1. Literature Review Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

2. Burmester GR 1, Mease P 2, Dijkmas BAC 3, Gordon K, Lovell D 4, Panaccione R 5, Perez J 6, Pangan AL 6 Adalimumab Safety and Mortality Rates from Global Clinical Trials of Six Immune-Mediated Inflammatory Diseases. Ann Rheum Dis. Ann Rheum Dis. 2009;68:1863-9. 1 Charite-University Medicine Berlin, Free University and Humbolt University Berlin, Germany; 2 Sweedish Medical Center, Seattle, Washington, USA; 3 VU medical Centre and Jan van Breemen Institute, Amsterdam, Netherlands; 4 Evanston Northwestern Healthcare, Skokie, Illinois, USA; 5 University of Calgary, Calgary, Alberta, Canada; 6 Immunology Development, Abbott Laboratories, Parsippany, New Jersey, USA.

3. Introduction  Tumor necrosis factor (TNF) plays an important role in the pathogenesis of a variety of inflammatory disorders: Rheumatoid Arthritis (RA) Juvenile Idiopathic Arthritis (JIR) Psoriatic Arthritis (PsA) Ankylosing Spondylitis (AS) Crohn’s Disease (CD) Psoriasis (Ps)  Anti-TNF Rx have been developed and used effectively in all of these inflammatory disorders. Murdaca G, et al. Anti-TNFα inhibitors: a new approach for inflammatory immune mediated diseases. Int J Immunopathol Pharmacol. 2009;22:557-65. Schiff MH, et al. Safety of adalimumab (HUMIRA) in global clinical trials and US post marketing surveillance of pts with RA. Ann Rheum Dis. 2006;65:889-894.

4. Introduction  Anti-TNF drugs approved for RA, PsA, AS, Ps Adalimumab (Humira*) ADA Etanercept (Enbrel*) ETC Infliximab (Remicaide*) IFX  Anti-TNF drugs approved for CD Adalimumab (Humira*) ADA Certolizomab (Cimzia*) CTZ Infliximab (Remicaide*) IFX  Anti-TNF drugs approved for JIA Adalimumab (Humira*) ADA Etanercept (Enbrel*) ETC Murdaca G, et al. Anti-TNFα inhibitors: a new approach for inflammatory immune mediated diseases. Int J Immunopathol Pharmacol. 2009;22:557-65.

5. Introduction  Based on the review of clinical trials, Anti-TNF drugs have been associated with an increased risk for serious infections, especially tuberculosis (TB), and malignancy.  Many of the previous reviews for Anti-TNF drugs have been a composite analysis of multiple Anti-TNF drugs either confined to one type of inflammatory disorder or inclusive of many different types.  Studies of this type have been hampered by retrospective analysis, short longitudinal follow up, variability of the Anti- TNF drugs themselves, and the co-administration of other treatments known to independently increase this risk for infection and malignancy, i.e., Azathioprine (AZA), 6- mercaptopurine (6MP), methotrexate (MTX). Reddy JG and Loftus EV jr. Safety of infliximab and other biologic agents in the IBD. Gastro Clin North Am. 2006;35:837-55. Lichtenstein GR, et al. Mgm Crohn’s Disease in Adults. AM J Gastroenterol. 2009 Feb;104(2):465-83.

6. Aim  The authors sought to specifically assess the safety of a single Anti-TNFα, adalimumab (Humira), in the treatment of six immune mediated disorders over time and to compare adalimumab malignancy and mortality rates with data on the general population.  Six Inflammatory Disorders included: Rheumatoid Arthritis (RA) Psoriatic Arthritis (PsA) Ankylosing Spondylitis (AS) Crohn’s Disease (CD) Psoriasis (Ps) Juvenile Idiopathic Arthritis (JIA) Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

