COX-2 & 2x: Improved Safety?

James Witter, M.D., Ph.D.

CLASS/VIGOR-AAC

Feb. 7-8, 2001

100 years of NSAIDs

• “Aspirin” first synthesized - 1899

• First endoscopic evidence of gastric mucosal damage by aspirin - 1938

• New “safer NSAIDs” developed - 1970’s

• Cox-2 discovered - 1992

• First “COX-2” approved - 1998

• First “large and simple” safety trials - 2001

NSAIDs/COX-2 and FDA(Arthritis Advisory Committee meetings)

• Dec. 2, 1986– “GI paragraph” databases discussed

• October 11-12, 1995– Revisions for NSAID class label – Citizen’s Petition-piroxicam

• March 24, 1998– NSAID/COX-2 Safety Issues

• December 1, 1998 (Celebrex approval)

• April 20, 1999 (Vioxx approval)

• February 7-8, 2001 (long-term safety)

GI paragraph

• Serious UGI toxicity with/without warning

• Only one in five (20%) with serious UGI event with warning symptoms

• Patients “at risk” (i.e. prior ulcer or bleed, older age, medications, poor health…)

• Trends, and risk, continue

• Minimize risk by lowest dose, shortest time

“Clinically Relevant Events”

• “It has been demonstrated that upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year”.

FDA, GI template warning label

• NSAID-induced gastropathy may result in 107,000 hospitalizations and 16,500 deaths

ARAMIS ‘98

NSAIDs: Safety

• Toxicity, both dose and duration dependent, involve a variety of organ systems as:– adverse events (AEs)

• mild

• moderate

• severe

– serious adverse events (SAEs)– death

NSAID template

• General structure for NSAIDs; describes precautions, warnings, adverse reactions:– GI tract– liver– kidney/fluid retention/edema– anaphylactoid reactions– hematological effects– skin...

NSAID template: liver

• Metabolic effects of hepatic insufficiency

• Elevations in AST or ALT (1% 3x ULN)

• Rare cases of severe (some fatal) reactions:– jaundice– fulminant hepatitis– liver necrosis– hepatic failure

NSAID template: kidney

• PD effects of renal failure or dehydration

• Effects on blood pressure (HTN)

• Fluid retention and edema in some settings

• Severe reactions such as:• renal papillary necrosis

• interstitial nephritis

• renal failure

NSAID template: skin

• Adverse events including:– photosensitivity– urticaria– severe (some fatal) reactions such as:

• Stevens-Johnson syndrome

• toxic epidermal necrolysis

• erythema multiforme

NSAIDs: Efficacy• Osteoarthritis (OA)

– signs and symptoms– NOT structure or disability (draft guidance)

• Rheumatoid arthritis (RA)– signs and symptoms– NOT structure, function, remission (guidance)

• Acute pain and dysmenorrhea• Other indications (AS, gout…)

COX-2: Early hopes

“Some experts believe they could become the ‘holy grail’ that has eluded arthritis researchersfor decades: medicines that not only ease pain, but actually slow the disease’s debilitatingprogression. ‘These could arrest the course ofthe disease,’ ”

Wall Street Journal May, 1996

AAC: March 24, 1998(Safety/Toxicity Issues: COX-2)

• Questions to AAC• Degree to which endoscopic studies can distinguish

between currently available NSAIDs

• Degree of correlation with clinical outcomes

• Some comments• Endoscopic studies generally under powered

• The measurable (endoscopic) drives out the important (clinical outcomes)

• Endoscopy “surrogate” for long-term outcomes

GI warning: COX-2 changes?

• Removal:– Requires “equivalence to placebo” , mutually

defined and agreed

• Major Revision:– Requires substantial, reproducible evidence

(endoscopic, clinical endpoints) of superiority over NSAIDs (? three, mutually agreed)

Importance of Words

• Equivalent to placebo• Saying two treatments are “similar” does not

necessarily mean they are the “same”.

