COX2 The Inside Story

1
COX-2The Inside Story

• Steven L. Shafer, MDProfessor of Anesthesia,
  Stanford UniversityAdjunct Professor of
  Biopharmaceutical Science, UCSFEditor-in-Chief,
  Anesthesia Analgesia

Most of the figures are taken from the FDAs web
sitefor the 2005 Joint Meeting of the Arthritis,
Drug Safety, and Risk ManagementAdvisory Panels
to assess the safety of COX-2 drugs.
2
Conflict of Interest

• Financial relationships to companies making
  NSAIDS none
• Off-label uses will be identified at the time of
  presentation (polyp prevention)

3
Merck pulls popular pain drug due to risks of
heart attacks
Sept. 30, 2004
Byron Cryer, 2005 FDA Presentation
4
Overview of NSAID Class

• NSAIDS Large class of marketed products with
  both OTC and Rx indications and use wide range
  of products with varying risk to benefit profiles
• Short term use
• Dysmenorrhea, Acute pain
• Chronic use
• Osteoarthritis, Rheumatoid arthritis FAP
  (Celebrex)
• Other proposed uses
• Ankylosing spondylitis, Alzheimer's disease,
  Colonic polyp prevention

2005 FDA Presentation
5
NSAID Mechanism of Action
CO
H
CO
H
2
2
Arachidonic acid
Arachidonic acid
COX
-
1
COX
-
2

Constitutive


Inducible

GI Mucosa
Platelet
Prostaglandins
Prostaglandins
Thromboxane
Mediate pain,
GI mucosal
inflammation, and fever
Hemostasis
Protection
Bakhle
et al.
Med
Inflamm
.
19965305
-
323.
Vane et al.
Inflamm
Res.
1995441
-
10.
(Miyamoto et al, JBC 1976 2512629)
Byron Cryer, 2005 FDA Presentation
6
NSAID Analgesia

• Logical Consequence of Mechanism
• Not intrinsically antinociceptive
• Instead, they are anti-hyperalgesic prevent the
  pain associated with inflammation.

7
NSAIDs and Synergy

• Ibuprofen Hydrocodone in mice
• Little intrinsic analgesia from ibuprofen
• Huge synergy with hydrocodone

Kolesnikov et al, Anesth Analg. 2003
Dec97(6)1721-3.
8
NSAIDs and Synergy

• Synergy for IT combinations of morphine and
• Naproxen
• Piroxicam
• Metamizol
• Diclofenac
• Ketoprofen

Miranda et al, Brain Res. 2005 Jun 2 Epub ahead
of print
9
NSAID Synergy

• Demonstrated with IP administration of morphine
  and diclofenac, ketoprofen, meloxicam,
  metamizol, paracetamol and piroxicam.
• Reversed by naloxone
• Mostly explained by mu opioid activation and
  antiflammatory effects acting in synergy.

Miranda et al, Can J Physiol Pharmacol. 2004
May82(5)331-8
10
Dick Mazze Study

• Chief of Staff at the Palo Alto VA
• Wanted to remove ketorolac from the formulary
• Had Back Surgery
• Became a believer after one dose

11
NSAID Mechanism of Action
CO
H
CO
H
2
2
Arachidonic acid
Arachidonic acid
COX
-
1
COX
-
2

Constitutive


Inducible

GI Mucosa
Platelet
Prostaglandins
Prostaglandins
Thromboxane
Mediate pain,
GI mucosal
inflammation, and fever
Hemostasis
Protection
Bakhle
et al.
Med
Inflamm
.
19965305
-
323.
Vane et al.
Inflamm
Res.
1995441
-
10.
(Miyamoto et al, JBC 1976 2512629)
12
NSAIDs What Are the Risks?

• GI Tract
• Ulcers, perforations, bleeding, obstruction
  strictures, enteropathy
• Kidney
• Sodium and fluid retention
• Hyperkalemia
• Acute renal failure
• Hypertension
• Platelet
• Inhibition of aggregation leading to increased
  potential for bleeding

Byron Cryer, 2005 FDA Presentation
13
Spectrum of NSAID-InducedGI Mucosal Injury
Small Intestine Ulcers Strictures
Diaphragms Enteropathy

• Upper GI
• GERD
• Subepithelial petechial hemorrhages
• Erosions
• Ulcers
• Stomach gt duodenum
• Bleeding
• Stomach duodenum
• Perforations/obstruction

• Colon
• Colitis
• Ulcers
• Strictures
• Diverticular bleed or perforation
• Collagenous colitis
• Relapse of IBD

Byron Cryer, 2005 FDA Presentation
14
Endoscopic Photograph of Gastric Ulcer
Byron Cryer, 2005 FDA Presentation
15
Incidence of EndoscopicNSAID-Induced Ulceration

• Mean Range
• NSAID Gastropathy gt 90
• Gastric Ulcer 15 10 to 30
• Duodenal Ulcer 5 4 to 10

Wolfe MM et al. N Engl J Med 19993401888-1899
Byron Cryer, 2005 FDA Presentation
16
NSAID-Induced GastropathyMorbidity, Mortality
and Costs in the U.S.

