# Presentation: 525813

## EtanerceptImmunexBLA 103795/5123

**Arthritis Advisory Committee**
**Bethesda, Maryland**
**June 24, 2003**

## Review Committee

**William Tauber, M.D.    Chair, Clinical**
**Chao Wang, PhD          Biostatistics**
**Karen Jones                  Project Manager**
**Debra Bower                 Bioresearch Monitoring**
**Daniel Kearns               Facility Review**

## Indications proposed in current BLA

**Enbrel® is indicated for reducing signs and symptoms    of ankylosing spondylitis**

## Rationale for Etanercept in AS: I

**Ankylosing Spondylitis (AS) is a chronic inflammatory  rheumatic disease unknown etiology**
**Non-Steroidal Anti-inflammatory drugs (NSAIDS) are FDA approved for treatment of signs and symptoms of Ankylosing Spondylitis**
**Disease Modifying anti-rheumatic drugs (DMARDS(RA)) used for Rheumatoid Arthritis are used in AS but are not FDA approved for use in AS.**
**Neither NSAIDS nor DMARDS (RA) have been demonstrated to affect the progression of disability with AS.**

## Rationale for Etanercept in AS:II

**Tumor necrosis factor (TNF) levels have been shown to be elevated in serum and synovial tissue of patients with AS.**
**Etanercept is licensed for the treatment of Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, Psoriatic Arthritis.**
**AS may share pathogenic mechanisms with these other disorders.**

## Outline of Discussion Topics

**Methodology for assessment of short term therapeutic benefit in AS**
**Phase III trials to investigate the safety and efficacy of etanercept in patients with ankylosing spondylitis**
**Phase II proof-of-concept trial**

## Ankylosing Spondylitis: Assessment of Short Term Therapeutic Benefit

**Assessments in Ankylosing Spondylitis (ASAS) Working Group**
**5 domains most important in assessment of short term benefit in AS:**
**physical function**
**pain**
**spinal mobility**
**spinal stiffness and inflammation**
**patient’s global assessment.**

## Derivation of ASAS Response Criteria

**Analysis of 5 randomized trials of NSAIDS in AS enrolling 1030 patients ******** 6 weeks treatment performed**
**4 domains differentiated drug effect from placebo: **
**Combined into ASAS 20 response criteria**
**spinal mobility excluded because of lack of responsiveness**

## Phase 3 Protocols: Assessment of Response

**Primary Endpoint at end of treatment**
**	****-ASAS Response Criteria (ASAS 20) at 12/24 wks**
**	****	****-An improvement of at least 20%/ 10units          ****	****Visual Analog Scale (VAS) (0-100mm) in at ****	****least 3 of the following domains:**
**	****	****	****o Patient Global Assessment**
**	****	****	****o Average of total and nocturnal pain**
**	****	****	****o BASFI average of 10 questions**
**	****	****	****o BASDAI- average of last 2 questions**
**	****	****-Absence of deterioration (20%/10units) in ****	****remaining domain****	**

## Secondary and Other Endpoints

**Secondary Endpoints**
**ASAS 50/70 at 12/24 weeks***
**Highest ASAS response achieved**
**Partial Remission**
**Other Outcome Endpoints**
**Individual components of ASAS Instrument**
**Acute Phase Reactants: ESR, CRP**
**Spinal Mobility Parameters**
**Peripheral tender/swollen joint count**
**Assessor Global Assessment**

## Phase II and III Studies

**Phase II**
**016.0626 Randomized, double blinded, single center**
**etanercept 25mg biw vs placebo, 16 weeks (N=40)**
**Phase III**
**016.0037 Randomized, double blinded, multi-center**
**etanercept 25mg biw vs placebo, 24 weeks (N=277)**
**47687 Randomized, double blinded, multi-center etanercept 25 mg biw vs placebo, 12 weeks (N=84)**

## Phase 3 Protocols: Study Population

**Inclusion**
**	****- Men and Women 18-70 years of age**
**	****-Diagnosis of Ankylosing Spondylitis- mod NY criteria **
**	****-Active Disease at baseline using (VAS)**
**	****	****VAS ******** 30 for avg duration and intensity morning ****	****	****stiffness **_**PLUS**_
**	****	****VAS ******** 30  for 2 of 3 parameters: **
**	****	****-pt global assessment**
**	****	****-nocturnal and total back pain**
**	****	****-Bath Ankylosing Spondylitis Functional Index ****	****(BASFI) 10 question  avg VAS**
**	****	**
**	****	****	****	**

