Asthma- Targeted therapies | Jindal Chest Clinic

Asthma is the most frequent chronic illness in children and is a common noncommunicable disease (NCD) that affects both adults and children. Coughing, wheezing, chest tightness, and shortness of breath are among the symptoms. This presentation target therapies for Asthma including its clinical use, etc. For more information, please contact us: 9779030507.

1. ASTHMA:
TARGETED THERAPY
Dr. S.K Jindal
www.jindalchest.com

2. Asthma:
Chronic Inflammatorydisorder of airways characterized by
Episodic, reversiblebronchospasmresulting from an
exaggerated bronchoconstrictorresponse to various stimuli
Affects 10% of children & 5%-7% adults
Highest in NZ, Low in Fiji ~ 1%

3. 70
60
50
40
30
20
85868788899091929394
Rate/1,000 Persons
Year
<18
18-44
45-64
65+
Total (All Ages)
Age (years)
Trends in Prevalence of Asthma by Age U.S.,
1985-1996
9596
80

4. 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%

5. INFLAMMATION
Airflow Limitation
SYMPTOMS
Cough Wheeze
Dyspnoea
TRIGGERS
Allergens, Exercise,
Cold Air, SO2 Particulates
Pathogenesis:
Airway
Hyperresponsiveness
Genetic*
INDUCERS
Allergens,Chemical sensitisers,
Air pollutants, Virus infections

6. Pathogenesis of Asthma
IL 4, IL5
IL 10,IL13
IL 5, IL 16
Eotaxin
Cytookines
IL6,IL12
PDE4, TGF B
ICAM ,V CAM, IL13

7. Immunology of Asthma
J Allergy Clin. Immunol. 2002 , 109 , S490-S502

8. The evolution of asthma treatment
J Allergy Clin Immunol 2007;120:1269-75
Targeted therapy

9. 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 2008;133;989-998
Am J Respir Crit Care Med 2005;

10. A new paradigm: A systemic disease
needs a systemic approach
Asthmaisasystemicdisease
Newclassesthatareeffectiveinseverepoorlycontrolledasthma
Anoraltreatmentthatisaseffectiveasinhaledcorticosteroids
withoutanysideeffects
Drugsthatmodifyorevencurethedisease
J Allergy Clin Immunol 2007;120:1269-75

11. Asthma : Novel therapies
Chest 2008;133;989-998

12. New corticosteroids
Soft & 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
Drugs 2004.64, 511–519
Br. J. Pharmacol. 2006. 148, 245–254
Chest 2006; 129:1176–1187

13. New bronchodilators
Levcromakalim
Nature Reviews Drug Discovery 3:831,2004

14. Eosinophilsand Asthma

15. Targeting Eosinophilsin Asthma
TRENDS in Molecular Medicine.2006;12 :11

16. Targeting IgE in Asthma
Journal of Asthma, 45:429–436, 2008

17. Omalizumab
Omalizumab(Xolair,Genentech)recombinanthumanizedIgG1monoclonalanti-
IgEantibody
BindstoIgEmoleculeatsameepitopeontheFcregionthatbindstoFcεRI
An89to99percentreductioninfreeserumIgEoccurssoonafteradministrationof
omalizumab

18. Omalizumab: Mechanisms of action

19. 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 1997:1828–34.

20. Evidence of Clinical Benefit
Moderate-to-severeasthmasymptomaticdespitereceivingICS
therapy.
Addingomalizumab
Significantlyreducedexacerbationsvsaddingplaceboduringthe
steroidstableandsteroid-taperingphases
AllowedgreaterreductionsinICSdoserequirements(allp<0.01).
J Allergy Clin Immunol 2001; 108:184–190
Eur Respir J 2001; 18:254–261

21. Evidence of Clinical Benefit
Inpooledanalysesofclinicaltrials,omalizumab
Significantlyreducedasthmaexacerbationsby38%,emergency
departmentvisitsby61%,hospitaladmissionsby52%,and
unscheduleddoctorvisitsby47%vscontrolsubjects
Benefitsofaddingomalizumabparticularlyevidentinpatients
receivinghigh-doseICStherapy,withfrequentasthmaexacerbations
andwithpoorlungfunction
Allergy 2005; 60:302–308
Chest 2004; 125:1378–1386

