AN UPDATE ON CYCLOOXYGENASE ENZYME AS THERAPEUTIC AGENTS
Dr. Kripa Shanker Gupta Post Grad Student 2nd Yr MAMC, N. Delhi
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 ?
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
Dietary linoleic acid
metabolism
Arachidonic acid esterification Cell Activation Events: mechanical trauma, cytokines growth factors Anti-inflammatory glucocorticoids Membrane phospholipids Phospholipase A2 (PLA2) Arachidonic acid Cyclooxygenase (COX)
Zyflo
GC induce lipocortin that inhibits PLA2
Lipooxygenase (LOX) Leukotrienes (Linear product)
Aspirin, Indomethacin, Ibuprofen Prostaglandins NSAIDs and thromboxanes (Cyclic/ring product) Aspirin inhibits irreversibly Indomethacin forms a salt bridge in the binding site Ibuprofen competes for substrate binding
Zyflo competes with AA for binding
Figure 1. Liberation of arachidonic acid and its metabolism to prostaglandins/ thromboxanes or to leukotrienes
Arachidonic Acid (6) derived from membrane phospholipids
aspirin indomethacin ibuprofen
X
PGG2 2GSH GSSG
O2 Cyclooxygenase Prostaglandin endoperoxide synthase Hydroperoxidase
PGH2 central intermediate (Head of pathway)
Figure 3. Conversion of arachidonic acid to PGH2
Thromboxane Synthase TXA2
platelet aggregation (Together) vasoconstriction
platelets
Prostacyclin PGI 2 central intermediate Synthase platelet disaggregation (Head of pathway) (Inhibits aggregation); endothelial vasodilation cells Isomerase (many cells) PGE2 wake (Eye opener), pain, fever, inflammation, renal arteriolar dilation Reductase fat cells PGF2 labor induction (Fetus)
PGH2
stomach acid secretion
Isomerase (CNS, mast & fat cells) PGD2 Sleep (Drowsy)
15-deoxy-12,14-PGJ2 induce fat cell differentiation (Jumbo)
Figure 3. Conversion of PGH2 to prostaglandins and thromboxane of the “2-series”
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
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
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
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
COX-1 enzyme Expression Constitutional Unchanged by glucocorticoids Expressed at baseline (in stomach, kidneys, platelets, intestines) Kinetics Instantaneous inhibition Inhibition via hydrogen bonding
COX-2 enzyme
Inducible (by cytokines)
Blocked by glucocorticoids
Expressed during inflammation (in macrophages, synoviocytes) Time-dependent inhibition ?Covalent bonding
A.
Physiological stimulus
B.
Inflammatory stimulus
(tissue injury, chronic arthritis) macrophages/other cells COX-2 induced by cytokines (e.g., TNF)
clotting, parturition, gastrointestinal and renal protection
COX-1 constitutive
TXA2
platelet aggregation
Prostacyclin
endotheliumanticlotting
stomach mucosa: H+, HCO3-, mucus
PGE2
Kidney: arteriolar dilation; Na+/H2O excretion
Proteases Prostaglandins Other inflammatory especially PGE2 mediators (histamine, etc)
PGF2
parturition
Inflammation, redness, swelling, pain
Figure 8. Actions of two known isoforms of cyclooxygenase (COX).
