Cox2i workshop

Chris Benham
Analgesics

1899

100 years of improvements

1999 c.1990
Cox-1
Cox-2
identified
 Aspirin , NSAIDs, Cyclo-oxygenase
• Aspirin, acetylsalicylic acid irreversibly inhibits
cyclo-oxygenase, blocks inflammatory
prostaglandin (PG) synthesis
- nociceptive pathways… analgesia
- hypothalamus … antipyretic
• Blocks production of cytoprotective PGs in gut wall
- about 1200 deaths pa in UK due to NSAIDs
• Blocks thromboxane production in platelets
- anti-coagulant
- platelets have no nuclei, no new enzyme
synthesis
- Aspirin effective on platelets in low doses
 Pain pathways
Cortex
Pain!

Peri-aqueductal Descending
pathways + Opioids Brain
Grey (PAG)
Stem

-
NSAIDs NSAIDs
- -
Excite
Noxious C-fibre
Transmission
stimulus activity
neuron
-
Opioids Dorsal horn
Of spinal cord
tissue Sensory nerve spinal cord
 NSAID improvements
• 1970s, gut sparing NSAIDs
e.g. etodolac, nimesulide,
meloxicam

• HOW?
- Used in vivo animal models
to empirically improve therapeutic index
- carrageenan induced oedema
- adjuvant induced arthritis
vs
- fasted rat stomach inflammation for GI effects

• Molecular basis of improved profile not understood

Novel NSAIDS
 Discovery of Cox-1 and Cox-2
• Cox-1 cloned 1988, Cox-2 cloned 1991
• 1990s in vitro screening against enzyme
isoforms
• 1999, Vioxx (rofecoxib), Celebrex,
(celecoxib) launched
• 2003 sales of Cox-2 inhibitors $5Bn

CYCLOOXYGENASES 1 AND 2 J. R. Vane, Y. S. Bakhle1, and R. M. Botting

Ann Review of Pharmacol and Toxicol 38: 97-120 (1998)
 Coxib Pharmacology

Rofecoxib more Cox-2 selective than celecoxib

Garret A. FitzGerald
Nature Reviews Drug Discovery 2, 879-890 (November 2003)
 Arachidonic acid metabolism pathways

PLA2
Non- selective compounds

Arachidonic acid

Cox location and

hence substrate
X Aspirin X
availability determines
products COX-1 COX-2
Induced
constitutive by inflammation (TNFa)

PG PGI2
Gut wall TXA2
endothelium
platelets Block stops
PGE2
Block causes PGF2
Inflammation
gastric ulcers PGD2 pain
Block stops platelet Block causes
aggregation Platelet aggregation
Smc proliferation
 Arachidonic acid metabolism pathways

PLA2
Cox-2 selective compounds

Arachidonic acid

Cox location and

hence substrate
X Cox2i

availability determines
products COX-1 COX-2
Induced
constitutive by inflammation (TNFa)

PG PGI2
Gut wall TXA2
endothelium
platelets Block stops
PGE2
PGF2
Inflammation
Protective Block causes PGD2 pain
PGs thromboxane Platelet aggregation
Smc proliferation
 Regulatory approval by the Food and
Drug Administration (FDA)
• FDA: Enforce laws from U.S. Congress (eg., Federal Food,
Drug and Cosmetic Act) and FDA regulations
• Regulations related to drugs: Section 21 Code of Federal
Regulations (21 CFR)
 Regulatory position at VIOXX
approval
• Vioxx received six-month priority review because:
– potentially provided significant therapeutic advantage over
existing drugs (fewer GI side effects, including bleeding)

• Original Vioxx safety database included

approximately 5000 patients
– No increased risk of heart attack or stroke
– Short duration

• FDA originally approved Vioxx in May 1999

VIGOR
 Cox-2 inhibitor side-effects?
• VIGOR 2000 (NEJM 2000 343:1520-1528 )
Comparison of upper GI events in RA patients treated
with naproxen or Vioxx
“2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib,
as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95
percent confidence interval, 0.3 to 0.6; P<0.001”
“The incidence of myocardial infarction was lower among patients in the naproxen
group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative
risk, 0.2; 95 percent confidence interval, 0.1 to 0.7 “
• Fewer GI events but ..
more MI with Vioxx protective effects of naproxen or
damaging effects of Vioxx?

• Further trials to seek expanded indications (APPROVE)

 Cox inhibition-balancing act
Non-selective compounds
GI damage

Pro-thrombotic anti-coagulant

Cox-2 selective compounds

GI protective prostaglandins

Some concerns
Pro-thrombotic
in 1999 about this
hypothetical
(at the time)risk
Post Marketing studies
 KO mouse studies suggest balance between
prostacyclin and thromboxane activity

Prostacyclin receptor (IP) knockout

results in thickening of blood vessel wall
And increase in wire induced damage
(c.f. Cox2i)
IPTP
Thromboxane receptor (TP) knockout
results in reduced thickening
and reduced damage

Double knockout is no different from

Wildtype (c.f. aspirin)

IPTP
Garret A. FitzGerald
Nature Reviews Drug Discovery 2, 879-89 ( 2003)
 APPROVe trial
• History of colorectal adenoma
• 25 mg rofecoxib vs placebo
• Cancer prevention and CV outcomes
• CV Outcome composite of MI, unstable
angina, stroke, thrombosis
• RR with rofecoxib 1.92 (1.19-3.11)

( Zarraga et al. J Am Coll Cardiol 2007, 49;1-14)

Merck yanks arthritis drug Vioxx

Drugmaker says ongoing trial shows medication

boosts risk of heart attack; shares tumble 27%.
October 6, 2004: 7:50 AM EDT

NEW YORK (CNN/Money) - Merck & Co. on Thursday

recalled its arthritis drug Vioxx after an ongoing trial
confirmed the medication increases the risk of heart
attack and strokes. The news sent stock down nearly
27 percent and erased $25 billion from its market
value.

