Arthritis Advisory Committee August 16, 2001 Biologic License Application: anakinra (KINERET) for rheumatoid arthritis Arthritis Advisory Committee August 16, 2001

Anakinra: Proposed Indication Kineret is indicated for the reduction in signs and symptoms of moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs). Kineret can be used alone or in combination with other disease‑modifying antirheumatic drugs (DMARDs).

Anakinra: Background The agency accepted a BLA filing in December, 1999, that contained the results of 2 randomized trials in RA At the time of BLA filing, the agency recommended that Amgen begin additional studies to address issues not covered by existing data

Background (cont.) Amgen began several additional clinical trials in RA in 2000: 1 year trial of radiographic progression 6 month randomized safety study with long-term open-label extension JRA Combination with TNF antagonists

Kineret BLA Upon review of the originally submitted data, the agency informed Amgen that the data were suggestive of biologic activity, but that additional safety and efficacy data would be needed Amgen responded to agency request with data from 3 additional trials

Trials of Anakinra Study Phase Subjects Doses Notes 990145 3 506 100 mg Clinical, x-ray EP 0560 2 473 30, 75, 150 mg Phase 2  960180 2/3 419 .04,.1, .4, 1, 2 mg/kg Phase 2/3  960182 141 2.5, 10 30 mg Lower doses 990757 1414 Safety 20000125 58 Open-label Enbrel combo

Study 990145 10 radiographic EP: 1 yr 10 clinical EP: 6 mo Interim analysis of 506 subjects randomized as of May 18, 2000 Study remains blinded

990145: Study Design Patients with active RA,  1 bony erosion, on stable dose MTX 1:1 randomization to anakinra 100 mg sc qd or placebo Independent blinded joint assessors 10 EP: ACR20 at 6 mo * Stable doses of NSAIDs and low dose corticosteroids were allowed

990145: Study Conduct Placebo Anakinra Randomized 253 (100%) Received  1 dose 251 (99%) 250 (99%) Completed 6 months 186 (74%) 197 (79%) Reasons for not completing:   Adverse event 22 (9%) 33 (13%) Subject request 29 (12%) 12 (5%) RA progression 10 (4%) 3 (1%) Death 0 (0%) Other 6 (2%) 8 (3%) The mean age was approximately 56 year old and the BL demographics were well balanced between study arms.

990145: Baseline Disease Activity   Placebo (N=251) Anakinra (N=250) RF positive 196 (78%) 189 (76%) NSAID use 194 (77%) Corticosteroid use 131 (52%) 133 (53%) MTX dose (mg/wk, mean) 15.6 Duration of RA (yrs, mean) 10.4 11.1

990145: Disease Activity (cont.) Placebo (N=251) Anakinra (N=250) TJC (0-68) 24 27 SJC (0-66) 20 MD global (0-100) 57 Patient global (0-100) 52 53 Pain, VAS (0-100) 56 59 HAQ (0-3) 1.3 1.4 CRP (mg/Dl) 2.6 2.7 ESR (mm/hr) 43 42

990145: ACR Responses Placebo (N=251) Anakinra (N=250) P value ACR20 6 mo 22% (55) 38% (94) P<0.001 ACR50 8% (20) 17% (43) ACR70 2% (5) 6% (14) Higher responses also seen in subjects without ISRs

990145: Time Course

990145: ACR Components Baseline (mean) Placebo (N=251) Anakinra P value TJC (0-68) 26 -8.6 -12 P=0.006 SJC (0-66) 20 -6.4 -6.8 P=0.7 MD global (0-100) 57 -20 -25 P=0.01 Patient global (0-100) 53 -8.9 -18 P<0.001 Pain (VAS, 0-100) -19 P=0.003 HAQ (0-3) 1.3 -0.18 -0.29 P=0.02 CRP (mg/dL) 2.6 -0.10 -0.51 P=0.001 ESR (mm/hr) 42 -6.0 -16

990145: Subset Analysis Similar clinical response seen in patient populations subsetted by: Male vs. female Ethnicity Disease duration < 15 yrs (upper quartile) TJC > 30 (upper quartile)