Newer isoforms ( Variants )
COX 1 Variants
COX – 2 Variants
COX -1 V 1 (COX – 3) PCOX – 1A PCOX – 1B COX – 1 SNPs Other
COX -2 V 1 PCOX – 2 B COX – 2 SNPs Other
Isoforms
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 Antiinflammatory 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
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
Preferential COX – 2 inhibitors
Competitive
Aspirin
Nimesulide Meloxicam Nabumetone
Phenylbutazone Ibuprofen Naproxen Diclofenac Piroxicam Ketorolac
Selective COX -2 inhibitors
Analgesic with Antipyretic without anti inflammatory action
Paracetamol Metamizol Nefopam
Celcoxib Rofecoxib Valdecoxib Etoricoxib Parecoxib Lumoracoxib
Figure 4. Structure and mechanism of action of aspirin
CH2 OH Ser
COOH O O C CH3 O C CH3 Cyclooxygenase O (active) C O 3 CH O C CH3 O O C CH3 CH2 C C 3 3 O CH CH COOH OH Ser
Acetylated Cyclooxygenase (inactive)
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;
NSAID
Loss of PGI2 induced inhibition of LTB4 mediated endothelial adhesion and activation of neutrophils
↑ Leukocyte-Endothelial Interactions
Capillary Obstruction
Ischemic Cell Injury
Proteases + Oxygen Radicals Endo/Epithelial Cell Injury
Mucosal Ulceration
Endoscopic Picture of Gastric Ulcer10
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
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
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
Comparison of GI Benefits
Adjusted Odds Ratio of Risk
5 4 3.3 3 2 2.1 1.0 1.3
Risk of Hospitalization of Upper GI Bleeding in High Risk Patients
1
0
Non-use
Celecoxib
Rofecoxib
NSAIDs
Adapted from Cardiovascular Safety of Celecoxib & Risk-Benefit Assessment - Celebrex, Pfizer, 2/16/05
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
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
CLASS AND VIGOR TRIALS
RISE IN CVS EVENTS
Celecoxib clinical trials
Four Main Trials
CLASS APC PreSAP ADAPT
CLASS Trial
Purpose
Patients
GI toxicity Pain alleviation efficacy 8000 patients Average age of 60 y.o. With Osteoarthritis or Rheumatoid Arthritis Without history of GI disease
CLASS Trial: Celecoxib vs. NSAIDs
With Aspirin Without Aspirin Celecoxib NSAIDs Celecoxib NSAIDs
GI event (%) GI plus ulcers (%) Negative heart effect (%) 2.01 4.70 6.1 2.12 6.00 5.7 0.44 2.40 1.5 1.27 2.91 1.2
CLASS Trial: Serious CV Events
Celecoxib
Aspirin Users Heart Attack Combined Atrial Any serious chest pain Non-Aspirin Users Heart Attack Combined Atrial Any serious chest pain 0.3% 0.3% 0.6% 0.2% 0.1% 0.4% 0.2% 0% 0.2% 2.5% 1.4% 3.9% 0.8% 0.4% 4.6% 2.8% 1.6% 3.2%
Diclofenac
Ibuprofen
Adapted from COX-2 CV Safety - Celecoxib, Dr. James Witter, MD, PhD. 2/16/05
CLASS Trial: Conclusions
GI risk is lower than NSAIDs No significant difference between NSAIDs and Celecoxib for CV risk
NO RISK
APC Trial
Purpose
Reduce probability of adenomatous polyps (reduction of colon cancer) 2000 patients Average age of 60 y.o. Prior adenomas
Patients
APC Trial: Baseline Characteristics
Placebo
CV History 47.3 (%) Aspirin 31.4 use
Celecoxib (200mg)
48.9 29.3
Celecoxib (400mg)
45.8 29.8
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.
APC Trial: Death Rates
Placebo
Death from CV causes Death from non-CV causes Death from any cause 0.1% 0.7% 0.9%
Celecoxib 200 mg
0.4% 0.4% 0.9%
Celecoxib 400 mg
0.9% 0.4% 1.3%
Adapted from Celecoxib in Adenoma Prevention - The APC Trial, Dr. Ernest Hawk, MD, MPH, NIH, 2/15/2005
APC 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
Purpose
Reduce risk of cancerous polyps
1500 patients Average age of 61 y.o. Had growths surgically removed
Patients
PreSAP Trial: CV Death Rates
Cause of Death
CV causes CV causes or heart attack
Placebo
0.6% 1.1%
Celebrex 400mg
0.2% 1.2%
CV causes, heart attack, or stroke
CV causes, heart attack, stroke, or heart failure
1.9%
1.9%
2.0%
2.1%
CV causes, heart attack, stroke, heart failure, or angina
CV causes, heart attack, stroke, heart failure, angina, or need for a CV procedure
*Relative to placebo
2.4%
2.7%
3.0%
3.6%
Adapted from Celecoxib in Adenoma Prevention - The PreSAP Trial, Dr. Bernard Levin, MD FDA, 2/16/2005
PreSAP Trial: Data
Estimated probability of CV death, heart attack, stroke, or CHF (log)
Adverse CV event risk in Celecoxib vs. Placebo
Celecoxib Placebo
Months since first dose
PreSAP 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
NO RISK
ADAPT Trial
Purpose
Reduce risk of Alzheimer’s Disease
2625 patients Average age of 70 y.o. At risk of Alzheimer’s
Patients
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
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
Comparison of Risk of Death, Heart Attack, and Stroke
Celecoxib vs. Placebo NSAID
Naproxen Relative Risk
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
Summary of Trials
CLASS
Sig. CV risk No
APC
Yes
PreSAP
No
ADAPT
Yes
Age (yrs)
Population Size VS. NSAID or Placebo
60
8059 NSAID
60
2035 Placebo
61
1500 Placebo
70
2625 NSAID
Ave. Celebrex exposure
>6 months
2.3 years
2.5 years
1.6 years
VIGOR - Summary of GI Endpoints
Rates per 100 Patient-Years RR: 0.46† (0.33, 0.64) Rofecoxib Naproxen RR: 0.38† (0.25, 0.57) RR: 0.43* (0.24, 0.78)
5 4 3 2 1 0
Confirmed Clinical Upper GI Events Confirmed Complicated Upper GI Events
All Clinical GI Bleeding
†p < 0.001.