• Total hospitalizations/year 107,000
• Total costs of hospitalization (12,500/hospitali
  zation) 1.4 billion
• Deaths/year 16,500
• Each 1 spent on NSAIDs resulted in an additional
  0.35 in costs to manage adverse effects
• Average cost to treat an episode of NSAID-induced
  gastropathy was 2,172 (in 1992)

Singh. Am J Med. 1998105(suppl
1B)31S-38S. Johnson et al. Pharmacoeconomics.
19971276-88.
Byron Cryer, 2005 FDA Presentation
17
The GI Paragraph

• Serious gastrointestinal toxicity such as
  bleeding, ulceration and perforation of the
  stomach, small intestine or large intestine, can
  occur at any time, with or without warning
  symptoms, in patients treated with nonsteroidal
  anti-inflammatory drugs (NSAIDs). Minor upper
  gastrointestinal problems, such as dyspepsia, are
  common and may also occur at any time during
  NSAID therapy. Therefore, physicians and patients
  should remain alert for ulceration and bleeding,
  even in the absence of previous GI tract
  symptoms. Patients should be informed about the
  signs and/or symptoms of serious GI toxicity and
  the steps to take if they occur. The utility of
  periodic laboratory monitoring has not been
  demonstrated, 305 nor has it been adequately
  assessed. Only 1 in 5 patients who develop a
  serious upper GI adverse event on NSAID therapy
  is symptomatic. It has been demonstrated that
  upper GI ulcers, gross bleeding or perforation,
  caused by NSAIDs, appear to occur in
  approximately 1 of patients treated for 3 to 6
  months and in about 2 to 4 of patients treated
  for 1 year. These trends continue, thus
  increasing the likelihood of developing a serious
  GI event at some time during the course of
  therapy. However, even short-term therapy is not
  without risk.

18
The GI Paragraph

• NSAIDs should be prescribed with extreme caution
  in patients with a prior history of ulcer disease
  or gastrointestinal bleeding. Most spontaneous
  reports of fatal GI events are in elderly or
  debilitated patients and therefore special care
  should be taken in treating this population. To
  minimize the potential risk for an adverse GI
  event, the lowest effective dose should be used
  for the shortest possible duration. For high-risk
  patients, alternate therapies that do not involve
  NSAIDs should be considered. Studies have shown
  that patients with a prior history of peptic
  ulcer disease and/or gastrointestinal bleeding
  and who use NSAIDs, have a greater than 10-fold
  risk for developing a GI bleed than patients with
  neither of these risk factors. In addition to a
  past history of ulcer disease, pharmacoepidemiolog
  ical studies have identified several other
  co-therapies or co-morbid conditions that may
  increase the risk for GI bleeding such as
  treatment with oral corticosteroids, treatment
  with anticoagulants, longer duration of NSAID
  therapy, smoking, alcoholism, older age, and poor
  general health status.

19
Gastroprotection

• Use lowest effective NSAID dose
• Misoprostol
• Proton pump inhibitors
• Better NSAIDS

Byron Cryer, 2005 FDA Presentation
20
GastroprotectionMisoprostol (MUCOSA trial)
of patients with serious upper GI complications
at 6 months
p0.049
Placebo NSAID (n4439)
Misoprostol NSAID (n4404)
Byron Cryer, 2005 FDA Presentation
Silverstein et al. Ann Intern Med 1995123241249
21
Gastroprotection Proton Pump Inhibitors
of patients with recurrent upper GI bleeding at
6 months
p0.005
76 reduction in upper GI bleeding
H. pylori eradication NSAID (n75)
Omeprazole NSAID (n75)
Byron Cryer, 2005 FDA Presentation
Chan et al. N Engl J Med 2001344967973
22
The COX-2 Hypothesis
CO
H
CO
H
2
2
Arachidonic acid
Arachidonic acid
?
COX
-
1
COX
-
2

Constitutive


Inducible

GI Mucosa
Platelet
Prostaglandins
Prostaglandins
Thromboxane
Mediate pain,
GI mucosal
inflammation, and fever
Hemostasis
Protection
Bakhle
et al.
Med
Inflamm
.
19965305
-
323.
Vane et al.
Inflamm
Res.
1995441
-
10.
(Miyamoto et al, JBC 1976 2512629)
23
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24
Timeline of IND/NDA Filings
PENDING NDAs
Bextra IM/IV NDA Filed
Bextra IM/IV IND Filed
Arcoxia NDA Originally Filed
Arcoxia IND Filed
Prexige IND Filed
Prexige NDA Filed
95
97
98
99
00
01
02
03
04
05
94
96

