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AN UPDATE ON CYCLOOXYGENASE ENZYME AS THERAPEUTIC AGENTS. Dr. Kripa Shanker Gupta Post Grad Student 2 nd Yr MAMC, N. Delhi. History. 1930 – Goldbatt : extraction of PGs from semen Von Euler : BP & smooth muscle contraction

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an update on cyclooxygenase enzyme as therapeutic agents

AN UPDATE ON CYCLOOXYGENASE ENZYME AS THERAPEUTIC AGENTS

Dr. Kripa Shanker Gupta

Post Grad Student 2nd Yr

MAMC, N. Delhi

history
History
  • 1930 – Goldbatt : extraction of PGs from semen

Von Euler : BP & smooth muscle contraction

  • 1950s – Purification of Prostaglandins
  • 1971 – John Vane : Aspirin acts through COX
  • 1980s – COX – constitutively expressed and unregulated.
  • Late 80s – COX induced by Inflammatory cytokines
  • 1991 – Second isoform of COX : COX – 2
  • 2002 – 3rd variant : COX – 3 ?
slide3
EICOSANOID FACTS
  • 20-carbon compounds
  • Include prostaglandins, prostacyclins, thromboxanes, leukotrienes
  • Physiological effects at very low concentrations
  • Many of their effects mediated by cyclic AMP or calcium second messengers
  • Unlike hormones, not transported in the blood
  • Local mediators that act where synthesized or in adjacent cells
slide4
Dietary linoleic acid

metabolism

Arachidonic acid

esterification

Membrane phospholipids

Cell Activation Events:

mechanical trauma,

cytokines

growth factors

Zyflo

Arachidonic acid

Anti-inflammatory glucocorticoids

Lipooxygenase

(LOX)

Cyclooxygenase

(COX)

Aspirin, Indomethacin, Ibuprofen

NSAIDs

Phospholipase A2 (PLA2)

GC induce lipocortin that inhibits PLA2

Prostaglandins

and thromboxanes

(Cyclic/ring product)

Leukotrienes

(Linear product)

Aspirin inhibits irreversibly

Indomethacin forms a salt bridge in the binding site

Ibuprofen competes for substrate binding

Zyflo competes with AA for binding

Figure1. Liberation of arachidonic acid and its metabolism to prostaglandins/ thromboxanes or to leukotrienes

slide5
aspirin

indomethacin

ibuprofen

O2

Cyclooxygenase

PGG2

2GSH

Hydroperoxidase

GSSG

Arachidonic Acid (6)

derived from membrane phospholipids

X

Prostaglandin

endoperoxide

synthase

PGH2

central intermediate

(Head of pathway)

Figure3. Conversion of arachidonic acid to PGH2

slide6
Thromboxane

Synthase

Prostacyclin

Synthase

PGI2

platelet disaggregation

(Inhibits aggregation);

vasodilation

 stomach acid secretion

TXA2

platelet aggregation

(Together)

vasoconstriction

platelets

endothelial

cells

Isomerase

(many cells)

Isomerase

(CNS, mast & fat cells)

PGE2

wake (Eye opener),

pain, fever, inflammation,

renal arteriolar dilation

PGD2

Sleep (Drowsy)

Reductase

fat cells

15-deoxy-12,14-PGJ2

induce fat cell differentiation

(Jumbo)

PGH2

central intermediate

(Head of pathway)

PGF2

labor induction (Fetus)

Figure3. Conversion of PGH2 to prostaglandins and thromboxane of the “2-series”

cyclooxygenase enzyme
Cyclooxygenase Enzyme
  • Earlier tissue homogenates used as source of enzymatic activity
  • Present in all cells
  • Purified enzyme by amide gel electrophoresis
  • Classified as integral microsomal membrane protein
  • Different PG synthesis rate and activity reported
evidence of cox isoforms
Evidence of COX isoforms
  • Autoinactivation rates of COX, inhibition of NSAIDS and time course profile of PGE2 and PGF2alpha synthesis

Activating platelets

– within minutes

PG Synthesis

Mitogen stimulated fibroblasts

– hours

  • Steroids inhibited the IL-1 induced COX activity but not basal COX activity
  • Cell Growth Studies – genes products inducible in-vitro exhibiting COX similarity
  • Western blot hybridization c DNA probe – 2 different mRNA 4 kbps and 2.8 kbps
discovery of cox 2
Discovery of COX - 2
  • Studies on cell division
  • Mitogen activated early genes activity in fibroblasts
  • Swiss 3T3 cells – sequence encoded new inducible gene
  • Mouse TIS10 cDNA expression increased prostaglandin E2 activity of which suppressed by NSAIDS
structural details
Structural Details
  • Both are dimer bound to microsomal membrane
  • 4 domains
    • Dimerization domain
    • Membrane binding domain
    • Catalytic domain – differ in structure
    • Terminal signal peptide domain – differ in length
  • Post/co translational glycosylation
slide14
A.

