BOEHRINGER INGELHEIM PHARMA GMBH & CO KG
Boehringer Ingelheim’s investigational clot-dissolving agent, known as TNK-t-PA, has been found therapeutically equivalent to Actilyse® (rt-PA; alteplase), the current gold-standard thrombolytic, which is also marketed by Boehringer Ingelheim. The new clot-dissolving agent was bio-engineered by Genentech, Inc., and was co-developed by Boehringer Ingelheim and Genentech.
The therapeutic equivalence of the two agents for the treatment of heart attack was the principal finding of an international, 17,000-patient clinical trial (ASsessment of the Safety and Efficacy of a New Thrombolytic agent, or ASSENT II). The study results were revealed today at the American College of Cardiology congress being held in the United States. The announcement comes only 17 months after the clinical study was initiated with the inclusion of the first patient, in October 1997. Including an extensive phase II program, more than 21,000 patients have been involved in the clinical trials of TNK-t-PA.
The 30-day post-treatment mortality with both TNK-t-PA and Actilyse® was 6.2% in the intention-to-treat analysis. This result shows a clear equivalence between the two treatments, according to the stringent criteria for equivalence employed in the trial. Further, this mortality is quite low, echoing the 6.3% absolute death rate seen in GUSTO I, the trial that established Actilyse® as the gold-standard thrombolytic.
ASSENT II also showed equivalent rates of intracranial haemorrhage (0.93% with TNK-t-PA; 0.94% for Actilyse® ) and total stroke (1.78% with TNK-t-PA; 1.66% with Actilyse® ). In addition, the risk of serious bleeding requiring transfusion was statistically significantly lower with TNK-t-PA (4.3%) versus Actilyse®(5.5%).
"What these findings mean is that the two drugs are virtually identical for mortality reduction, while TNK-t-PA has the added advantage of being given as a single bolus, rather than as an intravenous infusion," according to study chairman Frans Van de Werf, Professor of Medicine, University of Leuven, and Chairman, Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium.
Boehringer Ingelheim expects to apply for product registration of TNK-t-PA, under the name Metalyse® , in Europe and other geographic areas. (The drug will also be known internationally by the generic name tenecteplase, pending approval by the WHO.) At the same time, registration in the United States will be sought by Boehringer Ingelheim’s long-time international marketing and clinical development partner, Genentech, Inc. The two companies co-sponsored ASSENT II.
"The message of this trial, both for patients and physicians, is that the new thrombolytic, TNK-t-PA, is just as effective as Actilyse®, but with fewer bleeding complications, and the additional advantage of simple, fast administration," Prof. Van de Werf said. "Ultimately, this may lead to saving more lives by reducing time to treatment, and facilitating pre-hospital treatment."
Detailed trial results will be presented at the European Society of Cardiology congress to be held in Barcelona at the end of August. The new data will extend, but not alter, the primary finding of TNK-t-PA’s equivalence to Actilyse® .
"We are gratified by the results of this trial, which show that TNK-t-PA is an important new option for cardiologists," said Prof. Rolf Krebs, Vice Chairman of the Board and responsible for the Division Pharma at Boehringer Ingelheim. "The development of TNK-t-PA builds upon the experience of Boehringer Ingelheim as a leader in the treatment of acute myocardial infarction."
There are several important differences between Actilyse® (a recombinant form of the body’s natural molecule) and TNK-t-PA (a bioengineered variant): 1) Actilyse® must be given via infusion over 90 minutes, while TNK-t-PA is given as a single, rapid bolus; 2) TNK-t-PA has been designed to be more specific than Actilyse® for fibrin (a key component of intra-coronary clots), and to have a minimal impact on the body’s coagulation system, which may account for the observed reduction in the overall bleeding rate; 3) TNK-t-PA has been modified to resist the effect of.
PAI-1, a natural substance that can inhibit the clot-dissolving action of Actilyse® ; and 4) TNK-t-PA is given in a more individualized weight-adjusted fashion, which means that each patient receives the right amount of drug substance according to body weight.
The importance of a more individualized weight-adjustment strategy emerged from phase II clinical trials with TNK-t-PA, which were carried out in more than four thousand patients, many hundreds more patients than a Phase II usually enrolls. Thus, the investigators were able to proceed to the phase III trial with the assurance that the selected dose would be optimal, based on broad patient experience and taking both efficacy and safety into account.
To date, TNK-t-PA has been administered to more than 12,000 patients worldwide, including the more than 8,400 patients who received the drug in ASSENT II, a randomized, double-blind trial, carried out at more than 1,000 sites in 29 countries.
Boehringer Ingelheim, headquartered in Ingelheim, Germany, and Genentech have actively collaborated since 1984 on the clinical development and marketing of rt-PA and TNK-t-PA.
Genentech, Inc., South San Francisco, California, is a leading biotechnology company that discovers, develops, manufactures, and markets human pharmaceuticals for significant unmet medical needs.
Boehringer Ingelheim ranks among the top 20 pharmaceutical companies in the world. It generated revenues exceeding DM 8 billion in 1998. The corporation has some 160 affiliated companies and it conducts business on every continent. Its product range is focused on human pharmaceuticals – hospital, prescription, and self-medication – as well as animal health.
Facts about Actilyse® and TNK-t-PA Actilyse® , on the market since 1987, revolutionized the treatment of heart attack. Actilyse® was recognized as the gold-standard thrombolytic agent in 1993, as a result of the GUSTO I trial findings, in which the 35-day mortality rate with Actilyse® was an absolute 1% lower than the death rate with the older drug streptokinase (a relative risk reduction of 14%).
TNK-t-PA is the only thrombolytic agent ever found equivalent to Actilyse® in terms of mortality reduction and intracranial haemorrhage.
No thrombolytic agent has ever been found superior to Actilyse® .
Actilyse® is marketed for the treatment of heart attack and pulmonary embolism. Registration for the treatment of acute stroke has been applied for in Europe.