## Phase 3 Protocols: Study Population

**Exclusion**
**	****-Complete Ankylosis of Spine**
**	****-DMARDs other than Sulfasalazine, MTX or Hydroxychloroquine**
**	****-Prednisone >10mg/d or changed w/i 2 weeks baseline**
**	****-NSAIDS changing**

## Study 016.0037 (Study 1)

## CSR 016.0037 Clinical Protocol

**Study Design**
**	****- n= 277 active AS patients randomized 1:1 Etanercept or ****	****placebo for 24 weeks**
**	****-Randomization stratified for presence of DMARDs (Sulfasalazine, Methotrexate, and Hydroxychloroquine)**
**Dosing**
**	****-Etanercept 25 mg sc biw or Placebo sc biw**

## CSR 016.0037 Clinical Protocol

**Primary efficacy analysis**
**	****- MITT population ( all randomized and 1+ dose given)**
**	****- ASAS 20 at 12 (and 24 wks) compare etanercept with placebo Cochran-Mantel-Haenszel Test with stratification for DMARDs**

## Study Completion at 12 and 24 wks

|  | Placebo N=139  | Etanercept N=138 |
| --- | --- | --- |
| Patient Status | n/(%) | n/(%) |
| Randomized no drug  | 3/142 (2) | 4/142 (3) |
| Completed 12 wks | 134 (96) | 132 (96) |
| Completed 24 wks | 120 (86) | 126 (91) |
| D/C due AE | 1(1) | 7 (5) |
| D/C due LOE | 13 (9) | 3 (2) |
| Other  | 5 (4) | 2 (1) |

## Demographics 016.0037

|  | Placebo | Etanercept |
| --- | --- | --- |
| Characteristic | N=139 | N=138 |
| Mean Age(yrs) | 42 | 42 |
| Male | 76% | 76% |
| Caucasian | 91% | 94% |
| Mean Weight | 83.1kg | 82.2kg |
| HLA-B27+ | 84% | 84% |
| Duration AS(yrs) | 11 | 10 |

## Baseline Characteristics

|  | Placebo | Etanercept |
| --- | --- | --- |
| Characteristic | N=139 | N=138 |
| Patient Global | 63 | 63 |
| Pain (avg n+t) | 62 | 60 |
| BASFI | 56 | 52 |
| Inflammation | 64 | 61 |
| Any DMARD | 31% | 32% |
| Corticosteroids | 14% | 12% |

## Extra-Spinal Inflammatory Sx

| Symptom/Sign | Placebo N=139 | Etanercept N=138 |
| --- | --- | --- |
| Occular Inflam | 28% | 32% |
| Conjunctivitis | 8% | 7% |
| Uveitis/iritis | 31% | 28% |
| Inflammatory Bowel Disease | 4% | 5% |
| Psoriasis | 11% | 8% |

## Primary Endpoints

| Number (%) Achieving ASAS 20 |  |  |  |
| --- | --- | --- | --- |
|  | Placebo | Etanercept |  |
| Parameter | N=139 | N=138 | P-Value |
| ASAS 20
12 weeks | 38 (27) | 83 (60) | <0.0001 |
| ASAS 20
24 weeks | 32 (23) | 80 (58) | <0.0001 |

## ASAS 50 and ASAS 70

**ASAS 50 response computed and analyzed similar to ASAS 20 except that a 50% improvement in 3 of 4 components in addition to ********10mm point absolute improvement. Deterioration rules same as ASAS 20**
**ASAS 70 similar rules to ASAS 50 except that a 70% improvement needed**

## ASAS 20/50/70 at 12 and 24 weeks

**12 weeks**

**24 weeks**

## Partial Remission

**Criteria proposed by ASAS Working Group**
**Value of <20 (on a VAS scale of 0-100) in each of the four ASAS Response Criteria:**
**Patient Global Assessment**
**Average of Nocturnal/total back pain**
**BASFI**
**Last 2 questions of BASDAI**

## ASAS Defined-Partial Remission

## ASAS Individual ComponentsMean Percent Improvement from baseline at 12 wks

## Acute Phase Reactants Mean (median) values during treatment

|  | Placebo  | Etanercept |
| --- | --- | --- |
| Parameter | N=139 | N=138 |
| ESR/ BL | 25 (17) | 26(23) |
| 12 weeks | 26(16) | 13 (9)* |
| 24 weeks | 26 (19) | 11 (7)* |
| CRP/BL | 2.0(1) | 1.9 (1) |
| 12 weeks | 2.0(1) | 1(0.2)* |
| 24 weeks | 2.0 (1) | <1 (0.3)* |

