# Presentation: 378695

## 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 researchers
- for decades: medicines that not only ease pain,
- but actually slow the disease’s debilitating
- progression.  ‘These could arrest the course of
- the 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®

-             **Celebrex®**
-      December 30, 1998
- NDA 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

**C**elecoxib
**L**ong-term
**A**rthritis
**S**afety
**S**tudy

## 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

## 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

## Adverse Events (%): CLASS

## 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)

## Renal Adverse Events(%)

## CV (combined) AEs (%)

## Serious CV Events (%)

## Hepatic Adverse Events (%)

## Skin Adverse Events (%)

## ASA and GI: CLASS(some observations)

## ASA and CV: CLASS(some observations)

## 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?