2. Arthritis Advisory Committee March 4, 2003 Update on the Safety of TNF Blockers Li-ching Liang, M.D. FDA / CBER/ OTRR Arthritis Advisory Committee March 4, 2003 Li-ching Liang, M.D. FDA / CBER/ OTRR Arthritis Advisory Committee March 4, 2003

3. Arthritis Advisory Committee March 4, 2003 2 Update on Safety Outline Update safety data from clinical trials and post-marketing reports Focus on several issues with new data –Adalimumab and Tuberculosis –Malignancies/Lymphoma with all approved TNF blockers Update safety data from clinical trials and post-marketing reports Focus on several issues with new data –Adalimumab and Tuberculosis –Malignancies/Lymphoma with all approved TNF blockers

4. Arthritis Advisory Committee March 4, 2003 3 Adalimumab Safety Database At end of Phase 2 meeting, Agency recommended large safety database Abbott studied for safety: –2070 pts. in controlled trials (mean exposure 7 mo.) –>2400 pts. in open-label studies (median exposure 24 mo.) Interpretation of open label data difficult due to lack of concurrent control group though larger experience and duration of such trials are beneficial At end of Phase 2 meeting, Agency recommended large safety database Abbott studied for safety: –2070 pts. in controlled trials (mean exposure 7 mo.) –>2400 pts. in open-label studies (median exposure 24 mo.) Interpretation of open label data difficult due to lack of concurrent control group though larger experience and duration of such trials are beneficial

5. Arthritis Advisory Committee March 4, 2003 4 Adalimumab and TB: Early Clinical Trial Experience 8 cases seen of initial ~542 pts. treated (1.5%) After discussions with FDA, screening and prophylaxis measures begun: –Europe -> chest x-ray –USA -> PPD –For PPD+ patients, prophylactic anti-TB treatment per CDC Guidelines 8 cases seen of initial ~542 pts. treated (1.5%) After discussions with FDA, screening and prophylaxis measures begun: –Europe -> chest x-ray –USA -> PPD –For PPD+ patients, prophylactic anti-TB treatment per CDC Guidelines

6. Arthritis Advisory Committee March 4, 2003 5 TB: Later Experience Reduction but not elimination of TB following screening: –5 cases in subsequent 1900 patients Other factors may have reduced the TB rate: –lower doses used –fewer patients from highly endemic areas Reduction but not elimination of TB following screening: –5 cases in subsequent 1900 patients Other factors may have reduced the TB rate: –lower doses used –fewer patients from highly endemic areas

7. Arthritis Advisory Committee March 4, 2003 Adalimumab: Tuberculosis Most reported TB cases from Europe More frequent in patients receiving higher than licensed dose (40 mg q2wk) Most cases extrapulmonary Most occurred in first 8 months of therapy in controlled trials – May reflect reactivation of latent infection Box Warning Most reported TB cases from Europe More frequent in patients receiving higher than licensed dose (40 mg q2wk) Most cases extrapulmonary Most occurred in first 8 months of therapy in controlled trials – May reflect reactivation of latent infection Box Warning

8. Arthritis Advisory Committee March 4, 2003 7MalignanciesMalignancies Because of immunomodulatory properties of TNF-blockers, concerned about malignancies with long-term treatment. Assessment difficult because hard to maintain a comparator control arm in long-term studies –One approach: Compare observed malignancy rates to the expected rate in general population (e.g. using 1995-99 SEER Database adjusted for age, gender, race, geography) to calculate SIR - Standardized Incidence Ratio Because of immunomodulatory properties of TNF-blockers, concerned about malignancies with long-term treatment. Assessment difficult because hard to maintain a comparator control arm in long-term studies –One approach: Compare observed malignancy rates to the expected rate in general population (e.g. using 1995-99 SEER Database adjusted for age, gender, race, geography) to calculate SIR - Standardized Incidence Ratio

9. Arthritis Advisory Committee March 4, 2003 Malignancies & RA Interpretation of data is complicated: –Lymphoma incidence reported to be several fold higher among RA patients, especially those with higher levels of disease activity and inflammation* –Most patients enrolled in trials have highly active disease –Most receive concomitant DMARDs with immunosuppressive properties * Baecklund E. et al. BMJ 1998; 317:180-1. * Wolfe, F. Arthritis Rheum 1998; 41 (9): S188. Interpretation of data is complicated: –Lymphoma incidence reported to be several fold higher among RA patients, especially those with higher levels of disease activity and inflammation* –Most patients enrolled in trials have highly active disease –Most receive concomitant DMARDs with immunosuppressive properties * Baecklund E. et al. BMJ 1998; 317:180-1. * Wolfe, F. Arthritis Rheum 1998; 41 (9): S188.