Physiological stimulus

B.

Inflammatory stimulus

(tissue injury, chronic arthritis)

macrophages/other cells

clotting, parturition,

gastrointestinal

and renal protection

COX-2

induced by cytokines (e.g., TNF)

COX-1

constitutive

Proteases

Prostaglandins

especially PGE2

Other inflammatory

mediators

(histamine, etc)

Prostacyclin

endothelium-anticlotting

stomach mucosa:

 H+,  HCO3-,

 mucus

PGE2

Kidney:

arteriolar

dilation;

Na+/H2O

excretion

TXA2

platelet

aggregation

PGF2

parturition

Inflammation, redness,

swelling, pain

Figure 8. Actions of two known isoforms of cyclooxygenase (COX).

newer isoforms variants
COX 1 Variants

COX -1 V 1 (COX – 3)

PCOX – 1A

PCOX – 1B

COX – 1 SNPs

Other

COX – 2 Variants

COX -2 V 1

PCOX – 2 B

COX – 2 SNPs

Other

Newer isoforms ( Variants )
cox 3 a theory without evidence
COX – 3 : a theory without evidence?
  • acetaminophen as a "COX-3" inhibitor or even a "selective COX-3 inhibitor" in rat studies
  • induced enzyme appearing 48 hours after the start of the inflammation
  • COX – 1 gene with intron -1 changing protein folding and active site confirmation
  • Expressed more in brain cells
nonsteroidal anti inflammatory drugs nsaids
Nonsteroidal Anti-inflammatory Drugs(NSAIDs)
  • Common therapeutic indications
  • Common adverse effects
  • Different pharmacokinetics and potency
  • Different chemical families
  • Common mechanism of action (cyclooxygenase inhibition)
  • Different selectivities to COX I and II

Similarities more striking than Differences

common therapeutic uses
Common Therapeutic Uses
  • Analgesic(CNS and peripheral effect) may involve non-PG related effects
  • Antipyretic (CNS effect)
  • Anti-inflammatory (except acetaminophen) rheumatic fever, rheumatoid arthritis, other rheumatological diseases: due mainly to PG inhibition.
  • Dysmenorrhoea
  • Prophylaxis of diseases due to platelet aggregation (CAD, post-op DVT)
  • PDA Closure
  • Pre-eclampsia and hypertension of pregnancy (?excess TXA2)
  • Some are Uricosuric
cox inhibitors
Non Selective COX inhibitors

Non competitive

Aspirin

Competitive

Phenylbutazone

Ibuprofen

Naproxen

Diclofenac

Piroxicam

Ketorolac

Analgesic with Antipyretic without anti inflammatory action

Paracetamol

Metamizol

Nefopam

Preferential COX – 2 inhibitors

Nimesulide

Meloxicam

Nabumetone

Selective COX -2 inhibitors

Celcoxib

Rofecoxib

Valdecoxib

Etoricoxib

Parecoxib

Lumoracoxib

COX inhibitors
slide24
COOH

O

O

O

O

O

O

COOH

OH

O

C

C

C

C

C

C

CH3

CH3

CH3

CH3

CH3

CH3

O

CH3

CH2

O

C

Ser

Acetylated

Cyclooxygenase

(inactive)

Figure4. Structure and

mechanism of action of aspirin

CH2

OH

Ser

Cyclooxygenase

(active)

need of selective cox 2 inhibitors
Need of Selective COX -2 Inhibitors
  • inhibition of COX-2 - anti-inflammatory effects
  • inhibition of COX-1 - recognized toxicities of NSAIDs,
    • a) peptic ulcers and the associated risks of bleeding, perforation and obstruction;
slide26
NSAID

