BLA 99-0884: Enbrel for Early RA

Jeffrey N. Siegel, M.D.

Division of Clinical Trials Design and Analysis

Review committee Jeffrey Siegel, M.D. Chair, Clinical George Mills, M.D. Imaging Boguang Zhen, Ph.D. Biostatistics Susan Giuliani Project Manager Debra Bower Bioresearch Monitoring David Green, Ph.D. Pharm-tox Lisa Rider, M.D. Consultant

Current indication

Enbrel is indicated for reduction in signs and symptoms of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). Enbrel can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone.

Indications sought in current BLA

Extend indication to signs & symptoms in early RA patients

Seek general claim of prevention of structural damage

Outline of presentation

Trial design Modifications to protocol Background information on radiographic

endpoints Efficacy results Safety data

Primary endpoints

Co-primary endpoints:– Clinical: ACR-N AUC at 6 mo– Radiographic: Improvement in erosion scores

at 12 mo– Hochberg method of assessing statistical

significance: both EPs must achieve statistical significance at 0.05 level OR either at 0.025 level

Additional endpoints

Disability based on Health Assessment Questionnaire (HAQ)

Health-related quality of life (HRQL) Major clinical response

Outline of presentation

Trial design Modifications to protocol Background information on radiographic

endpoints Efficacy results Safety data

16.0012: Modifications During trial, the agency discussed with Immunex

evidence from recent reports that many patients with early RA treated with MTX developed few, if any, erosions

The agency asked Immunex if it would wish to seek an approval based on non-inferiority if the study did not demonstrate superiority to MTX.

The agency noted that the basis for a non-inferiority determination should be determined prospectively

Modifications (cont.)

Immunex revised analysis of radiographic endpoint to a demonstration of non-inferiority

Changed variable from erosion score to total Sharp score (erosion score + joint space narrowing score)– Reason: Data unavailable to establish effect

size for erosion score

Outline of presentation Trial design Modifications to protocol Background information on radiographic

endpoints Efficacy results Safety data

Non-inferiority trials

In some clinical settings, efficacy may be demonstrated from a finding of non-inferiority in an active control trial: – Reproducible historical experience indicates

that in a trial with a given design that the active control will reliably give a result of a given size

0

Progression Rate

Margin

active minus placebo (historical)

Efficacy of active control

New drug superior

New drug meets non-inferiority std.

No evidence ofefficacy

New drug minus Active

Steps to Establish Non-Inferiority

Determine from historical trials that active control reliably has an effect of at least a certain size

Plan trial design to be similar to that of prior trials (stage of disease, concomitant therapy, endpoint, etc.)

Set a non-inferiority margin to be excluded (smaller than the total active control effect)

Ensure appropriate trial conduct (e.g., concomitant meds, study drug compliance)

Historical control data

Sponsor derived effect size of active control from several studies, including:– A multi-year observational study of recent-

onset RA (Wolfe and Sharp, 1998)– A 3-arm, randomized, controlled study

comparing placebo, MTX and ARAVA (MN301/303)

Non-inferiority: assumptions

Mean yearly progression rate ~6 u/year (Sharp score) in untreated patients

Mean progression rate on MTX ~2 u/yr Preserving 70% of MTX benefit means

ruling out a difference of 1.2 u [(4-1.20/4 = 0.70]

Limitations of non-inferiority trial design

Historical controls do not provide reproducible data to establish effect size for MTX

Effect size for MTX based on different patient population from current study:– shorter duration of disease– different MTX regimen

Non-inferiority design: conclusions

Because cannot formally establish a minimal effect size, non-inferiority cannot per se be taken as evidence of efficacy

Therefore, interpretation of the trial must be based on totality of the data, including additional analyses

Outline of presentation Trial design Modifications to protocol Background information on radiographic

endpoints Efficacy results Safety data

Disposition of subjectsPatients enrolled: 653

MTX Enbrel10 mg

Enbrel25 mg

Randomized, butnot treated 224 213 216

Rec’d 1 dose(mod ITT)

217(97%)

208(98%)

207(96%)

Completed 12mo evaluations

202(93%)

188(90%)

193(93%)

Radiographic procedures

Hand, foot films obtained: baseline, 6, 12 mo Read: 6 trained readers, blinded, random

order Inter--reader correlation coefficient 0.8 Agency review of radiographs:

– Data complete, of uniformly good quality– Readings generally consistent and accurate

Primary endpoint analysis

Primary analysis specified a mixed model estimating annual x-ray progression rates using 0, 6 & 12 month films and baseline covariates

Non-inferiority analysis to exclude margin of 1.2 u/year

Protocol specified sequential test of:– non-inferiority– if non-inferiority demonstrated, test superiority