- * P value <0.001

## DCART 20 and DCART 40

**DCART 20= 4 criteria of ASAS Response Criteria + chest expansion( spinal mobility) and CRP( acute phase reactants). DCART 20 same requirements ASAS20 for first 4, the other two 20% improvement relative to baseline w/o absolute numeric change. DCART 20=5 of 6 improvement, no worsening remaining domain.**
**DCART 40= uses 4 ASAS Response Criteria but requires 40% improvement relative to baseline plus absolute 20 unit(mm) improvement 3 of 4 w/o worsening remaining domain**

## ASAS DCART 20/40 Exploratory Analysis

|  | Placebo | Etanercept |
| --- | --- | --- |
| Parameter | N=139 | N=138 |
| DCART 20 | n (%) | n (%) |
| 12 weeks | 11 (8) | 51 (37)* |
| 24 weeks | 10 (7) | 46 (33)* |
| DCART 40 |  |  |
| 12 weeks | 21 (15) | 59 (43)* |
| 24 weeks | 18 (13) | 57 (41)* |

- * P value <0.001

## ASAS 20/12 weeks Non-Skeletal Inflammatory Condition

**Similar response rates to etanercept for patients subsetted by whether they did or did not have a history of:**
**uveitis or iritis( n= 82)**
**Inflammatory bowel disease(n=13) **
**bacterial dysentery, urethritis, Chlamydial infection or sexually transmitted disease(n= 24)**

## ASAS 20 at 12 weeks: Subset with Psoriasis

## ASAS 20 at 12 weeks: Subsetted by Baseline Variables

**Similar ASAS 20 response rates at 12 weeks in patients subsetted by :**
**Race**
**Weight**
**Disease Duration**
**Geographic site**

## Impact of Age upon ASAS 20 at 12 wks

- Quartiles

## Impact of Gender on ASAS 20 -12 wks 

## ASAS 20 at 12 weeks: Subsetted by Baseline Disease Severity

**Similar effect size for ASAS 20 response rates at 12 weeks for patients above or below the median at baseline for: **
**Average back pain**
**Patient global assessment**
**BASFI**
**BASDAI **
**Same effect size in presence or absence of Hip Disease**

## ASAS 20 at 12 weeks prior or concomitant meds

**Effect size for etanercept at 12 weeks did not appear to be affected by concomitant use of  the following medications:**
**NSAIDS (n=247)**
**Corticosteroids (n=36)**
**DMARDs (n=87)**
**Sulfasalazine (n=59)**
**Methotrexate (n=32)**

## ASAS 20 at 12 and 24 weeks HLA B27 positive vs negative

## Adverse Events all Intensities

|  | Proportions of Patients (n(%) |  |
| --- | --- | --- |
| Event | Placebo N=139 | Etanercept 138 |
| Any Adverse Event | 105 (76) | 99 (72) |
| Infections | 42 (30) | 57 (41) |
| Injection site reactions | 13 (9) | 41 (30) |
| Injection site ecchymosis | 23 (17) | 29 (21) |
| Headache | 16 (12) | 19 (14) |
| Accidental Injury | 6 (4) | 17 (12) |
| Diarrhea | 13 (9) | 11 (8) |
| Rash | 9 (7) | 11 (8) |
| Dizziness | 3 (2) | 8 (6) |
| Rhinitis | 9 (7) | 8 (6) |
| Abdominal Pain | 7 (5) | 8 (6) |
| Nausea | 7 (5) | 7 (5) |
| Asthenia | 7 (5) | 5 (4) |

## Important Safety Outcomes

| Safety Outcomes | Placebo 
N=139
n/N % | Etanercept 
N=138
n/N % |
| --- | --- | --- |
| Serious Adverse Events | 5 (4) | 9 (7) |
| Withdrawals for Safety | 1 (1) | 7 (5) |
| Grade 3 /4 Adverse Events/ Infections | 4 (3) | 14 (10) |
| Grade 3 /4 Abnormal Laboratory | 0 (0) | 2 (1) |