22. Omalizumab: clinical trials

23. Investigation of Omalizumab in severe Asthma
Treatment (innovate) study
INNOVATEdouble-blind,multicentre,parallel-groupstudy
Patientstreatedwithhigh-doseICSsplusaLABAwithreducedlungfunctionanda
recenthistoryofclinicallysignificantexacerbationwereevaluated
Reduced
Severeexacerbationsby50%,
Emergencydepartmentvisitsby44%
Improvedlungfunction,asthmasymptoms
Asthma-relatedqualityoflife
INNOVATE. Allergy
2005; 60:309–316

24. INNOVATE study
INNOVATE. Allergy
2005; 60:309–316

25. Clinical Use
Patientslikelytobenefit
Withevidenceofsensitizationtoperennialaeroallergens
Requirehighdosesofinhaledcorticosteroids
(>800ugBDP)
Frequentexacerbationsofasthma
Unstabledisease(FEV1<60%)
IgElevelbetween30and700IU/mL
Thosewithseveresymptoms-pooradherencetodailymedication
CHEST 2006; 129:466–474
N Engl J Med 2006;354:2689-95.

26. Preparation for Use
Omalizumabsuppliedasalyophilized,sterilepowderin
single-use,5-mlvials-150or75mgonreconstitutionwith
sterilewater(notnormalsaline)forinjection
Mustbeusedwithinfourhoursifatroomtemperatureoreight
hoursifrefrigerated
Totaldosenottoexceed375mgwithnosingleinjection>150
mg
Chin Med J 2008;121(7):640-648

27. Dosage
Recommendeddose-0.016mgperkgbodywtperIUofIgE
everyfourweeks,administeredsubcutaneouslyateithertwo-
weekorfour-weekintervals
MonitoringoftotalserumIgElevelsduringcourseoftherapy
notindicated,becauselevelselevatedasaresultofpresenceof
circulatingIgE–anti-IgEcomplexes
N Engl J Med 2006;354:2689-95.

28. Dosing Table

29. Response to Treatment
& Adverse Effects
Patientsshouldbetreatedforatleast12weeksbeforeefficacyassessed
Mostcommonadverseevents-viralinfections,URTI,sinusitis,and
headaches
Rash,diarrhea,nausea,vomiting,epistaxis,menorrhagia,hematoma,and
injectionsitereactions
Anaphylaxis
Epithelialorsolid-organcancers
Omalizumabshouldnotbeusedinpatientswithcancerorastrongfamily
historyofcancer

30. Areas of Uncertainty
Inclinicalpractice,thereisconsiderablevariabilityof
responsetoomalizumabtherapy
RelativebenefitofOmalizumabincomparisonwithother
availabletherapies,suchasleukotrienemodifiersor
theophyllinenotknown
Theefficacyandsafetyofomalizumabnotbeenestablished
fordurationsoftreatmentexceedingoneyear
Nofirmguidelinesexist(NAEPPlevelB)
Journal of Asthma, 2008 45:429–436,

31. Regulatory T-cells in Asthma
CHEST 2008; 133:989–998

32. Role of Th2 cells in asthma
Nature Genetics 5: 376-387, 2004

33. Targeting T-cells in Asthma
Neutralizing Th2 Cytokines
IL-4 primary factor driving B-cell
isotypeswitching from IgMto 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
J. Clin. Invest. 114:1389–1397 (2004).
IL 13

34. SOLUBLE IL-4R
RecombinanthumansolubleIL-4receptor(sIL-4R),inactivatesIL-4,
evaluatedinsteroiddependentasthmapatientsfollowingwithdrawalofICS
therapy
ReductioninexhalednitricoxideaftersinglesIL-4Rdose;stabilizationof
asthmasymptoms,despiteICStherapywithdrawal
Administeredonceweeklyfor12weeks,sIL-4RpreventedFEV1decline
AsthmaexacerbationsimilarbetweensIL-4Randplacebogroups
Chin Med J 2008;121(7):640-648
J Allergy Clin Immunol 2001; 107:963–97

