ATACAND

1
ATACAND(candesartan cilexetil)
C

• Cardiovascular and Renal DrugsAdvisory Committee
• Bethesda, Maryland
• July 18, 2002

2
ATACAND Introduction and Regulatory Overview
C

• Cindy Lancaster, MS, MBA, JD
• Director, Regulatory Affairs
• AstraZeneca

3
Agenda for Presentation

• Regulatory Overview Cindy Lancaster, MS, MBA,
  JD Director, Regulatory Affairs AstraZeneca
• Comparison of Vasilios Papademetriou, MD,
  Antihypertensive Efficacy DSc, FACCof
  Candesartan Cilexetil Professor of Medicineand
  Losartan Georgetown University
• Epidemiologic and Clinical William B. Kannel,
  MD, FACCSignificance of Incremental Professor
  of Medicine andChanges in Blood Public
  HealthPressure Boston University School of
  Medicine
• Summary Cindy Lancaster, MS, MBA, JD Director,
  Regulatory Affairs AstraZeneca

4
Consultant and Sponsor Representatives

• Consultant
• Donald Vidt, MD, FACC
• Principal Investigator for Study 230
• Consultant, Department of Hypertension and
  Nephrology, The Cleveland Clinic Foundation
• Professor of Medicine, Ohio State University
• AstraZeneca
• Eric Michelson, MD, FACC
• Senior Director, Clinical Research
• Conrad Tou, PhD
• Associate Director, Biostatistics
• Jennifer Sugg, MS
• Senior Statistical Scientist
• Glenn Carlson, MD
• Senior Director, Medical

5
Introduction

• ATACAND (candesartan cilexetil)
• Selective AT1 subtype angiotensin II receptor
  antagonist (ARB)
• June 1998Approved for the treatment of
  hypertension
• Can be used alone or in combination with other
  antihypertensive agents
• Usual recommended starting dose 16 mg QD

6
Regulatory HistoryAgency Interactions (1)

• Original NDA
• Included 1 positive comparative study versus
  losartan, SH-AHM-0001
• Randomized, double-blind, multicenter,
  placebo-controlled, parallel-group, 8-wk duration
• Patients (N 337) with a mean diastolic blood
  pressure of 95 to 114 mm Hg
• Compared candesartan cilexetil 8 and 16 mg
  QD,losartan 50 mg QD, and placebo
• The proposed labeling did not include comparator
  text versus losartan

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Regulatory HistoryAgency Interactions (2)

• Study 175positive results versus losartan
• available in 1998
• Randomized, double-blind, multicenter,
  titration-to-effect, parallel-group, 8-wk
  duration
• Patients (N 332) with a mean diastolic blood
  pressure of 95 to 114 mm Hg
• Initiated treatment with candesartan cilexetil
  16 mg QD or losartan 50 mg QD
• After 4 wk, patients with a mean sitting DBP
  90 mm Hg were titrated to candesartan cilexetil
  32 mg QD or losartan 100 mg QD

8
Regulatory HistoryAgency Interactions (3)

• August 1998 meeting with the Agency
• Discussed use of SH-AHM-0001 and Study 175 to
  support a comparator claim versus losartan for
  the treatment of hypertension
• SH-AHM-0001
• A starting dose comparison does not provide a
  meaningful comparison because the starting dose
  is an arbitrary point and does not represent how
  the drugs perform over their dose ranges
• Study 175
• It was not a forced-titration design. Only poor
  responders would be titrated to the highest dose
  of the drugs in a titration-to-effect study

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Regulatory HistoryAgency Interactions (4)

• Agency requirements to support comparator claim
• Establish bioequivalence of losartan and
  overencapsulated tablets used in blinding of
  comparator product
• Study candesartan cilexetil and losartan at the
  maximum approved doses for the treatment of
  hypertension
• Statistically significant results replicated in
  adequate and well-controlled trials
• If once-daily dosing is studied, then the
  limitations should be clearly stated in
  promotional claims
• Acceptable study designs parallel dose-response
  or forced-titration

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Description of Comparative Trials in Labeling

• Results of a specific dosing regimen of
  once-daily administration at the maximum approved
  dose from 2 clinical trials with hypertensive
  patients
• Once-daily administration is an appropriate
  dosing regimen for candesartan cilexetil and
  losartan because
• Both drugs are regularly prescribed for use once
  daily
• Once-daily administration is the dosing regimen
  primarily used in on-going and completed studies
• Statistically greater blood pressure reduction
  was demonstrated with candesartan cilexetil
  compared with losartan at the maximum approved
  dose when administered once daily
• The proposed labeling is specific to effects on
  blood pressure reduction

11
Labeling

• PROPOSED ADDITION TO CLINICAL PHARMACOLOGY,
  Clinical Trials subsection (for insertion after
  the first paragraph in this section)
• Two identically designed, concurrently
  conducted, 8-week, multicenter, double-blind,
  randomized, forced-titration studies were
  performed to compare the antihypertensive
  efficacy of candesartan cilexetil and losartan
  at their once-daily maximum doses. Candesartan
  cilexetil initiated at 16 mg once daily and
  forced- titrated at 2 weeks to 32 mg once daily
  was statistically significantly more effective
  than losartan 50 mg once daily forced-titrated at
  2 weeks to 100 mg once daily in reducing
  systolic and diastolic blood pressure at 8
  weeks. In these studies, both agents were well
  tolerated.
• Currently approved labelingINDICATIONS AND
  USAGE
• ATACAND is indicated for the treatment of
  hypertension. It may be used alone or in
  combination with other antihypertensive agents.

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Regulatory Precedent

• Comparator Claim for ZESTRIL/Prinivil
  (lisinopril)
• CLINICAL PHARMACOLOGY, Pharmacodynamics and
  Clinical Effects, Hypertension  
• . . . In controlled clinical studies, ZESTRIL
  20-80 mg has been compared in patients with mild
  to moderate hypertension to hydrochlorothiazide
  12.5-50 mg and with atenolol 50-200 mg and in
  patients with moderate to severe hypertension to
  metoprolol 100-200 mg. It was superior to
  hydrochlorothiazide in effects on systolic and
  diastolic pressure in a population that was ¾
  Caucasian. ZESTRIL was approximately equivalent
  to atenolol and metoprolol in effects on
  diastolic blood pressure, and had somewhat
  greater effects on systolic blood pressure.

13
Labeling

• Proposed labeling is consistent with
• The general requirements of the content and
  format of labeling for human prescription drugs
• Guidance during the design of the CLAIM program
  from the Division on how these studies should be
  described in labeling
• Placement of comparator information in labeling
  of other antihypertensive products
• ZESTRIL, COZAAR, ACCUPRIL, ALTACE, DIOVAN,
  TEVETEN
• AstraZeneca will continue to work with the
  Division to finalize labeling