* p = 0.005. ( ) = 95% CI.
Source: Bombardier, et al. N Engl J Med. 2000.
VIGOR - Confirmed Thrombotic Cardiovascular Events
Patients with Events (Rates per 100 Patient-Years)
Event Category Confirmed CV events Cardiac events Cerebrovascular events Peripheral vascular events Rofecoxib N=4047 45 (1.7) Naproxen N=4029 19 (0.7) Relative Risk (95% CI) 0.42 (0.25, 0.72)
28 (1.0)
11 (0.4) 6 (0.2)
10 (0.4)
8 (0.3) 1 (0.04)
0.36 (0.17, 0.74)
0.73 (0.29, 1.80) 0.17 (0.00, 1.37)
Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study Compared with Phase II/III OA Study
3.5 Cumulative Incidence %
3.0
2.5 2.0 1.5 1.0 0.5 0.0
Rofecoxib (VIGOR) Rofecoxib (OA)
Ibuprofen, Diclofenac, Nabumetone (OA)
Naproxen (VIGOR)
0
2
4
6 8 10 Months of Follow-up
12
14
Effect of Celecoxib & Rofecoxib on PGIM
Urinary 2,3 dinor-6-keto-PGF1 (PGIM)
Urinary PGI-M (pg/mg creatinine) (Mean ± SE) 200 160 120 80 40 0
Single Dose Rx†
200 160 120
Two Weeks Rx††
*
80 40 0 Placebo N=12
**
Placebo Celecoxib Ibuprofen N=7 400 mg 800 mg N=7 N=7
†
** **
Rofecoxib Indomethacin 50 mg QD 50 mg TID N=12 N=10
* p<0.05 vs. placebo. **p<0.01 vs. placebo.
Proc. Natl. Acad Sci. USA 1999;96:272-277. †† J. Pharmacol. Exp. Ther. 1999;289:735-741.
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
Blood Vessel Wall Endothelial Cell
Arachidonic acid PGH2 Prostacyclin (PGI2)
Platelet
Arachidonic acid PGH2 Thromboxane (TXA2) Ca2+ aggregation cAMP aggregation
cAMP/vessel smooth muscle relaxes
Ca2+/vessel smooth muscle constricts
Figure 5. Normal physiologic interaction between PGI2 and TXA2 in platelet and endothelial cell biology
Blood Vessel Wall Smooth Muscle Cell
Endothelial Cell Platelet
TXA2 PGI2 TXA2 PGI2
2 PGI2
PGI
TXA TXA22
Injury 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.
Blood Vessel Wall Smooth Muscle Cell
Endothelial Cell
Blood Vessel Wall Smooth Muscle Cell
Endothelial Cell Injury: catheter, turbulence, etc.
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.
Blood Vessel Wall Smooth Muscle Cell
Endothelial Cell Platelet
Blood Vessel Wall Smooth Muscle Cell
Endothelial Cell Injury: catheter, turbulence, etc.
PGI2
TXA2 PGI2 TXA2
Reendothelialization
TXA2
Injury
Normal Physiology
PGI2 DAMAGED
Aggregated Platelets
HEALTHY
Figure 6. Reendothelialization of the artery wall following injury and the key role of platelet aggregation stimulated by TXA2 in response to injury.