7. Study Design  Retrospective analysis of 19,041 patients exposed to adalimumab in 36 global clinical trials (RA, PsA, AS, CD, Ps, JIA). Last patient inclusion date April 15, 2007.  Adverse Events reported per 100 patient-years format Serious adverse events (SAEs) reported after the first dose through 70 days after the last dose. Standardized incidence rates (SIRs) were calculated for malignancies using national and state specific databases. Standardized mortality rates (SMRs) were calculated for each disease using data from the World Health Organization. Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

8. Study Design Inclusion Criteria: (+) for active index disease RA PsA AS CD Ps JIA Met study enrollment criteria Exclusion Criteria: Clinically active TB Active listeriosis Acute or chronic hepatitis B History of hepatitis C Persistent or serious infections requiring hospitalization Antibiotics 30D prior or IV and 14D prior PO Sx for demyelinating disorder Significant health issues Malignancy HIV Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

9. Study Design Serious Adverse (AEs) Events AEs occurring after 1 st dose up to 70 days (5 half-lives) SAEs defined as Life threatening illness Fatal Inpatient hospitalization Significant disability Birth anomaly/miscarriage Rates reported in number of events per 100 pt-yrs Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

10. Study Design  Malignancy and Mortality Data NCI, SEER database http://seer.cancer.gov/http://seer.cancer.gov/  Standardized Incidence Rates (SIRs) Ratio of Observed Events to Expected Events in a population Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

11. Study Analysis  Standardized Incidence Ratio (SIR) Ratio of Observed Events to Expected Events in a population Example: ► If 5 malignancies observed in a study trial ► If 20 malignancies expected in a general population ► Then SIR = 0.25 Meaning ► When SIR < 1.0, # observed events less than expected ► When SIR > 1.0, # observed events greater than expected SIR = # Observed Events # Expected Events SIR = 5 Observed Events 20 Expected Events http://seer.cancer.gov/seerstat/mp-sir.html Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

12. Results: Baseline Characteristics by Disease State RAPsAASJIAPsCD N = 19,04112345837164117118192228 x Age, yr 53.848.443.211.844.138.3 x Dur Dis, yr 10.614.611.13.818.511.7 ♀ %79.147.427.778.932.361.3 x exposure,yr.700.390.382.991.360.50 Exposure yr (range) 0.04- 9.03 0.04- 3.53 0.04- 3.04 0.04- 4.50 0.04- 4.01 0.04- 4.42 On IMM %61.855.617.849.70.340.2 On steroid%58.619.115.421.61.235.3 % US sites21.425.38.851.553.357.3 1472 of 19,041 (8%) patients received ADA > 5 YRS 12,345/19,041 (65%) of all pts treated had RA Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

13. Results: Serious AEs, event/100 pt-yrs (As of April 15, 2007) RAPsAASJIAPsCD N12345837164117118192228 Exposure PYs18284997125539824242373 Serious Infections4.652.811.112.761.325.18 TB0.290.30002.760.13 Opportunistic Infection 0.0900000.08 Malignancy0.760.30.0800.490.46 Lymphoma0.120.20.0800 NMSC0.1700.0800.120 Demyelinating Ds0.0500.08000.13 Lupus-like0.0700000.04 CHF0.2300.16000 PYs patient years; Malignancy (exclude NHL/NMSC), NMSC nonmelanoma skin cancer; CHF, congestive heart failure Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

14. Results: Time to 1 st Serious Infection N pts = 6807 3574 2258 1544 1316 699 207 64 Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

15. Results: Expected Events  Expected number of cancers for SIR calculations based on two sources: 5 yr age specific cancer incidence rates obtained from the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER) database (1993-2001) for all cancers other than non-melanoma skin cancer (NMSC). 10-yr age specific incidence rate for NMSC from NCI survey of 8 locations in US (1977-1978). Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

16. Malignancy (all types)  The SIR for malignancies in clinical trials for all diseases combined was 0.83 (95% CI, 0.72-0.96).  SIR < 1, means observed malignancy rate less than expected for entire ADA treated group. RAPsAASJIAPsCD N12345837164117118192228 Exposure PYs 18284997125539824242373 Malignancy SIR 0.760.30.0800.490.46 Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

