Biotech Values

[DewDiligence]

DU-176b Shows Comparable Safety to Warfarin in AF

[DU-176b, an oral FXa inhibitor, belongs to the same drug class as Xarelto from Bayer/JNJ and Apixaban from PFE/BMY. A phase-3 trial in AF has just begun (#msg-34100821).

The phase-2 trial described in this PR was too short and too small to show differences in efficacy (VTE prevention) between the arms; rather, it was intended to assess safety as measured by bleeding rates and elevated liver enzymes. On these metrics, DU-176b was comparable to warfarin in the qD arms but not in the BID arms, where DU-176b showed excess bleeding relative to warfarin.

One quirk of this trial: the docs and patients were blinded to which of the four DU-176b arms they were in, but the warfarin arm was open-label. I assume this was done because the extensive monitoring required by warfarin would be problematic if the physician were blinded.

AF is the second indication in which DU-176b has been tested in phase-2; the other indication is VTE prevention following hip surgery (#msg-31950663).]

http://finance.yahoo.com/news/New-Phase-II-Data-Provide-prnews-13765777.html

›New Phase II Data Provide Insight Into Optimal Dosing of Oral Factor Xa Inhibitor, DU-176b in Patients With Non-Valvular Atrial Fibrillation

Once-Daily Dosing of DU-176b Shows Similar Bleeding Rates to Warfarin

Sunday December 7, 2008, 12:30 pm EST

SAN FRANCISCO, December 7 /PRNewswire/ -- Patients with non-valvular atrial fibrillation receiving either 60 mg or 30 mg once per day of DU-176b, an investigational oral factor Xa inhibitor, experienced comparable safety and tolerability compared to those taking warfarin, according to new Phase II data presented today at the 50th Annual Meeting of the American Society of Hematology in San Francisco. These findings are the first results from a clinical study evaluating an oral Factor Xa inhibitor in atrial fibrillation patients. DU-176b is being developed solely by DAIICHI SANKYO Company, Limited, and Phase III trials have begun.

The objective of the multinational study was to assess the safety of four dose regimens of DU­176b in patients with non-valvular atrial fibrillation (AF), as compared to warfarin. While the incidence of major and clinically relevant non-major bleeding events were significantly higher in the twice-daily DU-176b treatment groups (60 mg or 30 mg twice per day), compared to warfarin, the incidence reported in the once-daily DU-176b treatment groups (60 mg or 30 mg once per day) were similar to that in the warfarin-treated patient group. Bleeding events were evaluated using guidelines established by the International Society on Thrombosis and Haemostasis (ISTH), the most sensitive scale currently used in clinical studies in cardiovascular disease.(1)

"These results are noteworthy and encouraging since we observed significantly fewer adverse bleeding events in patients receiving one dose of DU-176b per day, versus two doses per day, suggesting with this compound, the most convenient dosing regimens also appear to be safer," said Jeffrey I. Weitz, MD, FACP, FRCP, professor of medicine and biochemistry, McMaster University and director, Henderson Research Centre, Hamilton, Ontario. "This data provides insight into the optimal dosing for Phase III studies of DU-176b."

"Having clear results from such a robust Phase II study among atrial fibrillation patients gives us great confidence that we know the best doses to evaluate in our Phase III clinical trial," said Francis Plat, M.D., vice president, clinical development at DAIICHI SANKYO Pharma Development. "We are hopeful that DU-176b may one day provide the community with a safe and convenient advancement in the prevention of stroke in patients with non-valvular atrial fibrillation."

About the DU-176b Phase II Safety Study:

A total of 1,146 patients with atrial fibrillation (as determined by the CHADS2 index greater than or equal to 2) were enrolled in the study. Patients were randomly assigned to receive either one of the four fixed dose regimens of DU-176b (30mg/N=235 or 60mg/N=234 administered once daily; 30mg/N=244 or 60mg/N=180 administered twice a day), or warfarin (N=250) dose-adjusted locally to a target international normalized ratio (INR) of 2.0-3.0 for 12 weeks. The INR was determined weekly for four weeks and every two weeks thereafter. Investigators, sponsors and study subjects were blinded to the DU-176b dose; however, investigators and patients taking warfarin were aware they were randomized to the warfarin arm.

The primary endpoints of the study were the incidence of bleeding events (major and clinically relevant non-major) and elevated liver enzymes and/or bilirubin. Secondary endpoints included major adverse cardiovascular events, stroke, systemic embolism, acute myocardial infarction, hospitalizations due to cardiovascular conditions or cardiovascular death.

The incidence of major and clinically relevant non-major bleeding events was significantly higher with the 30 mg and 60 mg twice-daily DU-176b regimens (7.8%, p = 0.029 and 10.6%, p = 0.002 respectively) than it was in patients given warfarin (3.2%). In contrast, the incidence of major and clinically relevant non-major bleeding events with the 30 and 60 mg once-daily DU-176b regimens was comparable to that with warfarin (3.0 %, 3.8% and 3.2%, respectively). There were no significant differences in the numbers of patients with elevated liver enzymes or bilirubin across all treatment groups. Although the study was not powered to detect efficacy, there were no significant differences in the rates of secondary efficacy across treatment groups.

About Atrial Fibrillation

Atrial fibrillation (AF) is an irregular heartbeat caused when the upper chambers of the heart (the atria) beat inconsistently and rapidly. When this happens, blood can become stagnant near the walls of the atria and form blood clots. These blood clots can break off and travel through the blood stream to the brain where they can plug blood vessels possibly causing a stroke. These clots can also cause damage to other organs in the body by blocking peripheral arteries.

About 4.5 Million people in Europe have atrial fibrillation.(2) Patients with atrial fibrillation have five times higher risk of having a stroke.(3) These patients also tend to have more serious first strokes than those without atrial fibrillation, resulting in higher mortality rates and longer hospital stays.(4)

References

1. S. Schulman and C. Kearon on behalf of the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the ISTH. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Journal of Thrombosis and Haemostasis, 3: 692-694.

2. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Europace 2006;8:651-745

3. Hylek AM, et al. N Engl J Med. 2003; 349:1019-1026.

4. Jorgensen, H.S., et.al. Stroke 1996;27: 1765-1769

About DU-176b

DU-176b is an oral anticoagulant that directly inhibits Factor Xa, a clotting factor in the blood. DAIICHI SANKYO is developing DU-176b as a potential new treatment for the prevention of both arterial and venous thromboembolism. Notably, DAIICHI SANKYO has more than 25 years experience conducting research in the area of Factor Xa inhibition and was the first company to test these molecules in man.

About DAIICHI SANKYO

DAIICHI SANKYO is a global pharmaceutical company that focuses on researching and marketing innovative medications. The company was created in 2005 through the merger of two traditional Japanese enterprises, Daiichi and Sankyo. With net sales of more than 5.4 billion EUR in fiscal year 2007, DAIICHI SANKYO is one of the world's 20 leading pharmaceutical companies. The company's world headquarters is in Tokyo, and its European base is located in Munich. DAIICHI SANKYO has affiliates in 12 European countries and has been one of the strongest Japanese pharmaceutical companies located in Europe since it set up European production facilities and marketing offices in 1990. The company's research activities focus on the areas of cardiovascular diseases, hematology, diabetes, anti-infectives and cancer. Its aim is to develop medications that are "best" in their class or to create new classes of pharmaceutical drugs. For more information, please visit: http://www.daiichi-sankyo.eu‹