Asthma- Targeted therapies | Jindal Chest Clinic

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ASTHMA TARGETED THERAPY

• Dr. S.K Jindal
• www.jindalchest.com

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Asthma

• Chronic Inflammatory disorder of airways
  characterized by Episodic, reversible
  bronchospasm resulting from an exaggerated
  bronchoconstrictor response to various stimuli
• Affects 10 of children 5-7 adults
• Highest in NZ, Low in Fiji 1

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Trends in Prevalence of Asthma by Age U.S.,
1985-1996
Rate/1,000 Persons
80
Age (years)
70
lt18 18-44 45-64 65 Total (All Ages)
60
50
40
30
20
85
86
87
88
89
90
91
92
93
94
95
96
Year
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India Prevalence Studies
Adults Viswanathan (1966) Patna 2.78 Delhi 1.8
Chowgule (1998) Mumbai M 3.8 W 3.4 (17
using symptoms /or BHR) Jindal (2000)
Chandigarh M 4 W 1.27 Children Chhabra
(1998) Delhi Current 11.6 Gupta
(2001) Chandigarh Boy 2.6, Girl
1.9 Respir sympt 31 ISAAC (1998) Overall
Age 6-7 yrs 3.5 13-14 yrs 4.5
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Pathogenesis
INFLAMMATION
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Pathogenesis of Asthma
IL6,IL12
IL 5, IL 16
IL 4, IL5 IL 10,IL13
Eotaxin Cytookines
PDE4, TGF B ICAM ,V CAM, IL13
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Immunology of Asthma
J Allergy Clin. Immunol. 2002 , 109 , S490-S502
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The evolution of asthma treatment
Targeted therapy
J Allergy Clin Immunol 20071201269-75
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The need for new therapies

• Current therapies ICS ,LABA,SABA act locally
• More than 25 of patients using ICS LABA remain
  inadequately controlled and at high risk of
  exacerbation
• Small percentage of patients (5) who are not
  responsive

Chest 2008133989-998 Am J
Respir Crit Care Med 2005
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A new paradigm A systemic diseaseneeds a
systemic approach

• Asthma is a systemic disease
• New classes that are effective in severe poorly
  controlled asthma
• An oral treatment that is as effective as inhaled
  corticosteroids without any side effects
• Drugs that modify or even cure the disease

J Allergy Clin Immunol 20071201269-75
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Asthma Novel therapies
Chest 2008133989-998
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New corticosteroidsSoft Dissociated steroids

• Ciclesonide, a pro-drug becomes activated
  (desciclesonide) by action of esterases in lung
• Steroid-dependent asthma, administering
  ciclesonide, 640 or 1,280 g/d, significantly
  reduced oral prednisone requirements by 47 and
  63
• less systemic effects
• Long-term retention in lung
• No oral bioavailability
• High degree of binding to circulating proteins
• Dissociated steroids
• greater effect on non-genomic than genomic effect
• better therapeutic ratio
• suitable for oral administration

Chest 2006 12911761187
Drugs 2004.64, 511519 Br. J. Pharmacol. 2006.
148, 245254
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New bronchodilators
Levcromakalim
Nature Reviews Drug Discovery 3831,2004
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Eosinophils and Asthma
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Targeting Eosinophils in Asthma
TRENDS in Molecular Medicine.200612 11
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Targeting IgE in Asthma
Journal of Asthma, 45429436, 2008
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Omalizumab

• Omalizumab (Xolair, Genentech) recombinant
  humanized IgG1 monoclonal anti-IgE antibody
• Binds to IgE molecule at same epitope on the Fc
  region that binds to FceRI
• An 89 to 99 percent reduction in free serum IgE
  occurs soon after administration of omalizumab

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Omalizumab Mechanisms of action
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Evidence of Clinical Benefit

• Omalizumab reduces both early and late asthmatic
  responses with significant improvements in FEV1
  after allergen challenge.