• Statistically speaking, failing to show a “difference” is not showing “equivalence”.

• Equivalence requires that the hypothesis “treatment x and y are different” be rejected in a trial designed for this purpose.

COX-2: Safety Advantage?(mechanism-based?)

COX-2 Absent

Platelets

Result A (+)

Possible

Stomach

Result B (±)

COX-2 Present

Kidneys

Result C (-)

COX-2 agents: Different?

• Class– How many agents define a class?

• More potent inhibitors

• Label– Revise NSAID template or write new?

• Theory or Drug– In trials, testing the drug, the theory, or both?

COX-2 agents: Future?

• Other indications?– structural modification in OA or RA– prophylaxis of colon cancer– prophylaxis of Alzheimer’s disease

• New “unique” adverse events?

• Safety and efficacy in children?

Celebrex® December 30, 1998NDA 20-998 (Celecoxib)

452 volumes x 400 pages/volume = 180,800 pages !!!

Celebrex-NDA: OA• Celebrex:

• at 100 to 200 mg BID > placebo

• no obvious efficacy advantage of 200 mg BID

• 100 mg BID ~ 200 mg QD

• Comparable to Naproxen 500 mg BID

• Most patients (~70%) increase dose in open-label experience (dose creep)

Celebrex-NDA: RA

• Celebrex:• at 100 to 400 mg BID > placebo

• no obvious efficacy advantage of 400 mg BID

• Comparable to Naproxen 500 mg BID

• Most patients (~70%) increase dose in open-label experience (dose creep)

Celebrex-NDA: Pain

• No labeled indication for acute pain and dysmenorrhea

Celecoxib versus COX-2: (Efficacy Characteristics?)

• Analgesics efficacy < NSAIDs for acute pain ? Is this a problem with:

• pain models selected?

• nature of acute vs. chronic pain (COX-2 induction)?

• related to potency/selectivity of celecoxib?

• In short-term studies, no efficacy advantage compared to NSAIDs for OA and RA.

• Will there be any difference in long-term outcomes?

Vioxx-NDA: OA

• Vioxx:• at 12.5 and 25 mg QD > placebo

• no obvious efficacy advantage of 25 mg dose

• Comparable to:• ibuprofen 800 mg TID

• diclofenac 50 mg TID

• No open-label experience for dose-creep

Vioxx-NDA: RA

• No data submitted in NDA

Vioxx-NDA: Pain

• Vioxx indicated for acute pain and dysmenorrhea:

• at 50 mg daily (5-day studies) > placebo

COX-2 Efficacy

• Signs and Symptoms of:– Osteoarthritis (Celebrex, Vioxx)– Rheumatoid arthritis (Celebrex; the ‘x’ dose)

• Acute pain and dysmenorrhea (Vioxx)

• FAP (Celebrex; the 2x dose)– Familial Adenomatous Polyposis

• Adjunctive therapy

Long-Term Safety

• Despite their long history of usage, no NSAID has been tested in a “large and simple” long-term safety trial at doses exceeding the upper limit (i.e. 2x) of approved labeling in arthritis

COX-2: 2001+

CLASS

• Celecoxib

• Long-term

• Arthritis

• Safety

• Study

CLASS: basics-1

• Two protocols (035 and 102)• 035: Ibuprofen-800 mg TID

• 102: Diclofenac-75 mg BID

• Celecoxib 400 mg BID• 2x upper dose in RA

• Dose approved for FAP

• 386 sites (US/Canada) with 7968 patients

CLASS: basics-2

• Inclusion– Age to give written informed consent– OA or RA for 3 months requiring NSAIDs– Not pregnant

• Exclusion– Active malignancy, GI disease/ulceration– Significant renal, hepatic or coagulation defect– AST/ALT > 1.5x ULN

CLASS-Baseline demographics

• Mean/median age ~60 years– about 11% age75 years or older

• Most white females

• Approximately:– 27% with RA – 10% with history of GI bleed or GD ulcer– 21% taking ASA