990145: Subset by Age * Lower rates of response in the older age group were not noted in other studies

990145: Subset by RF Status

990145: Subset by ESR

Additional Efficacy Trials Study 560 and 960180: phase 2, 2/3 randomized, double-blind, placebo-controlled trials of anakinra Both studies: Active RA by ACR criteria Stable NSAIDs and prednisone 6 months blinded therapy Study 560 also assessed radiographic progression

Studies 560 & 960180 560 960180 Concomitant meds None Background MTX 10 endpoint 6 mo ACR 20 3 mo ACR20 Doses 30, 75, 150 mg sc qd .04, .1, .4, 1, 2 mg/kg sc qd Location Europe US, Canada, Australia In study 960180, 6 mo ACR20 was an important 20 endpoint Compare doses to 145 study

Study 560: Patient Population Similar baseline characteristics to 990145 with respect to: age, gender, corticosteroid use, RF+, baseline ESR Differences noted in 560: > 98% caucasian Shorter duration of RA: 4 yrs vs. 11 86% caucasian in 990145 TJC 35 in 560 vs. 27 in 990145

560: Clinical Responses Placebo (N=119) 30 mg 75 mg (N=116) 150 mg Week 12 Responders (n) 23% (27) 34% (41) 33% (38) p-value 0.053 0.075 0.103 Week 24 27% (32) 40% (47) 34% (39) 43% (49) 0.05 0.28 0.01 All the response rates are higher for anakinra than placebo, but the data show some inconsistency, with a lower response rate at 75 mg than at 30 mg. The p values shown are nominal values since the analytic plan did not describe a plan for adjusting for multiple comparisons Improvements were seen in all the components of the ACR

Study 960180 Similar baseline characteristics to 990145 with respect to: age, gender, RF+, baseline disease activity, ESR Differences noted in 960180: Higher corticosteroid use: 64% vs. 53% Shorter duration of RA: 7 years vs. 11

960180: Clinical Responses Test for dose response: p=0.004 at 6 mo Placebo (N=48) 0.4 mg/kg (N=55) 1.0 mg/kg (N=59) 2.0 mg/kg (N=46) Week 24 % Responders (n) 23% (11) 36% (20) 42% (25) 35% (16) Test using Agresti Coull method Only top 3 doses shown The 3 month data were also highly statistically significant Improvements were seen in all components of the ACR criteria Test for dose response: p=0.004 at 6 mo

960180: Sustained Responses RA guidance document recommends collection of response data during course of trial and not just at beginning and end Defined as patients with ACR20 at 4/6 monthly assessments with 1 assessment at 6 months

Signs & Symptoms: Summary Three randomized trials show a higher proportion of ACR20 responses in anakinra-treated subjects than placebo Responses seen within weeks and maintained to 6 months Effects seen on all components of ACR criteria Consistent effects across subsets of baseline demographics and baseline disease states

Radiographic Progression: RA Guidance Document A claim of inhibition of structural damage may be based on: A demonstration of efficacy for signs & symptoms, and A 1 year study showing a decrease in structural damage based on a validated index * Before beginning a discussion of the x-ray data, I wish to discuss the requirements for a claim of inhibition of inhibition of structural damage based on RA guidance document RA guidance doc based on consultations with this committee

560: Radiographic Assessment Hand, wrist x-rays obtained at baseline and 6 months Analyses: Change in Larsen score pre-specified Change in Sharp scores measured in post-hoc re-analysis Baseline and follow-up x-rays available for 74% of subjects (347 of 472)

560: Larsen Scores ` Placebo 30 mg 75 mg 150 mg Randomized (N) 121 119 116 117 M-ITT (N) 83 89 86 Baseline (0-180) Mean 15.4 16.7 14.9 12.1 Median 11 13 12 7 6 month change 6.5 3.5 4.2 3.9 p-value 0.07 0.15 0.09 HIGHLIGHT large amount of missing data HIGHLIGHT These data do not support a claim of inhibition of radiographic progression because they are 6 month and not 12 month data as specified in the RA guidance document. Nonetheless, they can be considered as evidence supportive of the primary finding. M-ITT defined as patients with baseline and 1 post-baseline film. Note that there is much missing data Note that means of baseline data are higher than medians, indicating skewed data Baseline data are generally well balanced, except for 150 mg group