AmJ Respir Crit Care Med 1997182834.
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Evidence of Clinical Benefit

• Moderate-to-severe asthma symptomatic despite
  receiving ICS therapy.
• Adding omalizumab
• Significantly reduced exacerbations vs adding
  placebo during the steroid stable and
  steroid-tapering phases
• Allowed greater reductions in ICS dose
  requirements (all p lt 0.01).

J Allergy Clin Immunol 2001 108184190 Eur
Respir J 2001 18254261
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Evidence of Clinical Benefit

• In pooled analyses of clinical trials,
  omalizumab
• Significantly reduced asthma exacerbations by
  38, emergency department visits by 61, hospital
  admissions by 52, and unscheduled doctor visits
  by 47 vs control subjects
• Benefits of adding omalizumab particularly
  evident in patients receiving high-dose ICS
  therapy, with frequent asthma exacerbations and
  with poor lung function

Allergy 2005 60302308 Chest 2004 12513781386
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Omalizumab clinical trials
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Investigation of Omalizumab in severe Asthma
Treatment (innovate) study

• INNOVATE double-blind, multicentre, parallel-
  group study
• Patients treated with high-dose ICSs plus a LABA
  with reduced lung function and a recent history
  of clinically significant exacerbation were
  evaluated
• Reduced
• Severe exacerbations by 50,
• Emergency department visits by 44
• Improved lung function, asthma symptoms
• Asthma-related quality of life

INNOVATE. Allergy 2005 60309316
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INNOVATE study
INNOVATE. Allergy 2005 60309316
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Clinical Use

• Patients likely to benefit
• With evidence of sensitization to perennial
  aeroallergens
• Require high doses of inhaled corticosteroids
• ( gt
  800ug BDP)
• Frequent exacerbations of asthma
• Unstable disease ( FEV1 lt 60 )
• IgE level between 30 and 700 IU/mL
• Those with severe symptoms - poor adherence to
  daily medication

CHEST 2006 129466474 N Engl J Med
20063542689-95.
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Preparation for Use

• Omalizumab supplied as a lyophilized, sterile
  powder in single-use, 5-ml vials -150 or 75 mg on
  reconstitution with sterile water (not normal
  saline) for injection
• Must be used within four hours if at room
  temperature or eight hours if refrigerated
• Total dose not to exceed 375 mg with no single
  injection gt 150 mg

Chin Med J 2008121(7)640-648
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Dosage

• Recommended dose - 0.016 mg per kg body wt per IU
  of IgE every four weeks, administered
  subcutaneously at either two-week or four-week
  intervals
• Monitoring of total serum IgE levels during
  course of therapy not indicated, because levels
  elevated as a result of presence of circulating
  IgEanti-IgE complexes

N Engl J Med 20063542689-95.
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Dosing Table
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Response to Treatment Adverse Effects

• Patients should be treated for at least 12 weeks
  before efficacy assessed
• Most common adverse events - viral infections,
  URTI, sinusitis, and headaches
• Rash, diarrhea, nausea, vomiting, epistaxis,
  menorrhagia, hematoma, and injection site
  reactions
• Anaphylaxis
• Epithelial or solid-organ cancers
• Omalizumab should not be used in patients with
  cancer or a strong family history of cancer

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Areas of Uncertainty

• In clinical practice, there is considerable
  variability of response to omalizumab therapy
• Relative benefit of Omalizumab in comparison with
  other available therapies, such as leukotriene
  modifiers or theophylline not known
• The efficacy and safety of omalizumab not been
  established for durations of treatment exceeding
  one year
• No firm guidelines exist ( NAEPP level B )

Journal of Asthma, 2008 45429436,
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Regulatory T-cells in Asthma
CHEST 2008 133989998
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Role of Th2 cells in asthma
Nature Genetics 5 376-387, 2004
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Targeting T-cells in Asthma

