Anti-TNF Therapy for Severe Asthma Refractory to Corticosteroids

Approximately 5% to 10% of patients with
asthma have severe disease that is
refractory or poorly responsive to inhaled
corticosteroid therapy

Tumor necrosis factor
› TNF-a – cachectin, cachexin
› TNF-b - lyphotoxin
Tumor necrosis factor and asthma
Anti-tumor necrosis factor in asthma

Pleiotropic pro-inflammatory cytokine
initially produced as a 26 kDa
membrane-anchored precursor protein
TNF reppresent 2 homologus protein
primarily derived from mononuclear
phagocytes (TNF-α) and Lymphocyte
(TNF-β)

Larry Borish : Middleton 7th edition

TNF-α is processed as a membrane-
bound protein from which the soluble
active factor (17 kDa free protein) is
derived via cleavage using the enzyme
TNF-α converting enzyme (TACE), known
as ADAM 17
The active form is a homotrimer (51 kDa)


Most potent inducer of TNF by
monocytes is LPS acting through TLR4
and CD14γ
TNF-α may be produced by neutrophils,
activated lymphocytes, natural killer
cells, endothelial cells, and mast cells


Activation results in a remarkably diverse
set of cellular responses, apoptosis,
inflammation and inhibit tumor genesis
and viral replication

C. Russo and R. Polosa:Clinical Science (2005) 109, 135–142

TNF-α and TNF-β bind to the same two
distinct cell surface receptors – TNFR I
(p55 or CD120a) and TNFR II (p75 or
CD120b)
2 receptors are expressed on the surface of many
cell types
› TNFR I expressed on cells susceptible to the
cytotoxic action of TNF-α
› TNFR II expressed strongly on stimulated B- and T-
cells

Subsequent phosphorylation of
NF-κB activates the p50–65
subunit, interact with DNA
chromatin structure to increase
the transcription of pro-
inflammatory genes, such as IL-8,
IL-6, and TNF-a

Summary of TNF-a biology and signaling

Christopher Brightling, Mike Berry : J Allergy Clin Immunol 2008;121:5-10

TNF interacts with endothelial cells to
induce intercellular adhesion molecule-1
(ICAM-1), vascular cell adhesion
molecule-1 (VCAM-1), and E-selectin,
permitting the egress of granulocytes
into inflammatory loci
TNF is a potent activator of neutrophils,
mediating adherence, chemotaxis,
degranulation, and the respiratory burst

TNF is responsible for the severe
cachexia that occurs in chronic
infections and cancer
TNF induces vascular leakage, has
negative inotropic effects, and is the
primary endogenous mediator of toxic
shock and sepsis


Role of TNF-a in the pathogenesis of asthma. TNF-a plays a central
role in many of the features of the asthma paradigm by exerting important
effects on both inflammatory and structural cells

TNF-a contributes to the dysregulated
inflammatory response seen in the
asthmatic airway was raised by the
findings of increased TNF-a mRNA and
protein in the airways of patients with
asthma
Administration of inhaled recombinant
TNF-a to normal subjects led to the
development ofAHR and an airway
neutrophilia Thomas PS, Barnes PJ: Tumor necrosis factor-alpha increases airway
responsiveness and sputum neutrophilia in normal human subjects. Am J Respir Crit Care Med 1995,

Mike Berry: Current Opinion in Pharmacology 2007

Administration of TNF-a to patients with
asthma also leads to an increase in AHR,
as measured by a reduction in
methacholine PC20 Thomas PS, Heywood G: Effects of inhaled
tumour necrosis factor alpha in subjects with mild asthma. Thorax 2002

It could be caused by a direct effect
of TNF-a on airway smooth muscle or
by the release of the cysteinyl-
leukotrienes LTC4 and LTD4

TNF-a induces histamine release from
human mast cells directly van Overveld FJ, Vermeire PA:
Tumour necrosis factor stimulates human skin mast cells to release histamine and
tryptase. Clin Exp Allergy 1991

Participates in a positive autocrine loop
that potentiates human mast cell
cytokine secretion Coward WR, Holgate ST: NF-kappa B and TNF-
alpha: a positive autocrine loop in human lung mast cells? J Immunol 2002


Chemoattractant for neutrophils and
eosinophils it increases the cytotoxic
effect of eosinophils on endothelial cells
It is involved in the activation of cytokine
release by T cells and it increases
epithelial expression of adhesion
molecules such as ICAM-1 and VCAM-1


TNF-a has several properties that might
be relevant to refractory asthma,
including
› recruitment of neutrophils
› induction of glucocorticoid resistance
› myocyte proliferation
› stimulation of fibroblast growth and
maturation into myofibroblasts by promoting
TGF-a expression


Serpil C. Erzurum, N Engl J Med 2006;354:754-758

Direct modulation of ASM contractile
function by mast-cell derived TNF-a,
mechanism in AHR
Mast cell number correlated positively
with the degree ofAHR Brightling CE, Holgate ST. Mastcell
infiltration of airway smooth muscle in asthma. N Engl J Med 2002

