By Chris Delporte
Genentech Inc. reported that trial results indicate a new drug cocktail using its TNKase (tenecteplase) has shown increased efficacy and safety as a clot buster in the treatment of acute myocardial infarction (AMI). The FDA originally approved TNKase in June of last year for the treatment of AMI.
TNKase, South San Francisco-based Genentech¿s single-bolus thrombolytic agent, was combined with the low-molecular-weight heparin Lovenox from Aventis Pharmaceuticals Inc., of Bridgewater, N.J., and with a 12-hour infusion of the glycoprotein IIb/IIIa inhibitor ReoPro from Centocor Inc., of Malvern, Pa. The ASSENT 3 (Assessment of the Safety and Efficacy of New Thrombolytic Regimens) trial enrolled 6,095 heart attack patients at more than 500 sites worldwide. Patients were randomized to receive one of three regimens within six hours of the onset of symptoms.
¿Essentially, in the treatment of heart attacks, there are a number of approved regimens and they all have their benefits and drawbacks,¿ Shelley Schneiderman, manager of corporate communications for Genentech, told BioWorld Today. ¿There is a new wave going on. Companies are saying, Let¿s look at all the approved regimens and see what¿s currently being treated and see what we can combine to bring about the best change. How can we find improvements with a combination of approved therapies?¿¿
Treatment arms of the study included full-dose TNKase plus Lovenox in Group A, with 2,040 patients. Group B, which included 2,017 patients, was comprised of half-dose TNKase plus unfractionated heparin (UFH) combined with ReoPro. Group C, with 2,038 patients, tested a full dose of TNKase, in addition to UFH. Genentech said that 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.
¿All these products are going to quickly dissolve clots that are causing the heart attack and restore blood flow,¿ Schneiderman said. ¿We want to look at whether or not we can improve efficacy, but not adversely impact safety.¿
ASSENT 3 was a descriptive study with two main, prespecified composite endpoints. The first was to evaluate efficacy. The second was an efficacy-plus-safety composite endpoint to evaluate efficacy improvements when adverse events were added to the analysis. The prespecified efficacy composite endpoint was measured as a composite of reduction of 30-day mortality, in-hospital reinfarction or in-hospital ischemia. The second endpoint combined those criteria, in addition to a reduction of adverse events, including in-hospital intracranial hemorrhage or in-hospital major bleeding complications.
Trial results indicated that Lovenox plus TNKase outperformed the other combinations in the study. According to Genentech, in addition to improved clinical efficacy and safety benefits, Lovenox plus TNKase yielded a low 30-day mortality rate of 5.35 percent, one of the lowest reported to date in a large trial. The other two test groups showed improvement in efficacy, but recorded an increase in major bleeding complications including non-cerebral bleeding, the need for transfusions and the occurrence of thrombocytopenia, a bleeding disorder due to low platelet count. All three groups, however, showed similar results in total stroke and intracranial hemorrhage rates. The company cautioned that all reperfusion therapies are associated with risk, such as risk of bleeding, intracranial bleeding and stroke.
¿Overall, we saw that there was a benefit to the combination therapy methodology,¿ Schneiderman said. ¿The Lovenox arm plus TNKase essentially performed in efficacy and was not associated with a decrease in safety. TNKase plus ReoPro improved efficacy, but at the expense of some safety side effects. Essentially what this means to the cardiology community is that there is a number of ongoing trials in the combination therapy field. And, right now, there are a number of things going on in practice that are off-label, where hospitals already are combining.¿
Schneiderman said that this was not designed as a label-enhancing trial. ¿We¿ve learned a lot from the trial information, and we currently are examining what we have in front of us,¿ she said. ¿We may ultimately approach the FDA and see if we can get some label additions. It¿s not in our immediate plans, but it certainly is in discussions.¿
Genentech has planned other analyses as part of this study, Schneiderman said. She pointed to a number of patient subgroups that have yet to be evaluated, including patients of different ages, patients with different co-morbid conditions, such as diabetes, and patients who, in addition to this group of therapies, may also have undergone angioplasty. ¿So our next approach is to look at all these subgroups and conduct analysis along those lines and see what we can best learn,¿ she said.
TNKase also is involved in other upcoming combination therapy trials with other available IIb/IIIa inhibitors. One trial is a collaboration between COR Therapeutics Inc., of South San Francisco; Schering-Plough Corp., of Madison, N.J.; and Genentech to study TNKase with Integrilin (eptifibatide) injection, an anti-platelet agent. Merck & Co. Inc., of Whitehouse Station, N.J., and Genentech will enroll approximately 800 patients and will examine TNKase at different dosing levels, all administered with Aggrastat (tirofiban HCI), Merck¿s anti-platelet agent, and heparin sodium. An additional arm of the trial will include TNKase with heparin. Aventis and Genentech have partnered for an additional trial involving varying dosing regimens of TNKase, Lovenox, ReoPro and heparin sodium.
Genentech¿s stock (NYSE: DNA) fell $1.60 on Friday to close at $46.50. The stock had gained $4.10 Thursday.