• Neutralizing Th2 Cytokines
• IL-4 primary factor driving B-cell isotype
  switching from IgM to IgE
• IL-5 is of crucial importance for eosinophilic
• inflammation
• IL-13 contribute to allergic inflammation by
  modulating Th1/Th2 balance and stimulating IL-5
  production

IL 13
J. Clin. Invest. 11413891397 (2004).
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SOLUBLE IL-4R

• Recombinant human soluble IL-4 receptor (sIL-4R),
  inactivates IL-4, evaluated in steroid dependent
  asthma patients following withdrawal of ICS
  therapy
• Reduction in exhaled nitric oxide after single
  sIL-4R dose stabilization of asthma symptoms,
  despite ICS therapy withdrawal
• Administered once weekly for 12 weeks, sIL-4R
  prevented FEV1 decline
• Asthma exacerbation similar between sIL-4R and
  placebo groups

Chin Med J 2008121(7)640-648 J Allergy Clin
Immunol 2001 10796397
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ANTI-IL-5 HMOABSMepolizumab

• Anti-IL-5 hMoAb (Mepolizumab) significantly
  reduced number of blood eosinophils, sputum
  eosinophils airway eosinophils by 55 for at
  least 4 weeks
• Higher dose of mepolizumab significantly reduce
  risk of development of severe asthma exacerbation
  by about 50
• Severe asthma not responding to conventional
  treatments- reduced number of circulating
  eosinophils and small, but significant
  improvement in FEV1, but no other clinical
  improvement

Am J Respir Crit Care Med 2003 167 199-204.
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Interleukin 13 and Asthma
Nature Reviews Drug Discovery 3831,2004
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AntiIL-13 mAb

• IL-13 induces airway hyperresponsiveness,
• mucus production, secretion of eotaxin, and
  changes in airway remodeling
• At least 3 different humanized mAbs under
  development, specific for human IL-13 are either
  in phase I or phase II human clinical trials

J Allergy Clin Immunol 20071191251-7
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Suplatast tosilate - 0ral agent

• Th2 cytokine inhibitor - suppresses IL-4 and IL-5
  synthesis
• Severe asthma( 0n ICS) - significant improvements
  in FEV1, morning PEF rate and daytime asthma
  symptoms at 4 weeks vs adding placebo
• Significantly reduced AHR and improved PEF
  symptoms in steroid-naive patients with mild
  asthma

J Allergy Clin Immunol 2003 111958966
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TNF ALPHA
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Clinical Evidence for use

• Etanercept (recombinant fusion protein)
• Marked and significant improvement in asthma
  control when added to high-dose ICS in
  treatment-resistant refractory asthma
• Infliximab(anti-TNF- monoclonal antibody)
• Reduced diurnal PEF variability in a trial of
  patients with moderate asthma despite receiving
  ICS therapy
• Fewer exacerbations during the 8-week study

N Engl J Med 2006354697708
Am J Respir Crit Care Med 2006 174753762
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TNF inhibitors The other side

• TNF-a inhibitors predispose to increased risk of
  serious and life-threatening infection,
  recrudescence of tuberculosis, reactivation of
  hepatitis B and malignancy
• Merits further study in larger trials in patients
  with severe asthma
• TNF-a-inhibitor therapy likely be used in
  combination with, not as a replacement for,
  standard treatment of refractory asthma

Am J Respir Crit Care Med 2007 175 926-934
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Phosphodiesterase-4 inhibitors
Nature Reviews Drug Discovery 3831,2004
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PDE-4 Inhibitors

• Roflumilast, orally active PDE-4 inhibitor,
  dose-related inhibition of late-phase
  bronchospasm following allergen challenge in mild
  asthma
• Improvements in lung function ( FEV1) , asthma
  symptoms, and reductions in rescue medication
  use, vs ICS
• Ciclamilast - mediates AHR through inhibition of
  PDE-4D mRNA expression and down-modulation of
  PDE-4 activity, reduced inflammation and mucus
  hypersecretion