Mast cells are the major source of TNF-
a in the airways
TNF-a induced AHR is mediated by
direct effects on ASM

1. enhanced receptor-associated
calcium signals as a result
of an increased expression,
function, or both of the receptor G
protein (Gaq or Gai)

2. altered signal transduction,
such as increased phospholipase
C (PLCb) expression, activity, or
both

Molecular mechanisms activated in ASM induced by TNF-a–activated
molecular mechanisms in ASM possibly contributing to AHR in
asthma


3. abnormal calcium handling by
exerting effects on key enzymes that
regulate inositol-1,4,5- trisphosphate
(IP3) metabolism, such as 5-
phosphatase I and II, effects
on function, and/or the expression of
Ryanodine receptors (RyR), IP3
receptor (IP3R), or calcium ATPases
called sarcoendoplasmic calcium
ATPases (SERCA), which regulate
calcium fluxes, or calmodulin (CaM)

4. changes in calcium sensitivity
mediated by effects on RhoA
expression or increases in both myosin
light chain kinase (MLCK) or myosin
light chain phosphatase (Pase)
content, activity, or both


3 TNFα antagonists licensed in USA
› 2 monoclona lAb : adalimumab (ADA) and
infliximab (INF)
› soluble receptor : etanercept (ETA)
Certolizumab pegol : Crohn ‘s disease
Sandborn WJ, et al (2007). "Certolizumab pegol for the treatment of Crohn's
disease". N. Engl. J. Med. 357 (3): 228–38

Golimumab : human monoclonal Ab,
phase III clinical trial treatmeat RA

prevention of the cleavage of the 26
kDa membrane-bound protein to the
active 17 kDa molecule

inhibition of TNFα
protein translation

acceleration of TNFα
mRNA degradation

inhibition of TNFα mRNA
transcription

Enrico Heffler, Mike Berry : Biodrugs 2007; 21

a : Indications approved by the Food and Drug Administration (FDA) and
European Union EMEA

Jan Lin : Clin Immunol. 2008 January ; 126(1): 13–30

Infliximab is a chimaeric mouse/human monoclonal anti-TNF-α antibody
etanercept is a soluble fusion protein combining two p75 TNFRs with an Fc
fragment of
human IgG1
adalimumab is a fully human monoclonal anti-TNF-α antibody

C. Russo and R. Polosa:Clinical Science (2005) 109, 135–142

This was the first description of the use of anti-TNFa in
asthma and, although an open study, it generated
considerable excitement in the field
Method
› TNFa BAL fluid of 26 healthy controls, 42 subjects with
mild asthma and 20 with severe asthma
› TNFa gene expression was determined in
endobronchial biopsy specimens from 14 patients
with mild asthma and 14 with severe asthma
› open label uncontrolled clinical study in 17 subjects
with severe asthma to evaluate the effect of 12
weeks of treatment with the soluble TNFa receptor-
IgG Fc fusion protein, etanercept
1

P H Howarth, S T Holgate : Thorax 2005;60:1012–1018

A : TNFa concentrations in bronchoalveolar lavage
B : TNFa gene expression in endobronchial biopsy
C : Immunoreactive TNFa positive cell counts in endobronchial biopsy specimen
D : Immunohistochemical staining and localisation of TNFa in submucosal cells

TNFa levels in BAL fluid, TNFa gene
expression and TNFa immunoreative cells
were increased in subjects with severe
corticosteroid dependent asthma
Etanercept treatment was associated
with improvement in asthma symptoms,
lung function, and bronchial
hyperresponsiveness


This was the first double-blind placebo-
controlled study of anti-TNFa in asthma
Method
› measured markers of TNF-α activity on
peripheral-blood monocytes (CD14)
› 10 refractory asthma, 10 mild-moderate
asthma and 10 placebo
› Investigated the effects of treatment with
the soluble TNF-α receptor etanercept (25
mg twice weekly), refractory asthma
Mike A. Berry, N Engl J Med 2006;354:697-708

Treatment periods lasted 10 weeks and were separated by a 4-week washout period. The washout phase was
chosen because the half-life of etanercept is 70 hours and, according to information provided by the manufacturer,
clinical experience in patients with rheumatoid arthritis suggested that symptoms return within one month after
treatment is stopped.


Open symbols in Panels A and B represent patients who received etanercept first in the
crossover trial, and closed symbols those who received placebo first


Compare patients with mild-to-
moderate asthma and controls, patients
with refractory asthma had increased
expression of membrane-bound TNF-α,
TNF-α receptor 1, and TNF-α–converting
enzyme by peripheral-blood monocytes


Clinical trial, as compared with placebo,
10 weeks of treatment with etanercept
was associated with a significant
increase in the concentration PC20,
improvement in the asthma-related
quality-of-life score and 0.32-liter
increase in postbronchodilator FEV1


Method
› Double-blind, placebo controlled, 38
moderate asthma with ICS but
symptomatic during a run-in phase
› Infliximab (5 mg/kg) or placebo by IV
infusion at Weeks 0, 2, and 6
› clinical response by monitoring lung
function, symptoms, and inhaled β2
agonist usage using hand held
electronic device
Edward M, Peter J. Barnes : Am J Respir Crit Care Med Vol 174. pp 753–762, 2006

ITT intention to treat; PEP primary endpoint group with sufficient PEF rate in the last
7 d before the penultimate clinic visit (approximately 8 wk); PP per protocol
(patients meet inclusion criteria and complete clinic visits).