Bextra IND Filed
Bextra NDA Approved 11/01

Celebrex IND Filed
Celebrex NDA Filed/approved 12/98
Vioxx IND Filed
Vioxx NDA Filed/approved 5/99
APPROVED NDAs
25
Rofecoxib (VIOXX) Confirmed Clinical Upper GI
Events, 5000 patients, 1998
Relative Risk (RR)Rofecoxib vs. NSAIDs
(Ibuprofen, diclofenac, nabumetone).
26
VIGOR (Jan-1999 to Mar-2000)

• 8076 rheumatoid arthritis (RA) patients
• Rofecoxib 50 mg QD
• 2 to 4 times recommended chronic dose
• Provides rigorous test of GI safety
• Naproxen 500 mg BID
• Most common NSAID regimen for RA

27
VIGOR Primary Endpoint (2000)Time to Confirmed
Clinical Upper GI Event
Bombardier et al, NEJM 2000 3431520
28
Rofecoxib 2003 GI Trial Summary
Confirmed Clinical Upper GI Events Relative
Risk with 95 CI
PYR Patient-Years.
29
Result of the VIGOR Trial

• Based on the VIGOR trial, and the prior safety
  data, the FDA removed the GI paragraph from
  rofecoxib

30
Celecoxib (Celebrex) CLASS Trial
(n8000)celecoxib v. diclofenac, ibuprofen
Silverstein et al, JAMA 2000 2841247
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CLASS Trial Time to Complicated Ulcer 13 months

Log-rank P values Celecoxib vs.
NSAIDs 0.450 Celecoxib vs. diclofenac 0.640 Celeco
xib vs. ibuprofen 0.414
()
Ibuprofen 800 mg TID
Diclofenac 75 mg BID
Celecoxib 400 mg BID
0
80
240
320
180
160
Days
FDA Presentation. 2/7/01.
33
CLASS Trial Subgroup Analysis
FDA Presentation. 2/7/01.
34
COX-2 GI Hypothesis

• Rofecoxib
• The most COX-2 selective drug
• Pre-approval trials (n5000) ?
• VIGOR (n8000) ?
• FDA label changed to reflect GI benefit vs.
  traditional NSAIDS
• Celecoxib
• No more COX-2 selective than diclofenac
• CLASS showed no benefit vs. diclofenac
• CLASS showed benefit vs. ibuprofen in subgroup,
  but benefit was wiped out by aspirin (as
  expected)
• FDA NO change in celecoxib label vs. traditional
  NSAIDs.
• With NO improvement in GI tolerability, and NO
  increase in efficacy, how did this become a
  multibillion dollar drug?

35
COX-2 and Cancer Hypothesis

• COX-2 is up-regulated in many forms of cancer
• PGE2 activates cellular signal transduction
  pathways that have been implicated in
  carcinogenesis.
• What a great indication colon in situ!

Dannenberg et al, Cancer Cell 2003 4431
36
APPROVe Colon Polyp Prevention Study

• Rofecoxib 25 mg vs. placebo
• Approximately 2600 patients
• 3 year study
• Polyps followed using colonoscopy
• Primary endpoint Cumulative incidence of
  patients with adenomatous polyps at Year 3

37
APPROVe results (Dec 2004)
Cumulative Incidence () (Number of Pts. with
Adenomas)
plt0.0001
MERCK Presentation to Arthritis Advisory
Committee, February 2005
38
COX-2 and Cancer Hypothesis

• APPROVe Study
• 25 reduction in cancer risk
• Highly significant
• Blocking COX-2 reduces risk of colon cancer!