Ann Allergy Asthma Immunol 2006 96679686
Eur J Pharmacol 2006 547125135
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Adenosine receptors New targets
Nature Reviews Drug Discovery 3831,2004
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Adenosine A2B Antagonists

• Activation of A2B receptors on mast cells
  stimulates release of proinflammatory mediators
  and cytokines, leads to increased IgE production
  by B cells
• Activation of A2B receptors on lung fibroblasts
  promotes their differentiation into
• myofibroblasts,suggesting a role in airway
  remodeling
• Selective A2B receptor antagonist (CVT-6883)
  reduced allergen-induced bronchospasm and
  inflammatory cell infiltration

J Pharmacol ExpTher200732012461251
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Chemokine/Chemokine Receptor Antagonists

• Chemokines are small peptides that attract
  inflammatory cells, including mast
  cells,eosinophils and Th2 cells into airways
• Signal via G-protein-coupled receptors for which
  small-molecule inhibitors can be developed
• Most studied target has been chemokine (C-C
  motif) receptor 3 (CCR3), predominantly expressed
  on eosinophils and mediates chemotactic response
  to CC-chemokine eotaxin, in asthma
• Antagonism has been associated with decreases
• in eosinophil infiltration and AHR in
  experimental
• asthma models

Am J Respir Cell Mol Biol 2007 366167
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Signal Transduction targets
TRENDS in Molecular Medicine.200612 11
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Transcription-factor blockade

• Transcription factors are potential targets for
  development of immunomodulatory agents to limit
  expression of inflammatory genes in asthma
• Kinase Inhibitors p38 mitogen-activated protein
  kinase and inhibitor of B kinase 2
• Identified and evaluated in models of arthritis
  and other Th1-mediated inflammatory diseases
• Role in asthma remains to be determined

Eur J Pharmacol 2006533118 132
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Peroxisome proliferator-activated receptor gamma
agonists

• Thiazolidinediones are PPAR-g agonists currently
  approved for NIDDM
• PPAR-g agonists have anti-inflammatory effects in
  addition to inhibition of GATA-3 levels that
  could be targeted for treatment of asthma
• Several small clinical trials ongoing
• Anecdotally, diabetic patients with asthma
  started taking thiazolidinediones for diabetes
  had improvement in asthma manifested by decreased
  symptoms and improved pulmonary function values

Clin Exp Allergy 2006361494-504. Diabetes Care
200225401.
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Toll-like receptor (TLR) agonists

• TLRs play a key role in activating
  antigen-presenting cells for both innate and
  adaptive immune responses
• Agonists or TLR4 and TLR9 have been developed and
  used in clinical trials
• TLR4 agonist
• Evaluated as a potential therapy for seasonal
  allergic rhinitis
• TLR9 agonists (immunostimulatory
  oligonucleotides)
• Tolamba currently being investigated for
  allergic rhinitis

N Engl J Med 20063551445-55.
J Allergy Clin Immunol 2004113235-41
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Targeted
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Pharmacogenetics The Future of Asthma
Therapeutics?
Gene    Species Full name
C5 mouse Complement factor 5
TIM1 mouse T-cell immunoglobulin and mucin-domain 1
ADAM33 human A disintegrin and metalloproteinase 33
DPP10 human dipeptidyl peptidase 10
PHF11 human plant homeodomain finger protein 11
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Summary

• Airway inflammation, a prominent feature in
  asthma, needs to be targeted with effective
  medication to achieve asthma control
• A major unmet need is to treat patients with
• severe asthma who are relatively
  corticosteroid-resistant more effectively
• A number of approaches currently in clinical
  development, show promise in targeting specific
• cytokines, inflammatory cells, or inflammatory
• mechanisms, may become available for clinical
  use in the future
• Long-term, multicenter clinical trials accurately
  assessing risks and benefits are needed

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