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

Core Introduction Manuel Worcel, MD NitroMed

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

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 1985 V-HeFT I Vasodilator-Heart Failure Trial 642 men 1986 to 1991 V-HeFT II Vasodilator-Heart Failure Trial 804 men 2001 to 2004 A-HeFT African American Heart Failure Trial 1050 black men and women † V-HeFT trials used ISDN + HYD as commercial products.

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

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

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.

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

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

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