Loss of PGI2 induced inhibition of LTB4 mediated

endothelial adhesion and activation of neutrophils

Loss of PGE2 and PGI2 mediated inhibition

of acid secretion and cytoprotective effect

↑ Leukocyte-Endothelial

Interactions

Capillary

Obstruction

Proteases +

Oxygen Radicals

Ischemic

Cell Injury

Endo/Epithelial

Cell Injury

Mucosal Ulceration

need of selective cox 2 inhibitors28
Need of Selective COX -2 Inhibitors
  • inhibition of COX-2 - anti-inflammatory effects
  • inhibition of COX-1 - recognized toxicities of NSAIDs,
    • a) peptic ulcers and the associated risks of bleeding, perforation and obstruction;
    • b) prolonged bleeding time; and,
    • c) renal insufficiency .
  • inflamed tissues target without disturbing the homeostatic functions of prostaglandins in noninflamed organs.
  • Theoretically, selective COX-2 inhibition should preserve the anti-inflammatory efficacy
what is selectivity
What is Selectivity
  • Ratio of COX – 1 / COX – 2 inhibition activity
  • COX -1 activity : ability to inhibit TXB 2 production from platelets
  • COX – 2 activity : ability to inhibit PGI 2 production from monocytes in response to stimuli
rise of coxibs
Rise of COXIBS
  • Large scale trials showed equal efficacy and lower GI side effects
  • Market taken by a storm
  • Celecoxib and then Rofecoxib became billion dollar drugs
  • Extensive chronic usage in Inflammatory disorders like RA, Osteoarthritis and other Inflammatory disorders
  • Newer Applications : Adenomas , AD
slide34
Risk of Hospitalization of Upper GI Bleeding in High Risk Patients

5

4

3.3

3

Adjusted Odds Ratio of Risk

2.1

2

1.3

1.0

1

0

Non-use

Celecoxib

Rofecoxib

NSAIDs

Comparison of GI Benefits

Adapted from Cardiovascular Safety of Celecoxib & Risk-Benefit Assessment - Celebrex, Pfizer, 2/16/05

big questions
Big Questions
  • Does COX-2 serve a physiological function(s)?
    • COX -2 in macula densa – response to Na+ restriction
    • Role in ovulation and fertility
    • Brain – temperature control
  • Does COX-1 serve an inflammatory function(s)?
    • No clear cut evidence – dubious gene knock out studies
correlation with gi symptoms
Correlation with GI symptoms
  • Theoretically COX – 2 inhibitors should be free of side effects
  • Increase in selectivity ratio should decrease the GI side effects.
disturbing reports from the long term trials of the coxibs

Disturbing Reports from the long term trials of the Coxibs

CLASS AND VIGOR TRIALS

RISE IN CVS EVENTS

celecoxib clinical trials
Celecoxib clinical trials
  • Four Main Trials
      • CLASS
      • APC
      • PreSAP
      • ADAPT
class trial
CLASS Trial
  • Purpose
    • GI toxicity
    • Pain alleviation efficacy
  • Patients
    • 8000 patients
    • Average age of 60 y.o.
    • With Osteoarthritis or Rheumatoid Arthritis
    • Without history of GI disease
class trial serious cv events
CLASS Trial:Serious CV Events

Adapted from COX-2 CV Safety - Celecoxib, Dr. James Witter, MD, PhD. 2/16/05

class trial conclusions
NO RISKCLASS Trial:Conclusions
  • GI risk is lower than NSAIDs
  • No significant difference between NSAIDs and Celecoxib for CV risk
apc trial
APC Trial
  • Purpose
    • Reduce probability of adenomatous polyps (reduction of colon cancer)
  • Patients
    • 2000 patients
    • Average age of 60 y.o.
    • Prior adenomas
slide47
Adapted from a New England Journal of Medicine article: “Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention”, March 17, 2005.
slide48
APC Trial:

Death Rates

Adapted from Celecoxib in Adenoma Prevention - The APC Trial, Dr. Ernest Hawk, MD, MPH, NIH, 2/15/2005

apc trial conclusions
RISKAPC Trial:Conclusions
  • Early trial suspension
    • Planned duration of 3-5 years
    • Stopped early but followed patients for about 3 years
  • Fair trial results
  • Significant difference between Celebrex CV risk and placebo CV risk
presap trial
PreSAP Trial
  • Purpose
    • Reduce risk of cancerous polyps
  • Patients
    • 1500 patients
    • Average age of 61 y.o.
    • Had growths surgically removed
slide52
PreSAP Trial:

