P1

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Joint Meeting of the Arthritis and Drug Safety
and Risk Management Advisory Committees

• February 16-18, 2005

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Leonard M. Baum, RPh

• Vice President, Regulatory Affairs
• Bayer HealthCare
• Consumer Care Division

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Agenda

• Regulatory Overview
• Naproxen
• ADAPT Trial
• Safety Evaluation
• Clinical Pharmacology
• Clinical Studies
• Postmarketing Surveillance
• Observational Studies
• Conclusions

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Roche/Bayer Presenters and Responders

• Presenters
• Leonard M. Baum, RPh
• Vice President, Regulatory Affairs
• Bayer HealthCare
• Martin H. Huber, M.D.
• Vice President, Global Head Drug Safety Risk
  Management
• Hoffmann La-Roche Inc.
• Responders
• Susan Sacks, Ph.D.
• Global Head, Epidemiology
• Hoffmann La-Roche Inc.
• Bharat Thakrar, Ph.D.
• Senior Epidemiologist
• Hoffmann La-Roche Inc.

Ernst Weidmann, M.D. Head, Global Safety Bayer
HealthCare Steve Zlotnick, Pharm.D. Director,
Medical Affairs Bayer HealthCare
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Outside Experts

• Kay Brune, M.D.
• Professor and Chairman
• Department of Experimental and Clinical
  Pharmacology and Toxicology
• Friedrich-Alexander University Erlangen -
  Nuremberg
• Ian M. Gralnek, M.D., MSHS
• Assistant Professor of Medicine, Division of
  Digestive Diseases
• David Geffen School of Medicine at UCLA

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Regulatory Overview

• Naproxen available in the United States since
  1976
• Prescription currently marketed by multiple
  manufacturers for the treatment of RA, OA,
  ankylosing spondylitis, gout, juvenile RA,
  dysmenorrhea, tendinitis, bursitis, and pain
• Aleve (OTC) approved in 1994
• Currently marketed by Bayer HealthCare for
  temporary relief of minor aches and pains, and
  for the temporary reduction of fever
• Multiple generic versions

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Naproxen

• Naproxen, a nonsteroidal anti-inflammatory drug
  (NSAID), belongs to the chemical class propionic
  acid derivatives
• Naproxen has anti-inflammatory, analgesic and
  antipyretic properties
• Naproxen known to inhibit platelet aggregation
• The major differences between members of the
  NSAID class are potency and pharmacokinetics

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Classes of NSAIDS

• Salicylic acid derivatives
• Aspirin, sodium salicylate, choline magnesium
  trisalicylate, salsalate, diflunisal
• Para-aminophenol derivatives
• Acetaminophen
• Indole and indene acetic acids
• Indomethacin, sulindac
• Heteroaryl acetic acids
• Tolmetin, diclofenac, ketorolac
• Propionic acids
• Naproxen, ibuprofen, flurbiprofen, ketoprofen,
  fenoprofen, oxaprozin
• Anthranilic acids (fenamates)
• Mefenamic acid, meclofenamic acid
• Enolic acids
• Oxicams (piroxicam, meloxicam)
• Alkanones
• Nabumetone
• Coxibs
• Celecoxib, valdecoxib, rofecoxib (withdrawn)

Source Goodman and Gilmans The Pharmacological
Basis of Therapeutics, 10th edition
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Relevance of Naproxen Data

• The safety profile for naproxen is well known
• Naproxen is a reference drug for many analgesic
  clinical trials
• Naproxen and other non-selective NSAIDs, are
  important treatment options for a broad range of
  patients and conditions

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Naproxen Exposure Data (Rx and OTC)
courses of therapy (2 tab x 10 days)
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The ADAPT Trial

• NIH sponsored study
• Bayer provided naproxen sodium for
  investigational use
• Study Design
• Naproxen sodium 220 mg bid
• Celecoxib 200 mg bid
• Placebo
• Patient Population
• 2400 patients, age 70 years or older, for
  prevention of Alzheimers disease
• Study Duration
• Began in 2001, planned for 7 years, suspended
  after 3 years

Sources NIH News Dec 20, 2004
Washingtonpost.com Feb 1, 2005, written by
Woloshin S et al.
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Publicly Reported Events Leading to the
Suspension of ADAPT

• DSMB review on Dec. 10, 2004 did not recommend
  stopping the study
• The APC study was suspended due to indications of
  an increase in cardiovascular and cerebrovascular
  risk of celecoxib vs. placebo (Dec. 17, 2004)
• NIA announced ADAPT trial suspension (Dec. 20,
  2004)
• Information released to public by study group,
  were based on preliminary findings, not through
  peer-reviewed journals

Sources Celebrex News Release Dec 17, 2004 NIH
News Dec 20, 2004 Washingtonpost.com Feb 1,
2005, written by Woloshin S et al.
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Summary

• Naproxen is a non-selective COX-1 / COX-2
  inhibitor
• Widely used
• Established safety profile
• Reference standard
• Unadjudicated preliminary findings of ADAPT needs
  to be looked at in context of the wide body of
  data on naproxen

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Martin H. Huber, MD

• Global Head, Drug Safety
• Hoffmann-La Roche Inc.

