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

Literature Review

Peter R. McNally, DO, FACP, FACGUniversity Colorado Denver

School of MedicineCenter for Human Simulation

Aurora, Colorado 80045

Burmester GR1, Mease P2, Dijkmas BAC3, Gordon K, Lovell D4, Panaccione R5, Perez J6, Pangan AL6

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.

11Charite-University Medicine Berlin, Free University and Humbolt Charite-University Medicine Berlin, Free University and Humbolt University Berlin, Germany; University Berlin, Germany; 22Sweedish Medical Center, Seattle, Sweedish Medical Center, Seattle,

Washington, USA; Washington, USA; 33VU medical Centre and Jan van Breemen VU medical Centre and Jan van Breemen Institute, Amsterdam, Netherlands; Institute, Amsterdam, Netherlands; 44Evanston Northwestern Evanston Northwestern

Healthcare, Skokie, Illinois, USA; Healthcare, Skokie, Illinois, USA; 55University of Calgary, Calgary, University of Calgary, Calgary, Alberta, Canada; Alberta, Canada; 66Immunology Development, Abbott Laboratories, Immunology Development, Abbott Laboratories,

Parsippany, New Jersey, USA.Parsippany, New Jersey, USA.

IntroductionIntroduction

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.


Anti-TNF drugs approved for RA, PsA, AS, PsAdalimumab (Humira*) ADAEtanercept (Enbrel*) ETC Infliximab (Remicaide*) IFX

Anti-TNF drugs approved for CDAdalimumab (Humira*) ADACertolizomab (Cimzia*) CTZ Infliximab (Remicaide*) IFX

Anti-TNF drugs approved for JIAAdalimumab (Humira*) ADAEtanercept (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.


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 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 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.Crohn’s Disease in Adults. AM J Gastroenterol. 2009 Feb;104(2):465-83.

AimAim

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.

Study DesignStudy 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 formatSerious 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.



Inclusion Criteria:

(+) for active index disease

RA

PsA

AS

CD

Ps

JIA

Met study enrollment criteria

Exclusion Criteria:Clinically active TBActive listeriosisAcute or chronic hepatitis BHistory of hepatitis CPersistent or serious infections requiring hospitalizationAntibiotics 30D prior or IV and 14D prior POSx for demyelinating disorderSignificant health issuesMalignancyHIV


Study DesignStudy DesignSerious Adverse (AEs) Events

AEs occurring after 1st dose up to 70 days (5 half-lives)

SAEs defined as Life threatening illnessFatalInpatient hospitalizationSignificant disabilityBirth anomaly/miscarriage

Rates reported in number of events per 100 pt-yrs



Malignancy and Mortality DataNCI, SEER database http://seer.cancer.gov/

Standardized Incidence Rates (SIRs)Ratio of Observed Events to Expected Events in a population


Study AnalysisStudy 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


Results: Baseline Characteristics by Disease StateResults: Baseline Characteristics by Disease State

RA PsA AS JIA Ps CDN = 19,041 12345 837 1641 171 1819 2228

x Age, yr 53.8 48.4 43.2 11.8 44.1 38.3

x Dur Dis, yr 10.6 14.6 11.1 3.8 18.5 11.7

♀ % 79.1 47.4 27.7 78.9 32.3 61.3

x exposure,yr

.70 0.39 0.38 2.99 1.36 0.50

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 % 61.8 55.6 17.8 49.7 0.3 40.2

On steroid% 58.6 19.1 15.4 21.6 1.2 35.3

% US sites 21.4 25.3 8.8 51.5 53.3 57.31472 of 19,041 (8%) patients received ADA > 5 YRS

12,345/19,041 (65%) of all pts treated had RA


Results: Serious AEs, event/100 pt-yrs (As of April 15, 2007)Results: Serious AEs, event/100 pt-yrs (As of April 15, 2007)

RA PsA AS JIA Ps CDN 12345 837 1641 171 1819 2228

Exposure PYs 18284 997 1255 398 2424 2373

Serious Infections 4.65 2.81 1.11 2.76 1.32 5.18

TB 0.29 0.30 0 0 2.76 0.13

Opportunistic Infection

0.09 0 0 0 0 0.08

Malignancy 0.76 0.3 0.08 0 0.49 0.46

Lymphoma 0.12 0.2 0.08 0 0 0.08

NMSC 0.17 0 0.08 0 0.12 0

Demyelinating Ds 0.05 0 0.08 0 0 0.13

Lupus-like 0.07 0 0 0 0 0.04

CHF 0.23 0 0.16 0 0 0

PYs patient years; Malignancy (exclude NHL/NMSC), NMSC nonmelanoma skin cancer; CHF, congestive heart failure


Results: Time to 1st Serious Infection Results: Time to 1st Serious Infection

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6 7 8 9

Time (Years since 1st dose Adalimumab)

Rate of Pts Without Serious

Infections

N pts = 6807 3574 2258 1544 1316 699 207 64


Results: Expected EventsResults: 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).


Malignancy (all types)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.


Exposure PYs

18284 997 1255 398 2424 2373

Malignancy

SIR

0.76 0.3 0.08 0 0.49 0.46


Malignancy (Lymphoma)Malignancy (Lymphoma)

↑ Lymphoma for RA pts only, SIR 2.98 (95% CI, 1.89-4).

RA PsA AS JIA Ps CDN, patients 12345 837 1641 171 1819 2228

N, lymphoma 23 2 1 0 0 2

Exposure PYs 18284 997 1255 398 2424 2373

# Lymphoma

(#/100 pt-yrs)

0.12 0.20 0.08 0 0 0.08

SIR 2.98 NS NS NS NS NS


Lupus-Like SyndromeLupus-Like Syndrome Lupus-like syndrome was infrequent among all patients

treated with ADA.


Exposure PYs 18284 997 1255 398 2424 2373

# Lupus-Like Syndrome cases

35 0 0 0 1 6

Obs Lupus-Like Syndrome

# / 100 pt-yr

0.07 0 0 0 0 0.04


Opportunistic Infections (OI’s)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


Exposure PYs 18284 997 1255 398 2424 2373

# of OI’s 17 0 0 0 0 2

Obs OI’s

# /100 pt-yr

0.09 0 0 0 0 0.08


Tuberculosis (TB)Tuberculosis (TB)

Important: TB presented with extra-pulmonary involvement in 33 of 53 (62%) cases reported in RA pts.


Exposure PYs 18284 997 1255 398 2424 2373

# cases TB 53 0 0 0 0 4

Obs # TB

# / 100 pt-yr

0.29 0.30 0 0 0 0.13


Serious Infections (SI’s)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.


Exposure PYs 18284 997 1255 398 2424 2373

# SI’s 53 0 0 0 0 4

Obs SI’s

# /100 pt-yr

4.65 2.81 1.11 2.76 1.32 5.18


Study Conclusions 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


Reviewer CommentsReviewer 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.


Reviewer CommentsReviewer 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.


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