CV Death Rates

*Relative to placebo

Adapted from Celecoxib in Adenoma Prevention - The PreSAP Trial, Dr. Bernard Levin, MD FDA, 2/16/2005

presap trial data
Celecoxib

Placebo

PreSAP Trial:Data

Adverse CV event risk in

Celecoxib vs. Placebo

Estimated probability of CV death,

heart attack, stroke, or CHF (log)

Months since first dose

presap trial conclusions
NO RISKPreSAP Trial:Conclusions
  • Trial suspended early
    • Planned duration of 3-5 years
    • Stopped because of APC trial
  • No significant difference between placebo CV risk and Celecoxib CV risk
adapt trial
ADAPT Trial
  • Purpose
    • Reduce risk of Alzheimer’s Disease
  • Patients
    • 2625 patients
    • Average age of 70 y.o.
    • At risk of Alzheimer’s
adapt trial data
ADAPT Trial:Data
  • Naproxen showed CV risk after 1.5 years
  • Planned duration of 7 years
    • Began: 2001
    • Stopped: 2004, 3 days after APC Trial was stopped
adapt trial conclusions
RISKADAPT Trial:Conclusions
  • Significant difference in data shows Naproxen as worse than Celecoxib
  • Celecoxib is still significantly worse than Placebo
  • Data contradicts previous Naproxen trials
  • Results are unexplainable
slide58
Comparison of Risk of Death, Heart Attack, and Stroke

Relative Risk

Celecoxib vs.

Placebo

NSAID

Naproxen

Diclofenac

Ibuprofen

0.1

0.1 0.3 1.0 3.0 10.0

Favors celecoxib

Favors comparator

Adapted from Cardiovascular Safety of Celecoxib & Risk-Benefit Assessment - Celebrex, Pfizer , Feb 15, 2005

vigor summary of gi endpoints
VIGOR - Summary of GI Endpoints

Rofecoxib

RR: 0.46†

(0.33, 0.64)

Naproxen

5

RR: 0.38†

(0.25, 0.57)

4

RR: 0.43*

(0.24, 0.78)

3

Rates per 100 Patient-Years

2

1

0

Confirmed Clinical Upper GI Events

ConfirmedComplicatedUpper GI Events

All Clinical

GI Bleeding

* p = 0.005.

( ) = 95% CI.

†p < 0.001.

Source: Bombardier, et al. N Engl J Med. 2000.

vigor confirmed thrombotic cardiovascular events
VIGOR - Confirmed Thrombotic Cardiovascular Events

Patients with Events (Rates per 100 Patient-Years)

Rofecoxib

N=4047

Naproxen

N=4029

Relative Risk

(95% CI)

Event Category

45 (1.7)

19 (0.7)

0.42

(0.25, 0.72)

Confirmed CV events

28 (1.0)

10 (0.4)

0.36

(0.17, 0.74)

Cardiac events

8 (0.3)

0.73

(0.29, 1.80)

Cerebrovascular events

11 (0.4)

0.17

(0.00, 1.37)

Peripheral vascular events

6 (0.2)

1 (0.04)

slide63
Rofecoxib (VIGOR)

Naproxen (VIGOR)

Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study Compared with Phase II/III OA Study

3.5

3.0

2.5

Ibuprofen, Diclofenac, Nabumetone (OA)

2.0

Rofecoxib(OA)

Cumulative Incidence %

1.5

1.0

0.5

0.0

0

2

4

6

8

10

12

14

Months of Follow-up

effect of celecoxib rofecoxib on pgim
Effect of Celecoxib & Rofecoxib on PGIM

Urinary 2,3 dinor-6-keto-PGF1a (PGIM)

Two Weeks Rx††

Single Dose Rx†

200

200

160

160

120

120

Urinary PGI-M (pg/mg creatinine) (Mean ± SE)

*

80

80

**

**

**

40

40

0

0

Placebo

N=7

Celecoxib 400 mg

N=7

Ibuprofen 800 mg

N=7

Placebo

N=12

Rofecoxib50 mg QDN=12

Indomethacin50 mg TIDN=10

* p<0.05 vs. placebo.