39
COX-2 and Prostacyclin(oops)
200
160
Mean urinary PGI-M SE (pg/mg creatinine)
120
80




40

0
Placebo (n7)
Celecoxib 400 mg (n7)
Ibuprofen 800 mg (n7)
Rofecoxib50 mg qd(n12)
Indomethacin50 mg tid(n10)
Celecoxib 800 mg (n7)
McAdam et al. Proc Natl Acad Sci USA.
199996272
Catella-Lawson et
al. J Pharmacol Exp Ther. 1999289735.
40
COX-2
COX-1
COX-1
PGI2
BP
Cardiac Fibrosis
TXA2
COX-2
COX-2
COX-1
Fitzgerald Presentation, FDA Arthritis Advisory
Board, February 2005
41
Fitzgerald Hypothesis
COX-1
COX-2
Thromboxane
Prostacyclin
Prothrombotic
Antithrombotic
McAdam,.FitzGerald, PNAS 1999, 96272
42
Fitzgerald Hypothesis
COX-1
COX-2
?
?
Traditional NSAID
Thromboxane
Prostacyclin
Prothrombotic
Antithrombotic
McAdam,.FitzGerald, PNAS 1999, 96272
43
Fitzgerald Hypothesis
COX-1
COX-2
?
COX-2 Selective
McAdam,.FitzGerald, PNAS 1999, 96272
44
COX-2
COX-1
COX-1
PGI2
BP
Cardiac Fibrosis
TXA2
COX-2
COX-2
COX-1
Fitzgerald Presentation, FDA Arthritis Advisory
Board, February 2005
45
VIGOR Confirmed CV/ Thrombotic Events Time to
Event Plot
Hazard Ratio Vioxx vs. Naproxen
Overall 2.4 gt 8 months 4.0
FDA Presentation, Arthritis Advisory Board,
February 2005
46
Here is what the Vigor study said

• The safety of both rofecoxib and naproxen was
  similar to that reported in previous studies.
  20,21 The mortality rate was 0.5 percent in the
  rofecoxib group and 0.4 percent in the naproxen
  group. The rate of death from cardiovascular
  causes was 0.2 percent in both groups. Ischemic
  cerebrovascular events occurred in 0.2 percent of
  the patients in each group. Myocardial
  infarctions were less common in the naproxen
  group than in the rofecoxib group (0.1 percent
  vs. 0.4 percent 95 percent confidence interval
  for the difference, 0.1 to 0.6 percent relative
  risk, 0.2 95 percent confidence interval, 0.1 to
  0.7).

47
Here is what the study should have said
48
CV Death, Non-fatal MI, Stroke Vioxx Studies
090 0851 (June 2000)
1 6-week OA studies. Data presented by FDA at
February 2005 Arthritis Advisory Committee
49
CV Events ADVNTAGE Trial (March and April, 2001)
Naproxen N2771 n Rate
Rofecoxib 25 mg N2785 n Rate
-
-
0
0.63
4
CV Deaths
12 week study FDA Presentation, February 2005
Arthritis Advisory Board
50
Meta-analysis CV risk of rofecoxibwas evident
in 2001
Juni et al, Lancet 2004 3642021
51
All cause mortalityAlzheimers 091 078
(Updated March 2004)
FDA Presentation, February 2005 Arthritis
Advisory Board
52
Rofecoxib APPROVeCV Events

• Rofecoxib 25

Placebo
FDA Presentation, February 2005 Arthritis
Advisory Board
53
Celecoxib vs. PlaceboColorectal Adenoma
Prevention
Cumulative Probability Of Cardiovascular Event
Solomon et al, NEJM 2005 352epub
54
COX-2 and Fitzgerald Hypothesis

• The Fitzgerald Hypothesis appears to be true
• aspirin story
• Concurrent aspirin should rebalance COX-2
  selective drugs

• In 8 out of 8 studies in which aspirin was used,
  the ? risk of CV events in patients on COX-2
  drugs was still present in the subgroup taking
  aspirin.
• P 0.004
• Something else is going on in addition to the
  Fitzgerald mechanism

55
Increased Incidence of MI andSudden
Cardiovascular Deathfrom Rofecoxib

• 25 mg
• 28, 686 - 39,187
• 50 mg
• 5,843 - 7,542
• 25 mg 50 mg combined
• 36,228-45,030
• Deaths in Vietnam, 1966-1971 47,359

http//capmarine.com/cap/statistics.htm
FDA Presentation, February 2005 Arthritis
Advisory Board
56
California Medicaid

• Strengths
• Large sample size over 7 million persons per
  year
• OTC aspirin data
• No censoring at age 65
• Matching with multiple cause-of-death data
• Long durations of follow-up with low drop-out
  rates
• Sicker population than private-payors
• Easier to detect drug safety signals
• Limitations
• No access to medical records (HIPAA)
• Very complicated data difficult to understand
  and analyze.

David Graham FDA Presentation, February 2005
Arthritis Advisory Board
57
Preliminary Results Medi-Cal Study Dose
Response for AMI Risk with Rofecoxib
2.4
Odds Ratio
1.5
Odds Ratio
1.3
1.2
David Graham FDA Presentation, February 2005
Arthritis Advisory Board
58
Preliminary Results Medi-Cal Study AMI Risk
with NSAIDS
Odds Ratio
David Graham (data only) FDA Presentation,
February 2005 Arthritis Advisory Board
59
Risk of AMI with Naproxen
Odds Ratio
Relative Risk
David Graham FDA Presentation, February 2005
Arthritis Advisory Board
60
And what did you bring to the FDA meeting?

• Every member at the dinner had brought and NSAID
  with him or her
• Aspirin 1
• Ibuprofen 3
• Naproxen 40

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