## Percent Serious Adverse Events

|  | Placebo
N=139 | Etanercept
N=138 |
| --- | --- | --- |
| Totals | 4% | 7% |
| Accidents | 1% | 2% |
| Infection/Fever | 1% | 3% |
| Gastrointestinal | 0% | 1% |

## Withdrawals for Safety

|  | Placebo | Etanercept |
| --- | --- | --- |
| Total | 1 (1%) | 7 (5%) |
| AE: Overall | 1 (1%) | 7 (5%) |
| Accidents | 0 (0) | 2 (1%) |
| Infections/Fever | 0 (0) | 1(1%) |
| Gastrointestinal | 0 (0) | 4 (3%) |
| Psychiatric  | 1 (1%) | 0 (0) |

## Infections: All Intensities

|  | Proportions of Patients
(n [%]) |  |
| --- | --- | --- |
|  | Placebo | Etanercept |
| Event | N=139 | N=138 |
| Any Infection | 42 (30) | 57 (41) |
| Any Infection not URI | 28 (20) | 33 (24) |
| URI | 16 (12) | 28 (20) |
| Flu syndrome | 10 (7) | 5 (4) |

## Summary: Efficacy

**Etanercept 25mg sc biw was superior to placebo in achievement of ASAS 20 Response Criteria at both 12 and 24 weeks. **
**Treatment difference is 33%**
**DMARDS did not appear to affect difference**
**Prognostic factors potentially associated with lower response**
**Older Age**
**Female gender**
**HLA-B27 antigen negative**
**Concomitant Psoriasis**

## Summary of Safety

**Etanercept 25 mg sc biw: higher observed incidence of certain adverse events compared to placebo**
**Serious adverse events (7% vs 4%)**
**Withdrawals for Safety (5% vs 1%) **
**Grade 3 /4 Adverse Events/ Infections (10% vs 3%)**
**Of the 7 safety withdrawals among etanercept recipients, 4 were for bowel symptoms, of which 2 were Inflammatory Bowel Disease, one a new diagnosis, the other a recurrence.****	****	****	****	****	****	**

## Study CSR-47687 (Study 2)

## CSR: 47687 Clinical Protocol

**Study Design**
**N=84 active AS patients randomized 1:1 Etanercept or placebo for 12 weeks**
**Randomization stratified for DMARDs (Sulfasalazine,Methotrexate,Hydroxychloroquine)**
**Dosing:Etanercept 25mg sc biw or Placebo**
**Primary efficacy analysis**
**MITT population (all randomized and one dose given)**
**ASAS 20  at 12 wks compare etanercept/placebo Cochran-Mantel-Haenszel test with stratification for DMARDs**

## Study 2 Population : Comparison with Study 1 Population 

**Study 2 population balanced between study arms, comparable with Study 1 population except :**
**Lower mean weight 75kg vs 82 kg**
**Prior use of DMARDs 69% vs 31% in study population 1**
**Lower incidence of ocular inflammation16% vs 30%, uveitis 22% vs 30%, higher psoriasis 15% vs 10% study1. The incidence of patients with history of IBD was similar at 6% study 2 vs 5% in study 1**

## Primary Endpoint

| Number (%) Achieving ASAS 20: Week 12 |  |  |  |
| --- | --- | --- | --- |
| Parameter | Placebo
N=39 | Etanercept
N=45 |  |
| Completed
12 weeks  | 100% | 96% | 
P-Value |
| ASAS 20 | 9 (23) | 27(60) | 0.0008 |

##  ASAS-Defined Partial Remission

|  | Placebo
N=39 | Etanercept
N=45 |  |
| --- | --- | --- | --- |
| Time point | n/(%) | n(%) | P-Value |
| Week 12 | 4 (10) | 8(18) | 0.3 |
| Any time  | 5(13) | 12 (26) | 0.1 |

## Adverse Events all Intensities

|  | Proportions of Patients (n(%) |  |
| --- | --- | --- |
| Event | Placebo 
N=39 | Etanercept N=45 |
| Any Adverse Event | 24 (62) | 25 (56) |
| Infections | 13(33) | 16 (36) |
| Injection site reactions | 6 (15) | 15 (33) |
| Injection site ecchymosis | 4 (10) | 8 (18) |
| Headache | 4(10) | 6 (13) |
| Accidental Injury | 2 (4) | 0 (0) |
| Diarrhea | 2 (5) | 2 (4) |
| Rash | 0 (0) | 2 (4) |
| Dizziness | 1 (3) | 1 (2) |
| Abdominal Pain | 3 (8) | 1 (2) |
| Nausea | 4(10) | 3(7) |
| Asthenia | 1 (3) | 5 (11) |