Concurrent Medications

• Prohibited– NSAIDs (RX, OTC)

– Anti-ulcer drugs

• H2 antagonists, proton pump, sucralfate, misoprostol

– Antibiotics for H. pylori

• Allowed– ASA for CV prophylaxis

– Antacids (short-term) including calcium for osteoporosis

– MTX < 25 mg/wk, azathioprine, corticosteroids

– Analgesics (APAP to oxycodone prn)

Aspirin use: CLASS

• Allowed at 325 mg daily• patients at risk for CV events

• Use was not stratified in the CLASS study

• Dose and duration of use may have varied

• No conclusions regarding ASA co-use can be drawn from CLASS, only observations and possible directions for future studies

CLASS-Statistical Issues

• Null hypothesis: Celecoxib = NSAIDs for primary outcome of complicated ulcers...– Estimated 40 events total:

• 8 events in 4000 celecoxib patients

• 32 events in 4000 NSAID patients

• Withdrawal rate of 35%

• Power = 90%

• Significance = 0.05 (two-sided)

Patient disposition-CLASS

Patients Celecoxib Diclofenac Ibuprofen

ITT 3987 1996 1985

-Completed (%) 45 47 35

-Withdrew (%) 55 53 65

Efficacy in OA/RA: CLASS

• Not more effective than NSAIDs based on:– Patient global– Patient assessment of pain (VAS)– HAQ and SF-36 scores– Patient withdrawals rate

• but less than rates in NDA (? dose effect)

CLASS GI outcomes-1

• Complicated ulcers (Primary Endpoint)– Total of 38 uncensored events in ALL groups– Celecoxib was not statistically significantly

different than individual or pooled NSAIDs

• Celecoxib did NOT meet primary endpoint of trial

CLASS GI outcomes-2

• However, when primary endpoint restricted to include those not taking ASA:– Total of 22 uncensored events in ALL groups– Celecoxib was different (p=0.03) than

ibuprofen, but NOT diclofenac

CLASS GI outcomes-3

• When endpoints expanded to complicated and symptomatic ulcers:– Total of 105 events in ALL groups– Celecoxib > ibuprofen but NOT diclofenac

• When restricted to non-ASA patients, the complicated and symptomatic ulcers show: – Total of 59 events in ALL groups– Celecoxib > ibuprofen but NOT diclofenac

GI Adverse Events

Event (%) Celecoxib Diclofenac Ibuprofen

All patientsAny event withdrawal

45.612.2

55.0*16.6*

46.213.4

ASAAny event withdrawal

54.014.9

59.120.7*

52.714.1

Non-ASAAny event withdrawal

43.311.5

53.815.4*

44.513.2

Adverse Events (%): CLASS

Celecoxib Diclofenac Ibuprofen

IncidenceAny -severe

81.816.3

82.918.1

79.5*17.6

WithdrawalAny 22.4 26.5* 23.0

SeriousAny 6.8 5.6 6.0

Deaths (%)

• Overall, 36 deaths for all causes• Celecoxib 19 (0.5 %)

• Diclofenac 9 (0.5 %)

• Ibuprofen 8 (0.4 %)

• Most (69%) in patients 65 years• Most cardiovascular in nature

• Celecoxib (58 %)

• Diclofenac (56 %)

• Ibuprofen (63 %)

Deaths (pt-yrs)

Celecoxib Diclofenac Ibuprofen All causes ASA Non-ASA

19 (0.8) 6 (1.2) 13 (0.7)

9 (0.8) 1 (0.4) 8 (1.0)

8 (0.7) 4 (1.6) 4 (0.5)

CV causes ASA Non-ASA

11 (0.5) 5 (1.0) 6 (0.3)

5 (0.5) 0

5 (0.6)

5 (0.4) 3 (1.2) 2 (0.2)

Renal Adverse Events(%)