†Proc. Natl. Acad Sci. USA 1999;96:272-277.

**p<0.01 vs. placebo.

††J. Pharmacol. Exp. Ther. 1999;289:735-741.

approve trial
APPROVe trial
  • Adenomatous Polyp Prevention on VIOXX
  • 2,586 Patients of adenomatous polyp randomized to 25 mg of rofecoxib or placebo
  • trial was stopped early
  • increased risk for serious cardiovascular events, such as heart attacks and strokes, first observed after 18 months
slide68
Arachidonic acid

Arachidonic acid

PGH2

PGH2

Prostacyclin (PGI2)

Thromboxane (TXA2)

 cAMP/vessel smooth muscle relaxes

 Ca2+aggregation

Blood Vessel Wall

Endothelial Cell

Platelet

cAMP aggregation

 Ca2+/vessel smooth muscle constricts

Figure 5. Normal physiologic interaction between PGI2 and TXA2

in platelet and endothelial cell biology

slide69
PGI2

TXA2

Injury

TXA2

PGI2

TXA2

PGI2

Endothelial Cell

Blood Vessel Wall

Platelet

Smooth

Muscle Cell

TXA2

PGI2

Injury

Normal Physiology

HEALTHY

Figure 6. Reendothelialization of the artery wall following injury and the key role of platelet aggregation stimulated by TXA2 in response to injury.

slide70
Endothelial Cell

Endothelial Cell

Blood Vessel Wall

Blood Vessel Wall

Injury: catheter,

turbulence, etc.

Smooth

Muscle Cell

Smooth

Muscle Cell

PGI2

TXA2

Injury

Aggregated

Platelets

DAMAGED

Figure 6. Reendothelialization of the artery wall following injury and the key role of platelet aggregation stimulated by TXA2 in response to injury.

slide71
Endothelial Cell

Endothelial Cell

Blood Vessel Wall

Blood Vessel Wall

Injury: catheter,

turbulence, etc.

Platelet

Smooth

Muscle Cell

Smooth

Muscle Cell

TXA2

PGI2

TXA2

PGI2

TXA2

Injury

Reendothelialization

Normal Physiology

PGI2

Aggregated

Platelets

DAMAGED

HEALTHY

Figure 6. Reendothelialization of the artery wall following injury and the key role of platelet aggregation stimulated by TXA2 in response to injury.

slide72
Endothelial Cell

Blood Vessel Wall

Normal Physiology

Platelet

Smooth

Muscle Cell

TXA2

TXA3

PGI3

PGI2

TXA2

favors platelet

disaggregation

favors platelet

disaggregation

Low dose aspirin intervention

Knocks down platelet TXA2

Dietary 3 fatty acid inter-

vention (cold water fish)

PGI3 activity >> TXA3

PGI2

TXA2

PGI2

TXA3

TXA2

PGI3

Platelets lack nucleic; cannot replace COX – TXA preferentially 

Figure7. Control of platelet aggregation.

Suppression of platelet aggregation by drug or dietary intervention

what fda says
What FDA says
  • FDA 1st release : Feb 18 , 2005
    • Supported the marketing of vioxx in market
    • Committee recommend black box warning on cardiovascular risk, dose should be only 12.5 mg instead of 25/50 mg
  • FDA 2nd release : Feb 18 , 2005
    • The effect is evident in every drug of this class and is dependant on both time period and the dose of the drug
what the fda says
What the FDA Says
  • Neutral: “Celecoxib requires further study to estimate longer-term CV risks…”
  • Positive: “There does not appear to be any clinically or statistically significant trend with celecoxib to suggest additional cardiovascular risks over the comparator drugs.”
  • Negative (almost): “Some studies appear to show an increased risk of CV events, but the findings are not consistent across the COX-2 selective NSAIDs.”
clinical trials of new cox 2 inhibitors

Clinical Trials of New Cox-2 Inhibitors

Etoricoxib

Valdecoxib

Parecoxib

Lumiracoxib

valdecoxib selective cox 2 inhibitor
Valdecoxib, selective Cox-2 inhibitor
  • Approved by the FDA in November 2001, but now under close watch

Risk-Benefit Analysis

    • Efficacy is comparable to nonselective NSAIDs
    • Better GI safety profile
    • Generally similar cardiovascular risks
    • Serious skin reactions (Stevens-Johnson)
    • Less promising than the new investigational drugs