17. Malignancy (Lymphoma)  ↑ Lymphoma for RA pts only, SIR 2.98 (95% CI, 1.89-4). RAPsAASJIAPsCD N, patients12345837164117118192228 N, lymphoma2321002 Exposure PYs18284997125539824242373 # Lymphoma (#/100 pt-yrs) 0.120.200.0800 SIR2.98NS Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

18. Lupus-Like Syndrome  Lupus-like syndrome was infrequent among all patients treated with ADA. RAPsAASJIAPsCD N12345837164117118192228 Exposure PYs18284997125539824242373 # Lupus-Like Syndrome cases 3500016 Obs Lupus-Like Syndrome # / 100 pt-yr 0.0700000.04 Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

19. Opportunistic Infections (OI’s)  OI’s were only seen in RA and CD: oral candidiasis most common.  RA had 17 OI’s: 6 histoplasmosis, 3 cytomegalovirus, 1 each for coccidiomycosis, toxoplasmosis, listeriosis, nocardiosis, aspergilloma, Pneumocystis jioveri, esophageal candidiasis and candida sepsis.  CD had 2 OI’s RAPsAASJIAPsCD N12345837164117118192228 Exposure PYs18284997125539824242373 # of OI’s1700002 Obs OI’s # /100 pt-yr 0.0900000.08 Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

20. Tuberculosis (TB)  Important: TB presented with extra-pulmonary involvement in 33 of 53 (62%) cases reported in RA pts. RAPsAASJIAPsCD N12345837164117118192228 Exposure PYs18284997125539824242373 # cases TB5300004 Obs # TB # / 100 pt-yr 0.290.300000.13 Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

21. Serious Infections (SI’s)  SI rates vary by disease state, but most common among RA and CD patients.  Pneumonia was the most common SI for RA.  Abscess was the most common SI for CD. RAPsAASJIAPsCD N12345837164117118192228 Exposure PYs18284997125539824242373 # SI’s5300004 Obs SI’s # /100 pt-yr 4.652.811.112.761.325.18 Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

22. Study Conclusions  Based on 10 years of clinical trial experience across six diseases, ADA has a stable safety profile and “acceptable” risk benefit ratio.  ↓Risk for Malignancy (all): SIR = 0.83  ↑Risk for Lymphoma in RA: SIR = 2.98  ↑Risk for TB: Note 62% extra-pulmonary in RA  ↑Risk for OI’s: RA #1 Lung & CD #1 Abscess  Risk for Demyelinating disease: infrequent  Risk for Lupus Syndrome: infrequent Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

23. Reviewer Comments Burmester, et al, do not answer the following questions? 1.What is the safety and risk profile for the non-RA indications for ADA? Comment: 65% of all pts in this ADA safety trial had RA, the other 5 inflammatory disorders comprised only 1/3 of the remainder of pts. Number of subjects examined in each of the 5 other disease states are too small to offer conclusive safety data for each. 2.What is the true long term safety and risk profile for ADA? Comment: Only 8% of all ADA pts received drug for > 5 yrs. The lead time for neoplastic risk may require a decade or more to estimate true risk. Furthermore risk stratification by disease state is needed, i.e., lymphoma risk is 2x RA than the general population. Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.

24. Reviewer Comments Burmester, et al, do not answer the following questions? 3.It is common in clinical practice to use both an Anti-TNFα + Immunomodulator in many of the 6 inflammatory disorders. In the study by Burmester, et al, mono-ADA therapy was more common in PS (99%), AS (80%), CD (60%) and JIR (50%) than in RA (40%) and reported among other Anti-TNFα Rx. Comment: It will be interesting to see if these mono-ADA trends are sustained over time and more importantly, whether mono-ADA coveys greater safety than combination of Anti-TNFα + Immunomodulator. Burmester CR, et al. Ann Rheum Dis. 2009;68:1863-9.