the study are published in the August 25 issue of The Lancet.
ASSENT 3 enrolled 6,095 heart attack patients at more than 500 sites worldwide. Patients were randomized to receive one of three treatment regimens within six hours of the onset of symptoms. Treatment arms included full-dose TNKase plus Lovenox (Group A, 2,040 patients); half-dose TNKase plus unfractionated heparin (UFH) in combination with a 12-hour infusion of the glycoprotein IIb/IIIa inhibitor ReoPro® (abciximab) (Group B, 2,017 patients); and full-dose TNKase plus UFH (Group C, 2,038 patients). The trial was the largest to study therapy regimens for heart attack patients basing heparin and low-molecular-weight heparin dosing on the latest American College of Cardiology/American Heart Association guidelines.
ASSENT 3 was a descriptive study with two main, pre-specified composite endpoints: a composite efficacy endpoint to evaluate efficacy outcomes, and an "efficacy plus safety" composite endpoint to evaluate efficacy improvements when safety adverse events were added to the analysis. The pre-specified efficacy composite endpoint was measured as a composite of: reduction of 30-day mortality, in-hospital reinfarction or in-hospital ischemia. The "efficacy plus safety" composite endpoint combined the above-stated efficacy endpoint with reduction of safety adverse events including in-hospital intracranial hemorrhage (ICH) or in-hospital major bleeding complications (other than ICH).
"Taking into account efficacy and safety, full-dose Tenecteplase with enoxaparin emerged as the most promising reperfusion therapy regimen in this trial," said ASSENT 3 principal investigator Frans J. Van de Werf, MD, chairman, department of cardiology, University Hospital Gasthuisberg, Leuven, Belgium. "This easy-to-administer therapy regimen lowered event rates, and exhibited an improved safety profile."
TNKase is the only available thrombolytic that is administered as a single bolus over five seconds in a dose based on the patient's weight. In ASSENT 3, Lovenox was administered as an initial intravenous bolus followed by twice-daily subcutaneous injections until discharge or revascularization for a maximum of seven days. Unlike unfractionated heparin, Lovenox does not require ongoing blood test monitoring for degree of anticoagulation.
Key Findings of ASSENT 3
As reported in the Lancet, both experimental Group A (Tenecteplase plus enoxaparin) and Group B (half-dose Tenecteplase plus UFH plus abciximab) yielded a reduction in events compared to Group C (Tenectepase plus UFH) for the pre-specified efficacy endpoint of reduction in the composite of 30-day mortality, in-hospital reinfarction or in-hospital ischemia. Group A demonstrated a rate of these events of 11.44 percent; Group B, 11.06 percent; and Group C, 15.41 percent.
While both Groups A and B improved the efficacy composite endpoint compared to Group C, only the Tenecteplase plus enoxaparin arm (Group A) maintained this benefit when safety adverse events were added to the analysis. Group A demonstrated the best results in reduction of events associated with the "efficacy plus safety" composite endpoint, including 30-day mortality, in-hospital reinfarction or in-hospital ischemia, and reduction in in-hospital ICH or major bleeding complications.
While Group B (Tenectepase plus UFH plus abciximab) did demonstrate an improvement in efficacy over Group C, Group B was associated with an increase in major bleeding complications including non-cerebral bleeding, need for transfusions and the occurrence of thrombocytopenia (bleeding disorder due to low platelet count), particularly in patients with diabetes or age 75 or older, compared to Group A and Group C. Thus, as reported in the Lancet, Group A showed the best results in the "efficacy plus safety" analysis, with an event rate of 13.75 percent compared with Group B (14.24 percent) and Group C (17.04 percent).
Generally similar across all three groups, the mortality rate, evaluated as part of the combined efficacy plus safety endpoint, was lowest in Group A, the full-dose TNKase plus Lovenox therapy regimen, at 5.35 percent, compared to half-dose TNKase plus reduced-dose UFH and abciximab (Group B) at 6.59 percent and full-dose TNKase plus weight-adjusted UFH (Group C) at 5.99 percent. The differences were not statistically significant.
"The clinical benefit of enoxaparin with tenecteplase is consistent with the benefit of enoxaparin in unstable angina, providing further confidence that this simple, easy-to-administer combination is an excellent regimen for acute myocardial infarction," said U.S. lead investigator Christopher Granger, MD, FACC, associate professor of medicine at Duke University Medical Center and co-director of cardiology clinical trials at the Duke Clinical Research Institute in Durham, N.C.
All reperfusion therapies are associated with risk, such as increased risk of bleeding, intracranial bleeding and stroke. In the ASSENT 3 trial, total stroke and intracranial hemorrhage rates were similar across all three groups (Stroke: Group A, 1.62 percent; Group B, 1.49 percent; Group C, 1.52 percent. ICH: Group A, 0.88 percent; Group B, 0.94 percent; Group C, 0.93 percent.)
TNKase is marketed in Europe and abroad by Boehringer Ingelheim as Metalyse?. Lovenox is marketed abroad by Aventis as Clexane?. ASSENT 3 was jointly sponsored by Aventis Pharma AG (maker of Clexane/Lovenox), Boehringer Ingelheim (marketer of Metalyse in Europe and other regions) and Genentech, Inc. (developer and marketer of TNKase in the United States). Results from ASSENT 3 will be presented on September 2, 2001, at the XXIII Congress of the European Society of Cardiology in Stockholm, Sweden.
About Heart Attack
According to the World Health Organization, cardiovascular diseases account for 12 million deaths in the world each year. Currently, heart attack is a leading killer of men and women in developed countries. It is projected that by 2010, heart disease will be the number-one cause of death in developing countries. This year, as many as 1.1 million people in the United States will have a coronary attack (includes heart attack and fatal coronary disease), and 4 million people throughout Europe will die of cardiovascular disease.
In the last decade, thrombolytic therapy has emerged as the standard of care for the pharmacological management of AMI. To continue to build upon the success of these products in improving treatment outcomes, cardiologists now are investigating various combinations of thrombolytics with other pharmacological agents used in the armamentarium against ischemic heart disease. The quest for this combination, or "optimal AMI cocktail," has led researchers to combine multiple therapies, such as thrombolytics, antithrombotics and antiplatelet agents, in an attempt to maximize artery-opening patency and improve patient outcomes.
For TNKase full prescribing information in the U.S., please call Genentech's medical information number at 1 (800) 821-8590 or contact the company at http://www.gene.com.
All thrombolytic agents increase the risk of bleeding, including intracranial bleeding, and should be used only in eligible patients. In addition, thrombolytic therapy increases the risk of stroke, including hemorrhagic stroke, particularly in elderly patients.
Genentech, Inc., is a leading biotechnology company that discovers, develops, manufactures and markets human pharmaceuticals for significant unmet medical needs. Fourteen of the currently approved biotechnology products stem from or are based on Genentech science. Genentech markets nine biotechnology products directly in the United States. The company has headquarters in South San Francisco, California, and is traded on the New York Stock Exchange under the symbol DNA.
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