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Safety Evaluation

• Clinical Pharmacology
• Clinical Studies
• Post-Marketing Safety Surveillance
• Post-Marketing Clinical Studies
• Observational Studies

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Pharmacological Difference between Naproxen and
COX-2 Inhibitors

• Naproxen is a non-selective COX-1 /COX-2
  inhibitor
• Naproxen is known to inhibit platelet aggregation
  and thus, is not expected to have an increased
  risk of myocardial infarction

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Clinical Trials and Post-Marketing Surveillance

• Clinical trials in the prescription and OTC
  naproxen NDAs did not provide any evidence of an
  increased risk of myocardial infarction or stroke
  
• A review of postmarketing surveillance data
  showed no signal for MI or cerebrovascular
  accident with exposures to prescription naproxen
  of more than 110,000,000 patients
• A review OTC postmarketing surveillance data did
  not identify a signal for MI or CVA with an
  estimate of 550,000,000 courses of therapy

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Proportional Reporting Rate (PRR)
Source Evans S et al. Pharmacoepidemiology and
Drug Safety 2001 10 483-86
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Post-Marketing Clinical Trials

• VIGOR
• Randomized RA patients 50 yo (or 40 yo and
  receiving long-term glucocorticoid therapy) into
  either rofecoxib 50mg qd (N4,047) or naproxen
  500mg bid (N4,029)
• Overall rate of cardiovascular events reported in
  association with naproxen is consistent with that
  expected in this population
• MI Rofecoxib (0.4) vs. naproxen (0.1)
• Ischemic cerebrovascular events 0.2 in both arms

Source Bombardier C et al. NEJM 2000 3431520-8
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Post-Marketing Clinical Trials

• TARGET
• Randomized OA patients 50 yo into either
  lumiracoxib 400mg qd (N9,156), naproxen 500mg
  bid (N4,754) or ibuprofen 800mg tid (N4,415)
• Naproxen arm showed lower rates for
  cerebrovascular events and MI
• Stroke Lumiracoxib (0.34) vs. naproxen (0.25)
• Ischemic stroke Lumiracoxib (0.32) vs. naproxen
  (0.23)
• Hemorrhagic stroke 0.02 in both arms
• Acute MI Lumiracoxib (0.38) vs. naproxen
  (0.23)

Source Farkouh ME et al. Lancet 2004 364 675-84
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Post-Marketing Clinical Trials

• TARGET (cont.)
• Rate of MI events was lower for naproxen than
  ibuprofen, using lumiracoxib as the reference
  point for both studies

Given in percent of patients with confirmed or
probable cardiovascular and cerebrovascular events
Source Farkouh ME et al. Lancet 2004 364 675-84
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Additional Post-Marketing Clinical Trials

• Alzheimers Trial
• Randomized mild to moderate AD patients (mean
  age 74 yo) into either rofecoxib 25mg qd,
  naproxen sodium 220mg bid, or placebo

Source Aisen PS et al. JAMA 2003 289 2819-26
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Trials with Celecoxib

• Pooled analysis of 41 celecoxib clinical trials
  (White et al)
• 2271 naproxen patients
• 1 non-fatal stroke
• 1 fatal stroke
• 2 non-fatal MIs
• Naproxen (relative to celecoxib) 4/393 (1.01 per
  100 patient years)
• Celecoxib (relative to NSAIDs) 56/4,969 (1.13
  per 100 patient years)
• Placebo (relative to celecoxib) 3/200 (1.5 per
  100 patient years)
• There is no evidence of an increased risk of MI
  or stroke compared to either celecoxib or placebo

Source White et al. Am J Cardiology 2003 92
411-18
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Observational Studies

• Case control studies and retrospective cohort
  studies can be performed in a shorter period of
  time
• Opportunity to detect/evaluate relatively
  infrequent events
• Reflect real world use of the drug
• More heterogeneous populations
• Concomitant medications, concurrent illnesses
• Value of observational studies increases when
  these studies are done in multiple populations

Source Strom B, Pharmacoepidemiology 2000 Wiley
and Sons
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Summary of observational studies of naproxen and
MI
Source Juni et al. Lancet 20043642021-29
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Sensitivity Analysis of Observational Studies

• Meta-analysis included multiple studies from same
  databases
• Performed analysis including only one study from
  GPRD and one study from Tennessee Medicaid
• Excluded Jick, Watson, Schlienger studies with
  GPRD and Ray (Lancet 2002, 359118-23) study with
  Tennessee Medicaid
• Resulting pooled RR 0.87 (0.72-1.03)
• No material change in conclusions of Juni et al.

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Summary

• A review of the observational studies shows no
  increased risk of MI with naproxen
• A review of the postmarketing surveillance data
  shows no signal for MI or cerebrovascular events
• The published clinical trials do not provide
  evidence of an increased risk of MI or
  cerebrovascular events
• Unadjudicated preliminary findings of ADAPT are
  inconsistent with the known data and
  pharmacologic properties of naproxen

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Conclusions

• The vast majority of data collected for over 30
  years indicates no signal for naproxen and
  myocardial infarction or cerebrovascular
  accidents.
• Naproxen Rx and Aleve OTC remain safe and
  effective
• Naproxen remains an important treatment option
  for patients