Boehringer Ingelheim’s Dabigatran Demonstrates Non-Inferiority To Lovenox
This article was originally published in The Pink Sheet Daily
Executive Summary
The drug maker is in discussions with U.S. regulators regarding submission for venous thromboembolism, but has not released a filing timeline.
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Boehringer Ingelheim released positive Phase III results comparing its investigational oral direct thrombin inhibitor dabigatran to Sanofi-Aventis' Lovenox (enoxaparin) for the prevention of venous thromboembolism during the International Society on Thrombosis and Haemostasis Congress in Geneva July 11. Results of RE-NOVATE demonstrated that oral dabigatran once daily, administered for an average of 33 days, was non-inferior to Lovenox, also administered for an average of 33 days, in preventing VTE and all cause mortality after total hip replacement surgery, the firm reported. The German drug maker told "The Pink Sheet" DAILY that it is in discussions with regulators in the U.S. regarding a potential filing for dabigatran, but has not released a timeline for the submission. In Europe, the drug has already been submitted to regulators for an initial, unidentified indication. RE-NOVATE is part of an extensive clinical trial program investigating the anti-coagulant. Other studies include RE-MODEL in VTE after knee replacement surgery in 2,000 patients; RE-MOBILIZE studying VTE after knee replacement surgery in more than 2,600 patients in North America; and RE-LY evaluating stroke prevention in atrial fibrillation in 15,000 patients. Other studies include RE-COVER and RE-MEDY investigating the drug for acute treatment and secondary prevention of VTE. In RE-NOVATE, 3,494 patients undergoing total hip replacement surgery in the European Union, South Africa and Australia were randomized to receive either oral dabigatran 150 mg or 220 mg once daily (half dose given on day of surgery, one to four hours post operatively) or Lovenox 40 mg once daily by subcutaneous injection starting 12 hours before surgery. Results showed that both oral doses of dabigatran were non-inferior to injected enoxaparin at reducing the risk of thromboembolic disease after primary elective total hip replacement surgery. The incidences for the primary efficacy composite endpoint of total VTE and all-cause mortality were 6 percent for the 220 mg dose and 8.6 percent for the 150 mg dose of dabigatran, compared to 6.7 percent for Lovenox. "The incidences of total VTE and all-cause mortality in both dabigatran dose groups were within the pre-specified non-inferiority margin of 7.7 percent," Boehringer reported. The incidences of major bleeding events were similar in all treatment groups, the firm added. Liver enzyme elevations were frequently monitored and also similar. "Those patients with elevations of greater than three times the upper limit of normal were infrequent and similar across all treatment groups," the firm said. The impact of dabigatran on the liver could be critical to securing FDA approval. AstraZeneca's failed Exanta (ximelagatran) was also an oral direct thrombin inhibitor similar to dabigatran. The company dropped the anti-thrombotic in 2006 over liver toxicity concerns after receiving a "not approvable" letter from FDA in 2004 (1 (Also see "End Of Exanta: AstraZeneca Drops Drug After New Report Of Liver Injury" - Pink Sheet, 14 Feb, 2006.)). Results of dabigatran following knee replacement surgery in the RE-MODEL trial were released in December 2006 during the American Society of Hematology meeting. That trial also demonstrated the safety and efficacy of 150 mg and 220 mg dabigatran compared to once daily 40 mg Lovenox for preventing VTE in patients undergoing knee surgery. Johnson & Johnson and Bayer HealthCare also released positive data on their investigational oral Factor Xa inhibitor rivaroxaban ( Xarelto) for VTE prevention after orthopedic surgery during the ISTH Congress, comparing it to Lovenox. Although a different class from dabigatran, oral Factor Xa inhibitors would address similar treatment needs during orthopedic surgery. J&J/Bayer said they expect to file Xarelto in 2008 (2 (Also see "J&J/Bayer’s Once-Daily Rivaroxaban Superior To Lovenox In Phase III Trial" - Pink Sheet, 9 Jul, 2007.)). - Jessica Merrill ([email protected]) |