CNN News Oct 6th 2004

 Regulatory perspective on Cox2i after
Vioxx withdrawal
• FDA requested a label change in May 2002, 18 months
after VIGOR results reported - too late

• FDA no role in Merck’s decision to withdraw product

– FDA response: ‘The Agency has not had an opportunity to
review the data from the study that was stopped in the depth
that Merck has, but agrees with the company that there appear
to be significant safety concerns for patients, particularly those
taking the drug chronically.’

• FDA issued a Public Health Advisory concerning the use

of Vioxx. based on Merck & Co., Inc. voluntarily withdrawing
 Vioxx event timeline
Arthritis advisory Merck halt long-term
EMA & MHRA
committee meet study (APPROVe)
review of CV risk
to discuss due to CV risk
non-selective
VIOXX versus
VIGOR results placebo
NSAIDS

VIGOR results FDA requested Merck voluntarily

released; new CV warnings withdraws Vioxx
risk MI on Vioxx label
 2007 update
• Vioxx settlement to total $4.85bn
• The maker of Vioxx has agreed to pay $4.85bn to
settle legal claims that the controversial drug caused
many users to suffer strokes and heart failure.
• Merck & Co said it was setting up a fund to compensate
victims, adding that claimants would only receive
payment if certain key conditions were met.
• To qualify, individuals must prove they suffered serious
illness, at the most two weeks after they bought the drug.
• The deal may end multiple lawsuits but Merck has not
admitted any liability.

BBC News Friday, 9 November 2007

 What about other Cox-2 inhibitors
• Many retrospective analyses of patients
treated by Cox inhibitors
• Cox-2 inhibitors should not be given to
patients with history of myocardial
infarction (Circulation 2006 113(25):2906-13 )
• Celebrex remains on market
- sales about $2Bn in 2006
$3Bn in 2014
 Point Estimates and Summary Relative Risks for
Cardiovascular Events With Rofecoxib and
Celecoxib (Observational studies)

Overrall analysis of rofecoxib shows significant risk, but not for celecoxib
Copyright restrictions may apply. McGettigan, P. et al. JAMA 2006;296:1633-1644.
 Point Estimates and Summary Relative Risks for
Cardiovascular Events With Naproxen and Diclofenac
Are other older NSAIDs safe?

Copyright restrictions may apply.

McGettigan, P. et al. JAMA 2006;296:1633-1644.
McGettigan, P. et al. JAMA 2006;296:1633-1644.

• Confirms risks of rofecoxib

• Suggests no increase in risk with
celecoxib
• No evidence of protective effect of
naproxen
• Questions safety of diclofenac

McGettigan, P. et al. JAMA 2006;296:1633-1644.

Study of risks continues..
 Cardiovascular Risk Associated with NSAIDs
among Myocardial Infarction Patients

97,698 patients
PLoS One. 2013;8(1):e54309. doi: 10.1371 44% taking NSAIDs
Cardiovascular Safety of Celecoxib,
Naproxen, or Ibuprofen for Arthritis

RCT of 24000 patients, Pfizer funded

Results:
All cardiovascular events
hazard ratio for celecoxib versus naproxen
was 0.97 (95% CI, 0.83 to 1.12; P=0.64),

hazard ratio for celecoxib versus ibuprofen

was 0.87 (95% CI, 0.75 to 1.01; P=0.06).

Conclusion: Celecoxib not inferior.

N Engl J Med 2016; :2519-2529
 Questioning the prostacyclin
dogma
Cyclooxygenase-1, not cyclooxygenase-2,
is responsible for physiological
production of prostacyclin in the
cardiovascular system
Nicholas S. Kirkby, Martina H. Lundberga, Louise S. Harrington, Philip
D. M. Leadbeater, Ginger L. Milne,
Claire M. F. Potter, Malak Al-Yamani, Oladipupo Adeyemi, Timothy D.
Warner, and Jane A. Mitchell

PNAS 2012;109:17597-17602
 Arachidonic acid metabolism pathways

PLA2
Cox-2 selective compounds

Arachidonic acid

Cox location and

hence substrate
X Cox2i

availability determines
products COX-1 COX-2
Induced
constitutive by inflammation (TNFa)
???????????
PG PGI2
Gut wall TXA2
endothelium
platelets Block stops
PGE2
PGF2
Inflammation
Protective Block causes PGD2 pain
PGs thromboxane Platelet aggregation
Smc proliferation
 Expression and activity of COX-1 and COX-2 in endothelium and vessels.

Kirkby N S et al. PNAS 2012;109:17597-17602

©2012 by National Academy of Sciences

 Effect of time postmortem on COX-1 and COX-2 expression and activity in mouse aorta.

Cox-2 increases

Cox-1 stays same

Cox-1 KO has very

Little Cox activity
Immediately
post-mortem

Kirkby N S et al.
PNAS 2012;
109:17597-17602

©2012 by National Academy of Sciences

 Conclusions
• Benefit – risk profiles of NSAIDs are not all
the same
• Non-selective NSAIDs have no CV benefit
• Cardiovascular risks do not correlate well
with Cox2i selectivity
• Possible molecule specific, off target
effects are important