1. BiDil® (isosorbide dinitrate/ hydralazine HCl)
Core Introduction
BiDil® (isosorbide dinitrate/ hydralazine HCl)
Cardiovascular and Renal Drugs Advisory Committee
Gaithersburg, Maryland
June 16, 2005

2. Core Introduction Manuel Worcel, MD NitroMed

3. BiDil® Mechanism of Action
Core Introduction
BiDil® Mechanism of Action
DV A-HeFT CSR p28;Underwood_ACC-5
Isosorbide dinitrate (ISDN)
Large and small artery dilator
Venous dilator
Nitric oxide donor
Hydralazine HCl (HYD)
Arteriolar dilator
BiDil
Fixed-dose combination ISDN/HYD (20 mg and 37.5 mg, respectively, per tablet)
O2NO H O O H
ONO2
1, 4, 3, 6-dianhydro-D-glucitol-2,5-dinitrate; C6H8N2O8
NHNH2 N
HCl N
1-hydrazinophthalazine monohydrochloride; C8H9ClN4

4. BiDil® Clinical Development in HF†
Core Introduction
BiDil® Clinical Development in HF†
DV NitroMed Briefing Book T1; V-HeFT I CSR; V-HeFT II CSR
1980 to V-HeFT I Vasodilator-Heart Failure Trial
642 men
1986 to V-HeFT II Vasodilator-Heart Failure Trial
804 men
2001 to A-HeFT African American Heart Failure Trial
1050 black men and women
† V-HeFT trials used ISDN + HYD as commercial products.

5. BiDil® Regulatory History
Core Introduction
BiDil® Regulatory History
DV NitroMed Briefing Book § 2.5
1997 Medco Research receives FDA “not approvable” letter for use of BiDil to treat HF in the general population
1999 NitroMed acquires NDA file for BiDil
2001 FDA informs NitroMed that an additional clearly positive study in black patients (A-HeFT) would be basis for approval of BiDil in black patients
2004 A-HeFT trial stopped following DSMB and Steering Committee recommendations and NDA amendment submitted in December

6. BiDil® Clinical Development in Black Patients With HF
Core Introduction
BiDil® Clinical Development in Black Patients With HF
DV NitroMed Briefing Book pp 110, 111
BiDil is effective:
Meaningfully reduced relative risk of mortality
Meaningfully reduced relative risk of HF hospitalization
Meaningfully improved QoL
BiDil is safe and generally well tolerated
Findings are concordant across a wide range of
Symptoms
Background medications

7. Core Introduction
Proposed Indication
BiDil® is indicated for the treatment of heart failure as an adjunct to standard therapy in black patients to improve survival, prolong time to hospitalization for heart failure, and improve quality of life.

8. Agenda Introduction Manuel Worcel, MD NitroMed V-HeFT I and II Trials
Core Introduction
Agenda
Introduction
Manuel Worcel, MD NitroMed
V-HeFT I and II Trials
Jay N. Cohn, MD U. of Minnesota Medical School
A-HeFT―Design and Study Population
Anne L. Taylor, MD U. of Minnesota Medical School
A-HeFT―Results and Conclusions
Clyde Yancy, MD UT Southwestern Med Ctr at Dallas
Integrated Summary of V-HeFT and A-HeFT Trials
Milton Packer, MD UT Southwestern Med Ctr at Dallas
General Q&A
Michael Sabolinski, MD NitroMed

9. Sponsor Representatives
Core Introduction
Sponsor Representatives
Manuel Worcel, MD
Chief Medical Officer
Michael L. Sabolinski, MD
Senior Vice President
Clinical Development & Regulatory Affairs
S. William Tam, PhD
Senior Director
Clinical & Regulatory Affairs
Ginny Braman
Associate Director
Dawn Spooner
Manager Clinical & Regulatory Affairs

10. Consultants Kirkwood Adams, Jr, MD
Core Introduction
Consultants
Kirkwood Adams, Jr, MD
University of North Carolina School of Medicine
Tad Archambault, PhD
Virtu Stat, Ltd.
Ralph D’Agostino, Jr, PhD
Wake Forest University School of Medicine
David DeMets, PhD
University of Wisconsin
Keith Ferdinand, MD
Heartbeats Life Center
Lloyd Fisher, PhD
University of Washington
Carol Gloff, PhD
Carol Gloff & Associates
Christopher O’Connor, MD
Duke University
Elizabeth Ofili, MD
Morehouse School of Medicine