10. Arthritis Advisory Committee March 4, 2003 9 Malignancies with Adalimumab Controlled Portions of Controlled Trials Malignancies Observed Number of Patients Mean Duration of Treatment Adalimumab- treated 8 (0.58%)13800.6 yr Placebo-treated0 (0%)6900.5 yr

11. Arthritis Advisory Committee March 4, 2003 10 Lymphomas with Adalimumab Controlled Portions of Controlled Trials Lymphomas Observed Number of Patients Mean Duration of Treatment Adalimumab- treated 2 (0.1%) 1380 0.6 yr Placebo- treated 0 (0%) 6900.5 yr

12. Arthritis Advisory Committee March 4, 2003 11 Observed vs. Expected Cancer Rates Adalimumab Clinical Development Program (thru 8/02) * Based on SEER database Cancer SiteObservedExpectedSIR*95% CI All lymphomas101.855.42(2.6-10.0) NHL91.705.28(2.4-10.0) Hodgkin’s Dis10.147.09(0.1-39.5) Breast711.150.63(0.3-1.3) Colon – rectum54.751.05(0.3-2.5) Lung16.670.15(0.0-0.8) Melanoma31.531.97(0.4-5.7) Prostate54.451.12(0.4-2.26) Cervix – Uteri42.301.74(0.5-4.4) Other sites1113.120.84(0.4-1.15) Total4645.821.00(0.7-1.3) * T

13. Arthritis Advisory Committee March 4, 2003 12 Summary of 10 Lymphoma Cases By Type Among Adalimumab-Treated Patients (REAL Classification) B cell lymphoma: Diffuse Large B-cell lymphoma (5) B cell lymphoma: Mantle cell lymphoma B cell lymphoma: Marginal Zone lymphoma B cell lymphoma: Follicular center lymphoma T cell lymphoma: Peripheral T cell lymphoma Hodgkin’s Lymphoma B cell lymphoma: Diffuse Large B-cell lymphoma (5) B cell lymphoma: Mantle cell lymphoma B cell lymphoma: Marginal Zone lymphoma B cell lymphoma: Follicular center lymphoma T cell lymphoma: Peripheral T cell lymphoma Hodgkin’s Lymphoma

14. Arthritis Advisory Committee March 4, 2003 EtanerceptEtanercept Malignancies and Lymphomas

15. Arthritis Advisory Committee March 4, 2003 14 Etanercept Malignancies in Placebo-Controlled Portions of Clinical Trials (6 month trials) Etanercept : Malignancies in Controlled Portions of Clinical Trials Placebo- treated Etanercept- treated No. Patients9212502 Mean Duration of Treatment0.5 yr Observed No. of Malignancies5 (0.5%)12 (0.5%) Observed No. of Lymphomas01 (Hodgkin’s)

16. Arthritis Advisory Committee March 4, 2003 15 Etanercept: Types of Malignancies in Controlled Portions of RA Trials Placebo-treated subjects (N=5) Etanercept-treated subjects (N= 12) Bladder Colon Cervix Prostate Metastatic adenoCA Breast (3) Prostate (3) Lung (2) Colorectal Leukemia Lymphoma (Hodgkin’s) Melanoma

17. Arthritis Advisory Committee March 4, 2003 16 Etanercept: Lymphomas in Clinical Trial Database 3389 patients representing 7364 pt-yrs of data Median exposure of 2.2 yrs. 6 lymphoma cases reported in all clinical trials –additional 3 cases reported after f/u period 2.6 cases expected* –SIR 2.31 (95%CI 0.85, 5.03) * Based on SEER database 3389 patients representing 7364 pt-yrs of data Median exposure of 2.2 yrs. 6 lymphoma cases reported in all clinical trials –additional 3 cases reported after f/u period 2.6 cases expected* –SIR 2.31 (95%CI 0.85, 5.03) * Based on SEER database