Electronic diary lung function, symptoms, and β2-agonist usage


A : Incidence of exacerbations over Weeks 0–8
B : freedom from exacerbation over time. Infliximab (n = 14) and placebo (n = 18)


Infliximab
(n 15) and placebo (n
18). *p < 0.05 or **p <
0.01 for comparison of
infliximab versus
placebo at given
time points,

Edward M, Peter J.
Barnes : Am J Respir
Crit Care Med Vol 174.
pp 753–762, 2006

Infliximab was associated with a
decrease in mean diurnal variation of
PEF at Week 8
Decrease in the number of patients with
exacerbations of asthma
Increased probability of freedom from
exacerbation with time
Infliximab decreased levels of TNF-a in
sputum
No serious adverse events

Method
› RDBCT, Etanacept once weekly for 12 weeks
39 severe corticosteroid refractory asthma
› Efficacy was measured by change from the
pretreatment baseline in Asthma Related
Quality of Life (AQLQ) and Asthma Control
(ACQ) Questionnaire scores (the primary
endpoints),
› Lung function, PEF and BHR
› Sputum and serum inflammatory cells and
cytokines, serum albumin and C reactive
protein as biomarkers of inflammation

J B Morjaria, S T Holgate : Thorax 2008;63:584–591

screening, baseline enrolment, during 12 weeks of etanercept treatment or placebo
and subsequent follow-up


Reduction of ACQ scores between
treatment and placebo
Improvement in systemic inflammation,
as measured by serum albumin and CRP
Minor adverse events, including injection
site pain and skin rashes, were more
frequent with etanercept


Method
› 309 severe and uncontrolled asthma,
despite high-dose ICS and long-acting
β2 agonists, were randomized 1:1:1:1
to monthly SC injections of placebo or
golimumab (50, 100, or 200 mg)
throughWeek 52
› prebronchodilator percent-predicted
FEV1and the number of severe asthma
exacerbations through Week 24
Sally E. Wenzel, Peter J. Barnes, Stephen T. Holgate : Am J Respir Crit Care Med Vol
179. pp 549–558, 2009

179. pp 549–558, 2009

Change from baseline in prebronchodilator percent-predicted
FEV1 through Week 24

179. pp 549–558, 2009

patients who completed Additional exacerbations
study participation through calculated for patients who
Week 24 withdrew early

Number of severe asthma exacerbations from baseline through Week 24

179. pp 549–558, 2009

All patients all group

179. pp 549–558, 2009

Unfavorable risk–benefit profile led to
early discontinuation of study-agent
administration after the Week-24
ThroughWeek 76, 20.5%of patients
treated with placebo and 30.3% of
patients treated with golimumab
experienced serious adverse events, with
serious infections
One death and all eight malignancies
occurred in the active groups
179. pp 549–558, 2009

Study N Severity Design Outcome Result

Howarth 15 GINA V Open label, 1: AQLQ Improvement in AQLQ,
Etanercept uncontrolled 2:FEV1, AHR FEV1,AHR
Berry 10 7 GINA V RCT, cross over 1: AHR and Improvement in AQLQ,
Etanercept 3 GINA IV AQLQ FEV1,AHR
2: FEV1, eNO, Increase sputum
sputum cell histamine
counts
Edward 38 Moderate RCT 1: morning PEF No change morning PEF
Infliximab asthma, ICS 2: FEV1, Decrease exacerbate of
onlly exacerbations, asthma
sputum markers Improved PEF variability
Morjaria 39 21 GINA V RCT 1: AQLQ No benefit compare
Etanercept 18 GINA IV 2: ACQ, FEV1, with placebo
PEF, AHR, Reduction ACQ
exacerbation

Sally 309 GINA V RCT 1: FEV1 Serious adverse effect
Golimumab 2: exacerbation

AHR, airway hyperresponsiveness; AQLQ, Asthma Quality of Life
Questionnaire; ENO, exhaled nitric oxide; FEV1, forced expiratory volume
in one second; ICS: inhaled corticosteroids; PEF, peak expiratory flow

TNF-a elevate in severe asthma
TNF-a and asthma
› Direct histamine release from mast cell
› Chemoattactant
› Increase adhesion molecule
› AHR, ASM contraction
Anti-TNFa, etanercept improvement
AQLQ in severe athma

Anti-TNF Therapy for Severe Asthma Refractory to Corticosteroids

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