PGI2 Blood Vessel Wall Smooth Muscle Cell Endothelial Cell Platelet
TXA2
Normal Physiology PGI2
TXA2
TXA2 TXA2 3
Low dose aspirin intervention Knocks down platelet TXA2 PGI3
TXA3
favors platelet disaggregation
PGI2 3
Dietary 3 fatty acid intervention (cold water fish) PGI3 activity >> TXA3
favors platelet disaggregation
Platelets lack nucleic; cannot replace COX – TXA preferentially Figure 7. Control of platelet aggregation. Suppression of platelet aggregation by drug or dietary intervention
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 The effect is evident in every drug of this class and is dependant on both time period and the dose of the drug
FDA 2nd release : Feb 18 , 2005
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
N O
N
Na
H2N S O O CH3
H3C O O N S O
O
CH3
Etoricoxib
Valdecoxib
Parecoxib
Lumiracoxib
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
Event Placebo - Parecoxib Placebo (N =151) Valdecoxib (N = 311) 0% 0.7% 0.7% 1.3% 1.3% 2.9% 1.6% 1% P-value
Deaths C V Disorder MI Cardiac Failure
.309 .177 .699 .669
Study 071 Higher risk in almost all CV categories adjudicated
CV Risks in CABG II Surgery Setting
Event Placebo - Placebo Placebo Valdecoxib (N = (N = 544) 548) 1 (0.2%) 3 (0.5%) 0 2 (0.4%) 1 (0.2%) 1 (0.2%) 3 (0.5%) 3 (0.6%) 6 (1.1%) 2 (0.4%) 2 (0.4%) 0 2 (0.4%) 4 (0.7%) Parecoxib Valdecoxib (N = 544) 4 (0.8%) 11 (2.0%)* 4 (0.7%) 5 (0.9%) 0 2 (0.4%) 7 (1.3%)
Deaths CV-Thromboembolic MI/arrest/ischemia/cardiac death CVA or TIA Vascular Thrombosis Pulmonary Embolism Renal failure/dysfunction
Study 071 Higher risk in almost all CV categories adjudicated
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, 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 1. Chronic Exposure Studies – 4087 patients, 13 trials 2. EDGE Study – diclofenac as active comparator
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
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
Cumulative Rate of GI Ulcers
Etoricoxib
Naproxen
Ibuprofen
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
Elevation in blood pressure
Mean Incidence (Etoricoxib)
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
Placebo-Controlled
Non-Naproxen-Controlled
Naproxen-Controlled
Higher Incidence
Lower Incidence
Higher Incidence
Incidence of Edema-Related Events
• One-year continuous exposure (Etoricoxib vs. Naproxen)
Mean Incidence (Etoricoxib)
Lower Extremity Edema
no dose-related effect consistent with rates observed for
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)
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 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
GI Safety and Tolerability
Multifold-fold reduction in upper GI ulcer complications compared to NSAIDs
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 Safety
Primary Endpoint: Anti-Platelet Trialist Collaboration myocardial infarction, stroke, or vascular death 33,933 patients in these trials Overall Results – APTC endpoint
Placebo Non-Naproxen NSAIDS
Lower RR (0.83)
Naproxen
Higher RR (1.49)
All Comparators
Higher RR (1.14)
Lumiracoxib
Lower RR (0.88)
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
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
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 Efficacy
• 3 Major Data Sets – Placebo-Controlled – Morphine-Controlled (opioid analgesic) – Ketorolac-Controlled (conventional NSAID) • Efficacy in controlling post operative pain (Phase III)
Mean Scorea
Conventional treatments for post-operative pain
2.0 1.5 1.0 0.5 0
-Scale ranged from 0-11
-High number indicates impaired function
Placebo (n=519) Parecoxib / Valdecoxib (n=520)
Days
2
3
4
5
6
7
8
9
10
Reduction in Need for Opioids
Placebo (n=519) Parecoxib / Valdecoxib (n=520)
75
Morphine Equivalents (mg)
66.2
50
43.2
Significant reduction in need for opiod analgesics with same levels of pain control
25
0
Side Effect Profile
Normal therapeutic dose does not appear to affect COX-1 enzyme Generally lower incidence of gastrointestinal ulceration and bleeding compared to nonselective NSAIDs Avoids respiratory depression and other common opioid side affects Often combined with Bextra for clinical administration
Cardiovascular Safety
Placebo N=1915 Parecoxib (20-60 mg) N=2680
Any CV Event Myocardial
7 (0.4) 2 (0.1)
12 (0.4) 4 (0.1)
Cerebrovascular Peripheral vascular Pulmonary embolism
1 (<0.1) 3 (0.1) 1 (<0.1)
2 (<0.1) 3 (0.1) 4 (0.1)
Study 069 – General Surgery Study No significant cardiovascular risk relative to placebo CV risk only found in CAGB surgery setting
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
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
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
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