Ranexa

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Ranexa (ranolazine)Extended Release Tablets
Cardiovascular and Renal Drugs Advisory Committee
Meeting December 9, 2003

• Michael Sweeney, MD, FRCP
• VP, Medical Affairs
• CV Therapeutics, Inc.

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RanexaTM (ranolazine)A Unique Anti-Anginal
Pharmacodynamic Profile

• Anti-anginal and anti-ischemic efficacy
  demonstrated
• Novel pharmacodynamic profile anti-ischemic
  properties do not depend on changes in
• Heart rate
• Blood pressure
• Complementary therapy to existing agents that
  depend on hemodynamic mechanisms

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Ranexa (ranolazine) Proposed Indication and
Dosing

• The sponsor seeks approval of Ranexa for the
• Treatment of chronic angina in patients with
  severe coronary artery disease
• Usual starting dose 500 mg bid, with upward
  titration to 750 mg and 1000 mg bid as needed

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Benefit-Risk

• Benefit
• Anti-anginal and anti-ischemic efficacy
• Achieved with minimalhemodynamic effects
• Well tolerated

• Risk
• Adverse events
• Theoretical risk of TdP due to prolongation of QTc

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Ranexa (ranolazine)Effects on Ventricular
Repolarization

• Extensively studied clinical and preclinical EP
  profile
• Small, dose-related mean increases in QTc
• 2 to 5 msec over proposed dose range
• Up to 20 msec under maximal inhibition of CYP3A4
• Ranolazine and preclinical markers of
  torsadogenic risk
• No early afterdepolarizations (EADs)
• No increased dispersion of ventricular
  repolarization
• Reverses these effects when caused by other drugs
  
• No case of TdP in clinical development

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Ranexa (ranolazine) for Chronic AnginaSponsor
Presentation
Unmet Medical Need Eugene Braunwald, MD, FACC Brigham and Womens Hospital
Clinical Efficacy and Safety Andrew Wolff, MD, FACC Sr VP, Clinical RD
Surrogate Markers of Pro-Arrhythmic Risk Peter Kowey, MD, FACC Lankenau Hospital and the Main Line Health SystemJefferson Medical College
Mechanistic Assessment of Repolarization Effects Luiz Belardinelli, MD VP, Drug Research and Pharmacological Sciences
Clinical Assessment of Repolarization Effects Andrew Wolff, MD, FACC Sr VP, Clinical RD
Benefit/Risk Jeremy Ruskin, MD, FACC Massachusetts General Hospital
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Advisors and Consultants (1)
Charles Antzelevitch, PhD, FACC Masonic Medical Research Laboratory Utica, NY
John Camm, MD, FACC St. Georges Hospital Medical School London, England
Bernard Chaitman, MD, FACC St. Louis University School of MedicineSt. Louis, MO
Gary Koch, PhD University of North Carolina Chapel Hill, NC
Samuel Lee, MD, FRCPC University of Calgary Calgary, Alberta, Canada
Marek Malik, MD, PhD, FACC St. Georges Hospital Medical School London, England
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Advisors and Consultants (2)
Craig M. Pratt, MD, FACC Baylor College of Medicine Houston, TX
Dan Roden, MD, FACC Vanderbilt University School of Medicine Nashville, TN
Peter Stone, MD, FACC Brigham and Womens Hospital Boston, MA