New clinical testing in progress

cv risks in cabg i surgery setting
CV Risks in CABG I Surgery Setting

Study 071

Higher risk in almost all CV categories adjudicated

cv risks in cabg ii surgery setting
CV Risks in CABG II Surgery Setting

Study 071

Higher risk in almost all CV categories adjudicated

black box warning valdecoxib
Black box warning : Valdecoxib
  • Contraindicated in CABG patients
  • Serious skin reaction : Steven johnson syndrome and erythema multiforme
  • Discontinue after first skin rash or mucosal lesion
etoricoxib
Etoricoxib
  • Etoricoxib, selective COX-2 inhibitor
  • Developed to diversify existing treatment options for inflammatory conditions
  • Currently approved in 60 countries
  • New Drug Application (NDA)

Recent Phase III clinical trials

    • Chronic Exposure Studies – 4087 patients, 13 trials
    • EDGE Study – diclofenac as active comparator
clinical efficacy
Clinical Efficacy

Osteoarthritis (OA), Rheumatoid Arthritis (RA), chronic low back pain, acute gouty arthritis, acute pain, and ankylosing spondylitis

Efficacy demonstrated by statistically significant improvements in 3 areas

1. Physical Function

2. Pain Subscale

3. Patient Evaluation

gastrointestinal safety and tolerability
Gastrointestinal Safety and Tolerability
  • Primary endpoints: gastroduodenal perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding)
  • Overall superior GI safety and tolerability compared to traditional NSAIDs (COX-1 expression, fewer discontinuations)

Support for etoricoxib as an alternate therapy for patients experiencing significant GI problems with nonselective NSAIDs

cumulative rate of gi ulcers
Cumulative Rate of GI Ulcers

Etoricoxib Naproxen Ibuprofen

renovascular safety
Renovascular Safety
  • Inhibition of renal prostaglandin synthesis complicates renal blood flow -> impaired kidney function

1. fluid retention (edema)

2. hypertension

3. Congestive Heart Failure

  • Edema, hypertension, and CHF were mild and infrequently led to discontinuations

Generally consistent with rates observed for nonselective NSAIDs

incidence of hypertension
Incidence of Hypertension
  • Elevation in blood pressure

Mean Incidence (Etoricoxib)

cardiovascular safety
Cardiovascular Safety
  • Primary Endpoint: Confirmed Thrombotic Serious Adverse Experiences

- unstable angina, myocardial infarction, ischemic stroke, and transient ischemic attacks

  • Pooled CV Phase IIb/III data: Over 6700 patients
thrombotic cardiovascular incidence
Thrombotic Cardiovascular Incidence

Placebo-Controlled

Non-Naproxen-Controlled

Naproxen-Controlled

Higher Incidence

Higher Incidence

Lower Incidence

incidence of edema related events
One-year continuous exposure (Etoricoxib vs. Naproxen)

no dose-related effect

consistent with rates observed for NSAIDs

Incidence of Edema-Related Events

Mean Incidence (Etoricoxib)

Lower Extremity Edema

etoricoxib conclusions
Great clinical efficacy for OA, RA, and other inflammatory conditions

Two unique treatment options – ankylosing spondylitis and acute gouty arthritis

No major CV risk pattern with current evidence

Significantly improved GI safety (ulcer incidence and upper GI complications)

Further studies needed: EDGE, MEDAL, EDGE II (>34500 patients, largest NSAID analysis)

Etoricoxib Conclusions
lumiracoxib selective cox 2 inhibitor
Lumiracoxib, selective COX-2 inhibitor
  • Developed as a new treatment option with lower GI side effects
  • Approved in 21 other countries, including the U.K.
  • Phase III clinical trials and NDA in progress
clinical efficacy93
Clinical Efficacy

Efficacy demonstrated for:

1. Osteoarthritis and Rheumatoid Arthritis

2. Other chronic pain conditions

3. Acute pain (post-surgical)

  • 50 clinical and clinical pharmacology trials - 13000 patients worldwide
  • As effective as celecoxib in pain relief
  • FDA approval and market viability dependent on side effect profile
renovascular safety95
Renovascular Safety

De Novo Hypertension

  • Kaplan-Meier Estimate (%)
  • Lower rates for Lumiracoxib than Ibuprofen
  • Same trend for aggravation and severe
  • Clinically significant