18. Arthritis Advisory Committee March 4, 2003 InfliximabInfliximab Malignancies and Lymphomas

19. Arthritis Advisory Committee March 4, 2003 18 Infliximab: All malignancies in controlled portions of controlled trials (includes ASPIRE data) Populationn Mean Duration of Treatment Observed No. Cases of All Malignancies % of Pts. 95% CI Infliximab- treated subjects RA Studies12981.1 yr151.2% 0.9, 1.4% All Studies24211.0 yr220.9% 0.7, 1.1% Placebo-treated subjects RA Studies4301.0 yr10.2%0.1, 0.3% All Studies4890.9 yr10.2%0.02, 0.7%

20. Arthritis Advisory Committee March 4, 2003 19 Infliximab: All malignancies seen in the controlled portions of controlled trials (including ASPIRE) * Basal cell CA(6) Squamous cell CA(4) Breast CA(3) Lymphoma(3) –Follicular cell center –NK lymphoma –(IG) Angiocentric Melanoma (2) * Total of 23 malignancies in 22 patients 1 blinded data where all malignancies counted as if observed in infliximab-treated subjects Basal cell CA(6) Squamous cell CA(4) Breast CA(3) Lymphoma(3) –Follicular cell center –NK lymphoma –(IG) Angiocentric Melanoma (2) * Total of 23 malignancies in 22 patients 1 blinded data where all malignancies counted as if observed in infliximab-treated subjects Rectal adenoCA Bladder CA Hypernephroma Pancreatic CA Endometrial CA

21. Arthritis Advisory Committee March 4, 2003 20 Infliximab: Lymphomas in controlled portions of controlled trials Populationn Mean Duration of Treatment Observed No. Cases of Lymphomas % of Pts. Infliximab- treated subjects RA Studies12981.1 yr10.1% All Studies24211.0 yr30.1% Placebo-treated subjects RA Studies4301.0 yr0- All Studies4890.9 yr0-

22. Arthritis Advisory Committee March 4, 2003 21 Infliximab: All malignancies in all clinical trial experience PopulationN Median Subj-Yrs Follow-up Obsv’d No. Cases Expt’d No. Cases SIR 95%CI Infliximab-treated subjects RA Studies12981.9 1718.620.91 (0.53, 1.46) All Studies24211.72723.551.15 (0.76, 1.67) Placebo-treated subjects RA Studies4301.4 24.100.49 (0.06,1.76) All Studies4891.444.310.93 (0.25,2.38)

23. Arthritis Advisory Committee March 4, 2003 22 Infliximab: Lymphomas in all clinical trial experience PopulationNMedian Subj-Yrs Follow-up Obsv’d No. Cases Expt’d No. Cases SIR 95%CI Infliximab-treated subjects RA Studies12981.940.636.35 1.73, 16.26 All Studies24211.760.866.98 2.56, 15.19 Placebo-treated subjects All RA Studies4301.400.14[NC] All Studies4891.400.15[NC]

24. Arthritis Advisory Committee March 4, 2003 23 Lymphoma with TNF Blockers Conclusions Lymphomas observed with all 3 TNF blockers –Small numbers/short exposure in controlled portions of clinical trials –For entire database, calculated SIRs are between ~2 and 7 compared to SEER database –A more appropriate comparison would be to RA population but accurate incidence rates unavailable Lymphomas observed with all 3 TNF blockers –Small numbers/short exposure in controlled portions of clinical trials –For entire database, calculated SIRs are between ~2 and 7 compared to SEER database –A more appropriate comparison would be to RA population but accurate incidence rates unavailable

25. Arthritis Advisory Committee March 4, 2003 24 Lymphoma with TNF Blockers Conclusions 1-3 cases of lymphomas are diagnosed in treated groups for each TNF product, vs. 0 in control groups (6 lymphomas vs. 0 across all controlled studies) Biological plausibility of lymphomas associated with immunomodulatory agents, along with these data presented, raise concern about causality 1-3 cases of lymphomas are diagnosed in treated groups for each TNF product, vs. 0 in control groups (6 lymphomas vs. 0 across all controlled studies) Biological plausibility of lymphomas associated with immunomodulatory agents, along with these data presented, raise concern about causality