Celecoxib Diclofenac Ibuprofen

Any event 6.8 6.7 10.3*

Withdrawals 1.0 0.6 1.3

BUN 40 mg% and/orCr 1.8 mg %

1.3 2.1* 1.4

CV (combined) AEs (%)

Celecoxib Diclofenac Ibuprofen

ASAEdema 4.3 4.5 6.8Anginal Disorder 4.1 3.4 2.9Thrombophlebitis 0.2 0.4 0.2

Non-ASA

Edema 4.1 3.9 6.1Anginal Disorder 0.7 0.4 0.5Thrombophlebitis 0.5 0.3 0.3

Serious CV Events (%)

Celecoxib Diclofenac Ibuprofen

Non-ASA

Atrial^ 0.3 0.1 0Anginal^ 0.6 0.4 0.2MI 0.3 0.2 0.2Thrombophlebitis^ 0.4 0.5 0

^ = combined events

Hepatic Adverse Events (%)

Celecoxib Diclofenac Ibuprofen

Any event 1.8 6.9* 1.9 x-ULN 3x AST 3x ALT 3x ALT 3x AP 3x ALT 1.8 TB 3x AP 1.8x TB

0.40.40.40.1

3.7*3.3*3.4*0.2

0.70.60.60.0

Withdrawals 0.3 3.5* 0.3

Skin Adverse Events (%)

Celecoxib Diclofenac Ibuprofen

RashOverall 6.2 2.8* 3.8* -severe 0.5 0.1 0.2 withdrawal 2.1 0.7* 1.3*

PruritisOverall 2.4 1.9 1.4* -severe 0.2 <0.1 0.1 withdrawal 0.7 0.4 0.3

ASA and GI: CLASS(some observations)

Celecoxib Diclofenac Ibuprofen

Complicated ulcer Adverse events Withdrawals

ASA and CV: CLASS(some observations)

Celecoxib Diclofenac Ibuprofen

Mortality MI Thrombophlebitis

Overall Safety-GI

• Celecoxib was unable to demonstrate statistical superiority to either ibuprofen or diclofenac when considering the primary endpoint of the CLASS trial

• However, celecoxib was able to demonstrate a trend in superiority to ibuprofen (only) in patients not taking ASA and with broader endpoints (complicated and symptomatic)

Overall Safety-Renal

• Celecoxib does not effect acid-base balance more than diclofenac or ibuprofen (phase 4)

• No large effect on renal adverse events relative to ibuprofen or diclofenac

• Although not seen in the CLASS trial, serious renal disease such as acute failure and interstitial nephritis are in the label

Overall Safety-Cardiovascular

• In CLASS, no apparent adverse effect on CV mortality or SAEs related to thrombosis relative to ibuprofen or diclofenac

• Does not exclude a lesser CV effect

• Events such as MI, CHF, VF, PE, CVA, vasculitis and other events are in the label

Overall Safety-Hepatobiliary

• Adverse events are not more frequent than seen with ibuprofen or diclofenac

• Although not seen in the CLASS trial, events such as hepatitis, jaundice and liver failure are in the label

Overall Safety-Skin

• Rash and pruritis (mild, moderate) are important adverse events that frequently lead to withdrawal

• Serious adverse events such as Stevens- Johnson syndrome, toxic epidermal necrolysis or erythema multiforme are in the label

Overall Safety-Deaths

• There were no deaths from hepatobiliary, renal, dermatologic or GI causes

• Deaths from CV causes appear to reflect the population studied rather than any new adverse effect of celecoxib

• Deaths from CV causes are not more common in the celecoxib group as compared to the controls

Overall Safety: Celecoxib

• From all data to date (NDA to CLASS), celecoxib appears more like NSAIDs than placebo

COX-2 versus NSAID: Safety

• With regards to any safety endpoint:– Is “beating” one NSAID the same as beating

them all?– Is “losing” to one NSAID the same as losing to

them all?