FDA Analysis of Larsen Scores, Non-Parametric Analysis Placebo 30 mg 75 mg 150 mg N 83 89 86 Mean 6.4 3.6 3.8 4.0 Median 6 3 2 P-valuea 0.04 0.02 0.06 * Wilcoxon test used a Wilcoxon test

560: Sharp Scores Amgen conducted an analysis of the Sharp scores, which suggested differences between study arms Limitations of analysis: Post-hoc, exploratory 133 fewer subjects included in Sharp readings compared to Larsen readings

Radiographic Assessments: Summary Prespecified analysis showed trends towards improved radiographic outcomes, but not statistically significant Post-hoc analyses also suggest activity of Kineret in inhibiting radiographic progression at 6 months, but firm conclusions cannot be reached due to limitations of analysis

Safety: Overall Exposure Study: 0560 & 960180 990145 990757 Total Total exposed 559 250 1116 1925 6 months or longer 318 197 875 1390 1 year or longer 175

560 & 960180: Deaths and SAEs Deaths: None occurred on blinded portion of trials Incidence of SAEs similar between placebo and anakinra arms Incidence of serious infections: 17/1240 on anakinra (1%) vs. 1/243 on placebo (<1%) Incidence of serious infection on anakinra is somewhat higher, but not statistically significant The incidence of malignancy was within the expected range, but follow-up was only for 6 months.

990145: Deaths and SAEs 1 death: 80 year old man, worsening of underlying chronic lung disease SAE: 12 on anakinra; 8 on placebo 3 infectious SAEs on anakinra; 1 on placebo No malignancies in anakinra arm Death occurred after D/C’ing study drug, p 10 wks on anakinra Serious infections in 2 subjects: 2 pneumonia; 1 pulmonary infection Apart from infections, no pattern of increased SAEs with anakinra

Abnormal Lab Values Leukopenia and mild increase in eosinophil counts only lab abnormalities noted Leukopenia seen in 12% (85/696) with anakinra vs. 4% with placebo (10/195) in studies 560 & 960180 8/696 (1%) discontinued for leukopenia (<3500/mm3) 1/3 in first 100 days; 1/3 in after >200 days *The incidence of leukopenia was not increased in the MTX combination trial compared to the trial of anakinra monotherapy

Leukopenia Most leukopenia was an increase of 1 grade (e.g. above 4400/mm3 to 3300-4400 range) 11/696 (2%) patients went from normal to grade 2 (e.g. >4400/mm3 to 2200-3300) In only 1 case was leukopenia associated with an infection: a non-serious UTI that resolved ANC at time of withdrawal: 1,800/mm3

AEs Occurring at a Higher Frequency with Anakinra Placebo (N=195) All anakinra (N=696) % ISR 26 58 Headache 6 12 Abdominal Pain 4 7 Rash 3 5

990757: Randomized Safety Study Double-blind, randomized, multicenter trial of safety of adding anakinra 100 mg sc qd to background anti-rheumatic medications US, Europe and Australia, 169 sites 1414 subjects: 4:1 randomization 6 months controlled, then 3 years open-label

990757: Study Design Patient population: Active RA Stable DMARD regimen for at least 3 months No uncontrolled medical conditions or recent malignancies DMARDs allowed as monotherapy or combination TNF antagonists not permitted Changes in NSAIDs, corticosteroids, DMARDs allowed as clinically indicated * Also excluded CellCept, cyclophosphamide, Prosorba column, cyclosporine

990757: Patient Population Similar demographic characteristics to other RA trials DMARDs 52% receiving MTX 16% on MTX + another DMARD (175/1116) 6% receiving MTX + 2 or more DMARDs (67/1116) 57% receiving corticosteroids No imbalances noted in baseline disease activity or demographics COPD, h/o pneumonia, asthma, CAD, DM were each present in 5-10% of subjects * Most common anti-rheumatic meds: MTX (52%), HQ (22%), SSA (14%), Arava (10%) gold (4%), azathioprine (4%)