## Important Safety Outcomes

| Safety Outcomes | Placebo 
N=39
n/N % | Etanercept 
N=45
n/N % |
| --- | --- | --- |
| Serious Adverse Events | 0(0) | 1 (2) |
| Withdrawals for Safety | 0 (0) | 0 (0) |
| Grade 3 /4 Adverse Events/ Infections | 2 (5) | 4 (9) |
| Grade 3 /4 Abnormal Laboratory | 0 (0) | 1 (2) |

## Study CSR: 016.0626 (Study 3)

## CSR 016.0626 Clinical Protocol

**Study Design**
**N= 40 active AS patients randomized 1:1 to Etanercept or placebo for 16 weeks**
**Dosing: Etanercept 25mg sc biw or placebo**

## CSR 016.0626 Clinical Protocol

**Primary Efficacy Analysis**
**MITT population ( all randomized and one dose drug)**
**20% response at 16 weeks in 3 of 5 Pre-specified Ankylosing Spondylitis Criteria (with one of the improved measures being spinal pain or morning stiffness without worsening in the remaining 2. For patients without joint swelling( one of the 5 measured elements) at baseline, improvement was required in 3 of the remaining 4 elements without concurrent worsening in the remaining one.**

## Five Pre-Specified Measures

**Patient global assessment-5 point scale over the past week, improvement = decrease of 1**
**Nocturnal spinal pain:  100mm VAS, improvement 20% in # mm**
**Duration of morning stiffness; duration of morning stiffness in minutes on the day preceding clinic visit. 20% fewer or more minutes **

## Five Pre-Specified Measures

**BASFI 10 questions VAS average**
**Swollen joint score: peripheral joint swelling in 44 diarthrodial joints rated on 4 point scale 0=no swelling, 1=mild, 2=moderate,3 = severe. Improvement defined as decrease in joint swelling by 20% in swelling score. If the swollen joint score was 0 at baseline, any increase in score=worsening**

## Primary Endpoint

| Primary Endpoint: Number(%) Achieving AS Response Criteria |  |  |  |
| --- | --- | --- | --- |
|  | Placebo | Etanercept | P-Value |
| Time point | N=20 | N=20 |  |
| Week 12 | 5 (25) | 14 (70) | 0.01 |
| Week 16 | 5 (25) | 15 (75) | 0.01 |

## Ad hoc Analysis: Modified ASAS 20 at 12/16wks

| Number(%) Achieving ASAS 20 at 12 and 16 weeks |  |  |  |
| --- | --- | --- | --- |
|  | Placebo
 | Etanercept
 |  |
| Time point | N=20
 | N=20
 | P-Value
 |
| Week 12 | 5 (25) | 13 (65) | <0.05 |
| Week 16 | 5 (25) | 17 (85) | <0.05 |

## Other Endpoints: Pain Assessment, DSFI, Krupp’s Fatigue Measure at 16 weeks

## Spinal Mobility (Study 1) Mean Percent Improvement from baseline at 12 weeks

- *

- *

- *

- *=Nominal p-value <0.05

## Spinal Mobility (Study 2) Mean Percent Improvement from baseline at 12 weeks

- *

- *=Nominal p-value <0.05

## Spinal Mobility (Study 3) Mean % Improvement from baseline at 12 weeks

- *=Nominal p-value <0.05

## Tender and Swollen Peripheral Joints (Study 1)Median Percent Improvement at 12 wks

- *=Nominal p-value <0.05

- *

## Conclusions: Efficacy

**Etanercept was demonstrated statistically superior to placebo in 3 trials assessing symptomatic treatment in active Ankylosing Spondylitis (AS). **
**Older age, female gender were associated with lower response rate.**
**Responses in HLA-B27- negative and concomitant psoriasis patients  were also lower but the number of patients with these conditions was small.**

## Conclusions: Methodology

**Results using ASAS 20 generally demonstrated responses of similar direction and magnitude to previously used measures used in the assessment of therapeutic benefit in AS. **

## Conclusions: Safety

**Safety profile of etanercept in ankylosing spondylitis similar to that seen in RA and other indications **
**There were more withdrawals for inflammatory bowel disease in etanercept patients compared to placebo recipients in study 1 but numbers were small.**