Edema (fluid retention)

  • Lower rates for Lumiracoxib than Ibuprofen
  • Few discontinuations

lumiracoxib

>95% CL

lumiracoxib

>95% CL

cardiovascular safety96
Cardiovascular Safety
  • Primary Endpoint:Anti-Platelet Trialist Collaboration
    • myocardial infarction, stroke, or vascular death
  • 33,933 patients in these trials
  • Overall Results – APTC endpoint
cardiovascular safety conclusions
Cardiovascular Safety Conclusions

No statistically significant difference

between lumiracoxib and NSAIDs for

MI, ischemic stroke, and APTC

events

Slightly better CV profile than Vioxx

  • Smaller changes in mean BP
  • Smaller relative risk compared to Naproxen
  • Less inhibition of vasoactive PGI-2 that suppresses platelet aggregation

(15% vs. 73%)

lumiracoxib conclusions
Lumiracoxib Conclusions
  • No new patient populations – less likely to see major market success
  • Improved GI and renovascular safety profile compared to nonselective NSAIDs
  • Phase III possibly suggests fewer cardiovascular risks than Vioxx
  • More clinical trials needed for approval
parecoxib selective cox 2 inhibitor
Parecoxib, selective COX-2 inhibitor
  • Developed to provide significant analgesia without GI profile
  • Medical need – inadequate treatment options for postoperative pain have prolong hospitalization and allow progression to chronic status
  • Not yet approved by the FDA (original NDA submitted Sept. 2001), but sold in 45 other countries
  • First injectable COX-2 inhibitor
  • Total of 65 studies completed, including 24 analgesia studies
clinical efficacy100
Clinical Efficacy

3 Major Data Sets

Placebo-Controlled

Morphine-Controlled (opioid analgesic)

Ketorolac-Controlled (conventional NSAID)

Efficacy in controlling post operative pain (Phase III)

Conventional treatments for post-operative pain

  • Scale ranged from 0-11
  • High number indicates impaired function

2.0

1.5

Mean Scorea

1.0

Placebo (n=519)

Parecoxib / Valdecoxib (n=520)

0.5

Days

0

2

3

4

5

6

7

8

9

10

reduction in need for opioids
75

66.2

50

43.2

Morphine Equivalents (mg)

25

0

Reduction in Need for Opioids

Placebo (n=519)

Parecoxib / Valdecoxib (n=520)

  • Significant reduction in need for opiod analgesics with same levels of pain control
side effect profile
Side Effect Profile
  • Normal therapeutic dose does not appear to affect COX-1 enzyme
  • Generally lower incidence of gastrointestinal ulcerationand bleeding compared to nonselective NSAIDs
  • Avoids respiratory depression and other common opioid side affects
  • Often combined with Bextra for clinical administration
cardiovascular safety103
Cardiovascular Safety

Study 069 – General Surgery Study

No significant cardiovascular risk relative to placebo

CV risk only found in CAGB surgery setting

parecoxib conclusions
Parecoxib Conclusions

Medical need

Unique advantages over current analgesics

1. better side effect profile

2. comparable or better efficacy

Minimal cardiovascular risk under normal surgical settings - only observed risk for CAGB surgery

Opens COX-2 inhibitors to a new subgroup of patients – great market potential

overall conclusions
Overall Conclusions
  • Greatly improved GI profile because of selectivity
  • Lumiracoxib and Parecoxib offer the most promising cardiovascular profile
  • Important to evaluate blood pressure effects and platelet aggregation independently
  • R & D to expand treatment groups and continue minimizing side effects
  • More clinical evaluation and analysis needed – statistically significant trends
further research
Further Research
  • Other emerging investigational drugs that have not yet been approved by the FDA
  • Further analysis of the relative CV profiles of all four drugs compared to Rofecoxib and Celecoxib
  • Possible alternate uses (chemopreventive effects and Alzheimer’s)
  • Status of each NDA
  • New Phase III clinical trials
current status
Current Status
  • Merck Has withdrawn Vioxx
  • USFDA says Rofecoxib should come with a warning
  • Researchers say It’s a CLASS Effect ?
  • India Has banned Rofecoxib and Valdecoxib
  • Celecoxib has been approved in Adenomatous polyp by US FDA
  • Some European countries have banned the drug , others follow suit of US FDA rulings
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