990757: Study conduct 80% completed 6 months of blinded therapy Withdrawal for AEs more common in anakinra arm: 12% vs. 6% Most common AE leading to withdrawal with anakinra was ISRs: 7% Withdrawal for disease progression more common with placebo 2% vs. 1%

990757: Deaths and SAEs 4 deaths on anakinra and 1 on placebo (both <1%) Similar rate of SAEs overall More SAEs in GI system: 2% (20/1116) vs. <1% (1/283) No predominant pattern More pulmonary SAEs: 2% (18/1116) vs. <1% (1/283) Difference related to infections Deaths on Kineret: interstitial fibrosis, suicide, metastatic melanoma, UGI bleed Malignancies were not observed at a higher frequency in the anakinra group than placebo, but follow-up is only 6 months. Cannot reach firm conclusions until long-term follow-up is completed.

990757: Serious Infections Overall infection rate similar between study arms: 41% on anakinra vs. 44% on placebo Serious infection rate higher on anakinra than on placebo: 2% on anakinra (23/1116) vs. <1% on placebo (1/283) Most common: pneumonia, cellulitis, osteomyelitis * Serious infections defined as SAEs that were infectious

Serious Infections None of the serious infections were fatal All resolved except one case of osteomyelitis Atypical infections uncommon: 1 patient developed MAI 1 mo after discontinuation 1 patient developed legionella None associated with leukopenia

Serious Infections: Risk Factors % with serious infection All anakinra 2% (23/1116) Male 2.8% (8/282) Female 1.8% (15/834) Corticosteroids (CS) Yes 3% (19/636) No 0.8% (4/480) Asthma 5.5% (6/109) 1.7% (17/990) Mean dose of CS 8 mg/d vs. 7. Serious infections not associated with doses >10 The incidence of serious infection was not increased in patients on CS who were also receiving DMARDs Use of particular DMARDs not associated Not assoc w older age group, higher BL disease activity

Study 2000125 (0125): Enbrel Combination Open-label pilot study of safety 58 patient with active RA Patients previously on Enbrel for  3 mo, but no other DMARDs Anakinra 1 mg/kg sc qd for 6 mo * Mean age 49, RA x 12 yrs, TJC 26, SJC 17

Study 0125 36% withdrew before 6 months (21/58) No deaths 7 SAEs 11 for AEs (19%), 8 for withdrawal of consent (14%) No deaths 7 SAEs 4 infectious (7% of subjects) 2 pneumonia, 2 cellulitis * 1 case of cellulitis was associated with an injection site abscess; the other was a case of facial cellulitis

0125: Lab Abnormalities 5 lab toxicities ( in grade of 2 or more) 2 WBC, 2 lymphs 2 of the cases of leukopenia occurred in subjects who also developed serious infections: Cellulitis Pneumonia

Leukopenia and Serious Infections Measurement 1 = BL, 2 = 1 mo, 3 = 2 mo #1: pneumonia 15 d after 2nd measurement; #2 10 d after 3rd measurement

Serious Infections in Anakinra Trials Study # of patients Incidence (%) 95% CI All placebo 5/729 0.7% 0.2-1.6% 560, 0180, 145 14/946 1.5% 0.8-2.5% 990757 23/1116 2.1% 1.3-3.1% 20000125 4/58 7% 1.9-17%

Summary: Etanercept Combination Study Data strongly suggest that there may be a somewhat higher incidence of serious infections when anakinra is given with etanercept Concurrent leukopenia observed before serious infection in 2 patients The widespread use of the TNF antagonists etanercept and infliximab raises concerns that they may be used in combination with anakinra, if it is approved

Summary of Safety Majority of patients develop mild-moderate ISR Minority develop low-grade leukopenia Higher incidence of serious infections in one large trial Concerns about combination with TNF antagonists Although anakinra was generally well tolerated, long-term safety has not been assessed.