More New Clot Busters

Applied Genetics News, April, 1999

The 48th Annual Scientific Section of the American College of Cardiology in New Orleans heard reports on clinical trials of three new clot-busting drugs: lanoteplase--being developed by Bristol-Myers Squibb (345 Park Ave., New York, NY 10154; Tel: 212/546-4000, Fax: 212/546-4020. Contact: William Dunnet; Tel: 609/813-3016), tenecteplase--from Genentech, Inc.

(1 DNA Way South, San Francisco, CA 94080; Tel: 650/225-1000, Fax: 650/225- 8326. Contact: Paul Laland; Tel: 650/225-2742, Website: www.gene.com), and recombinant nematode anticoagulant protein c2 (RNAPc2)--from Corvas International, Inc. (3030 Science Park Rd., San Diego, CA 92121; Tel: 619/455-9800 or 619/455-7895, Website: www.corvas.com) Karl Ludwig Neuhaus, investigator from Stadtische Klinikan Eassel, Germany presented findings of the InTIME-II (the second trial of intravenous nPA for "Treatment of Infarcting Myocardium Early") trial of lanetoplase, or nPA, a novel plasminogen activator. This was phase-III double-blind, placebo-controlled, clinical trial involving 15,078 patients at 855 sites in 35 countries. Patients were administered with either a single bolus of lanetoplase (120,000 units/kg) or front-loaded alteplase (up to 100 mg). Patients were at least 18 years of age and exhibited symptoms and ECG changes suggested of heart attack. Patients were randomized to either lanetoplase or alteplase with six hours of onset. Patients at risk for bleeding were excluded. Results of the study showed that the 24 hour mortality was lower for lanoteplase than for alteplase (2.39% vs. 5.54%). The observed rate of recurrent heart attack was also lower (4.89% vs. 5.54%). The combined indices of death, heart attack, severe heart failure, and nonfatal stroke was also lower for lanoteplase than alteplase (12.84% vs. 13.28%). Preliminary data suggested promising trends at six months. However, lanoteplase showed a greater incidence of bleeding (1.13% vs. 0.62%) at 30 days. The two treatments had identical non-fatal stroke rates. "Compared to alteplase, after 30 days, lanoteplase demonstrated a reduction in cardiac mortality due to a lower rate of reinfarction, severe heart failure, heart block and the need for revascularization," notes Eugene Braunwald, chair of the InTIME-II operations committee and professor of medicine at Harvard Medical School, Boston, Massachusetts. Genentech reported positive results of a 17,000 patient, multi- center phase III comparing its new single bolus thrombolytic, tenecteplase, with the company's own Activase (recombinant alteplase). The results of the assessment of the safety and efficacy of a new thrombolytic agent trial (ASSENT 2) will be submitted as part of a biological licensing application to the FDA as well as to the European Regulatory Authority during the third quarter of 1999 for approval of tenecteplase for the treatment of acute myocardial infarction. Boehringer Ingelheim co-sponsored the ASSENT 2 study and is a developmental collaborator with Genentech for tenecteplase. Final analysis of trial results will be presented during the European Society of Cardiology meeting in August, 1999 in Barcelona. "The Assent 2 results demonstrate that tenecteplase may have great promise as a potential new weight-adjusted thrombolytic agent for treatment of heart attack patients, with the added convenience of single bolus administration," reports Arthur D. Levinson, president and CEO of Genentech. Corvas presented data on a phase I trial of RNAPc2. Originally discovered and isolated from blood-feeding hookworms, rNAPc2 is now manufactured as a recombinant protein and has progressed to phase II trials. The phase I trial involved three treatment groups of six subjects, with four receiving rNAPc2 and two receiving placebos. All subjects were healthy male volunteers. Results demonstrated that rNAPc2 produced a dose-dependent anticoagulant effect over the five-day treatment period and was safe and well tolerated. "The anticoagulant and pharmokinetic profile of RNAPc2 in this study was consistent with the results of the phase Ia trial and reinforced the conclusion that administration of rNAPc2 produces a long lasting, predictable anticoagulant effect in man." says George P. Vlasuk, executive vice president, research and development at Corvas. The company has initiated an open-label- multicenter, international phase II dose-ranging efficacy study of rNAPc2 for the prevention of deep vein thrombosis following orthopedic surgery.