X-ray primary endpoint analysis

Mean 12-mo. Change in TSS(2-sided 95% CI)

MTX 1.33 (0.55, 2.12)

10 mg 1.4 (0.6, 2.2)

25 mg 0.8 (0.04, 1.64)

X-ray primary endpoint analysis

Difference in mean progression rates (2-sided 90% CI)

25 mg – MTX -0.50 (-1.16, 0.16)(2-sided 95% CI)

25 mg – MTX -0.50 (-1.28, 0.29)

Primary endpoint

Test of non-inferiority excluded margin of greater than 1.2 u/yr (max. outer bound 0.29)

Test of superiority of Enbrel 25 mg to MTX does not reach statistical significance (p=.21)

Additional analyses

Prespecified stratification by disease duration

Components of Sharp score: erosion scores 6 month vs. 12 month data Subjects w/ no radiographic progression

Analysis by disease duration: TSS

0

0.5

1

1.5

2

2.5

TSS

ann

ual c

hang

e (u

/yr)

< 18 mo > 18 mo

MTXEnbrel 10Enbrel 25

N=478 N=154

Components of total Sharp score

Total Sharp score (TSS) is summation of:– erosion score– joint space narrowing

Enbrel 25 mg showed decrease in erosion score compared to MTX (0.9 vs. 0.4 u/yr, p = .047)

No difference in joint space narrowing (0.4 u/yr)

Time course of x-ray changes

Analyze 0-6, 6-12 mo rate of change Agency observed substantial skewing of

data, violating assumptions of mixed model. Therefore non-parametric test more appropriate

For its analysis, agency used raw data for last observation and first observation adjusting for time interval

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Cha

nge

in e

rosi

on s

core

(u

/yr)

MTX Enbrel

MTXEnbrel

12 mo change in erosion scores

P=0.001

Changes over time: erosions

0

0.2

0.4

0.6

0.8

1

1.2

Rad

iogr

aphi

c pr

ogre

ssio

n (u

)

0-6 mo 6-12 mo 0-12 mo

MTXEnbr 25

P = 0.0006 P = NS

Changes over time: TSS

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Rad

iogr

aphi

c pr

ogre

ssio

n (u

)

0-6 mo 6-12 mo 0-12 mo

MTXEnbr 25

P = 0.0006 P = NS

Patients w/ no radiographic progression

0102030405060708090

100

Pro

port

ion

of s

ubje

cts

(%)

Erosions: 12 mo TSS: 12 mo

MTXEnbr 25

P = 0.004 P = 0.174

Subset analysis

Based subset analysis on 12-month change in erosion scores

No important differences based on age, ethnicity, gender, duration of disease (0-18 mo vs. 18-36 mo)

Also assess baseline prognostic variables: ESR, erosions at baseline

Erosion score/Baseline ESR > 30

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

12 m

o ch

ange

ero

sion

sco

re

<30 mm/h >30 mm/h

MTXEnbrelN=115

N=121

N=92N=96

Erosions/baseline erosions

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

12 m

o ch

ange

ero

sion

sc

ore

< 2 >= 2

MTXEnbrel

N=137

N=145

N=69N=72

Radiographic EP

Although the trial excluded pre-specified margin for non-inferiority, there are limitations to the interpretation of these data

Meaningful secondary endpoints showed a difference compared to active control, e.g. erosion scores, 6 month data, patients with no radiographic progression

Clinical EP: Summary

10 endpoint of 6 month AUC showed statistically significant difference between Enbrel 25 mg and MTX

Landmark analysis of proportion of subjects achieving ACR20 and 50 at 6 and 12 months not statistically significant

Additional endpoints

Disability (HAQ) Health-related quality of life Major clinical response

Disability

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

HA

Q d

isab

ility

inde

x

MTX Enbrel 10 Enbrel 25

Baseline12 mo

Health related Quality of life

Physical summary score:– Same across trial arms at baseline, ~ 2 SD below

US norms– Improved in all arms at 12 months

» Less improvement in 10 mg arm than 25 mg Enbrel arm

Mental health summary score:– Similar to US norms at baseline– Higher in all arms at 12 months

Major Clinical Response (MCR)

Rationale for criteria of ACR70:– Represents a degree of improvement rarely

seen in placebo arms of controlled studies of DMARDs:

» Placebo (MTX vs. placebo): 0%

» Placebo (CsA vs pl/background MTX): 0%

Definition:– 6 consecutive months of an ACR70

Major Clinical Response (MCR)

0

2

4

6

8

10

12

Pro

port

ion

of s

ubje

cts

(%)

MTX Enbr 10 Enbr 25

MCR

P = 0.06

Safety

Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports

Deaths in trial 16.0012

2 observed during 12 month study period– 10 mg: Lung ca, dx month 2 – 25 mg: non-infectious complications of an

aortic aneurysm repair

SAEs

MTX 10 mg 25 mgInfections 4 4 5Malignancy (excl. skin) 1 2 3DVT, pulm. Embolus 0 2 2Interstitial pneumonitis 3 0 0Angina, MI 4 3 0Other 9 3 8Total events (patients): 21 (17) 14 (9) 18 (15)

Infectious SAEsMTX Enbrel 10 Enbrel 25

Pneumonia (3) Pneumonia Pneumonia (3)

UTI Bacteremia (2) Sepsis

Septic arthritis

Malignancies

25 mg– Prostate, carcinoid (lung), Hodgkin’s

10 mg– breast, lung

MTX– colon– 1 additional ca, at beginning of second year:

bladder

Thrombotic SAEs

25 mg:– DVT (2):

» 3 mo on study. Risk factor: OCP

» 1 week on study. Risk factor: Baker’s cyst

10 mg:– DVT: 2 weeks on study. No risk factors– Massive PE associated with dx of lung ca

MTX: none

Safety

Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports

Subjects not completing 52 weeks dosing

MTX Enbrel 10mg

Enbrel25 mg

AEs 21 9 10

Abnl LFTs 3 3 1

LOE 7 15 9

Other 14 15 9

Total 45 42 29

AEs causing dropoutsMTX Enbrel

10 mgEnbrel 25

mgAlopecia, oral/nasal

ulcers, vomiting9 0 0

Infection 3 3 1

Malignancy 1 2 2

MTX pneumonitis 3 0 0

ISR 0 0 1

Other AEs 5 4 6

Safety

Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports

Other adverse events

Overall adverse event rate higher in MTX arm than with Enbrel:– MTX 95% vs. Enbrel 90%

Rate of ISR (37% vs. 7%), bleeding at injection site (14% vs. 10%) higher in Enbrel arm than MTX

No other pattern of increased adverse events observed with Enbrel

Safety

Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports

Safety in other clinical trials

In previous controlled trials, saw higher incidence of:– injection site reactions– infections

Upper respiratory infections (URIs) were major contributor to higher rate of infection

Serious infections seen in long-term extension studies

Phase 4 safety study: 16.0018

3-year, open-label study of 1200 subjects receiving Enbrel

638 enrolled at time of BLA submission Goals:

– Assess long-term safety, including mortality rate, incidence of malignancy and autoimmune disease compared to historical control databases

Long-term safety in DMARD-refractory RA

Size of database– 782 patients overall (16.0018 and others)

» 2-3 years: 71 patients

» 1-2 years: 502 patients

AE rate:– None occurred with an incidence higher than in

controlled studies– No AE with pattern of increased incidence with

longer duration of exposure

Long-term safety

Infections– Types of infection similar to that seen in

controlled trials– No infection with a higher incidence with long-

term treatment

Long-term safety: serious infections

Infections assoc with hospitalization or IV antibiotics– Incidence of 5.5/100 patient-years– Types of infections expected for patients with

RA in their age group No increase in rate with longer duration of

exposure

Safety

Serious AEs, deaths Drop-out for adverse events Other AEs Long-term safety Post-marketing reports

Post-marketing reports

Post approval of Enbrel, there were reports of deaths from serious infection and sepsis– Associated risk factors: diabetes, active infection, h/o

recurrent infection Actions taken:

– Issue dear doctor letter with warning about use of Enbrel in patients with DM, active infections or a history of chronic infections

– Agency asked sponsor to initiate clinical trial to assess degree of risk

Safety study of Enbrel in patients at risk of infection

Since clinical trials excluded patients at higher risk for infection, it is unknown whether Enbrel may predispose certain subgroups of patients to serious infection

Safety study in at-risk patients

1000-patient, randomized, 4-month, double-blind, placebo-controlled trial of Enbrel

Inclusion criteria:– RA by ARA criteria– At increased risk for infection:

» DM requiring insulin or oral hypoglycemics» Chronic pulmonary disease (COPD or asthma)» h/o pneumonia in past year» Recurrent bronchitis, sinusitis or UTI (at least 2 episodes in

past year)

Safety study in at-risk patients

Sample size calculations:– Assumes event rate of 10% in control– 94% power to exclude a 2x relative risk for

Enbrel (95% CI)– Power of study would be lower if event rate

below 10%

Conclusions

For x-ray data, 95% CI excluded inferiority of 1.2 u/yr– Secondary endpoints suggest superiority of Enbrel in

preventing erosions Primary signs & symptoms endpoint showed

superiority for Enbrel 25 mg– Landmark 6, 12 month ACR 20/50 higher for Enbrel

25 mg, but not statistically significant Overall AE/SAE rate not higher with Enbrel