35. ANTI-IL-5 HMOABS
Mepolizumab
Anti-IL-5hMoAb(Mepolizumab)significantlyreducednumberofblood
eosinophils,sputumeosinophilsairwayeosinophilsby55%foratleast4weeks
Higherdoseofmepolizumabsignificantlyreduceriskofdevelopmentofsevere
asthmaexacerbationbyabout50%
Severeasthmanotrespondingtoconventionaltreatments-reducednumberof
circulatingeosinophilsandsmall,butsignificantimprovementinFEV1,butno
otherclinicalimprovement
Am J Respir Crit Care Med 2003; 167: 199-204.

36. Interleukin –13 and Asthma
Nature Reviews Drug Discovery 3:831,2004

37. Anti–IL-13 mAb
IL-13inducesairwayhyperresponsiveness,
mucusproduction,secretionofeotaxin,andchangesinairway
remodeling
Atleast3differenthumanizedmAbsunderdevelopment,
specificforhumanIL-13areeitherinphaseIorphaseII
humanclinicaltrials
J Allergy Clin Immunol 2007;119:1251-7

38. Suplatasttosilate-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; 111:958–966

39. TNF –ALPHA

40. 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 2006;354:697–708
Am J Respir Crit Care Med 2006; 174:753–762

41. TNF inhibitors –The other side
TNF-αinhibitorspredisposetoincreasedriskofseriousandlife-
threateninginfection,recrudescenceoftuberculosis,reactivation
ofhepatitisBandmalignancy
Meritsfurtherstudyinlargertrialsinpatientswithsevere
asthma
TNF-α-inhibitortherapylikelybeusedincombinationwith,not
asareplacementfor,standardtreatmentofrefractoryasthma
Am J Respir Crit Care Med 2007; 175: 926-934

42. Phosphodiesterase-4 inhibitors
Nature Reviews Drug Discovery 3:831,2004

43. PDE-4 Inhibitors
Roflumilast,orallyactivePDE-4inhibitor,dose-related
inhibitionoflate-phasebronchospasmfollowingallergen
challengeinmildasthma
Improvementsinlungfunction(FEV1),asthmasymptoms,
andreductionsinrescuemedicationuse,vsICS
Ciclamilast-mediatesAHRthroughinhibitionofPDE-4D
mRNAexpressionanddown-modulationofPDE-4activity,
reducedinflammationandmucushypersecretion
Ann Allergy Asthma Immunol 2006; 96:679–686
Eur J Pharmacol 2006; 547:125–135

44. Adenosine receptors : New targets
Nature Reviews
Drug Discovery
3:831,2004

45. Adenosine A2B Antagonists
ActivationofA2Breceptorsonmastcellsstimulatesreleaseof
proinflammatorymediatorsandcytokines,leadstoincreasedIgEproduction
byBcells
ActivationofA2Breceptorsonlungfibroblastspromotestheirdifferentiation
into
myofibroblasts,suggestingaroleinairwayremodeling
SelectiveA2Breceptorantagonist(CVT-6883)reducedallergen-induced
bronchospasmandinflammatorycellinfiltration
J Pharmacol ExpTher2007;320:1246–1251

46. Chemokine/Chemokine Receptor
Antagonists
Chemokinesaresmallpeptidesthatattractinflammatorycells,including
mastcells,eosinophilsandTh2cellsintoairways
SignalviaG-protein-coupledreceptorsforwhichsmall-moleculeinhibitors
canbedeveloped
Moststudiedtargethasbeenchemokine(C-Cmotif)receptor3(CCR3),
predominantlyexpressedoneosinophilsandmediateschemotactic
responsetoCC-chemokineeotaxin,inasthma
Antagonismhasbeenassociatedwithdecreases
ineosinophilinfiltrationandAHRinexperimental
asthmamodels
Am J Respir Cell Mol Biol 2007; 36:61–67

47. Signal Transduction targets
TRENDS in Molecular Medicine.2006;12 :11

48. Transcription-factor blockade
Transcriptionfactorsarepotentialtargetsfordevelopmentof
immunomodulatoryagentstolimitexpressionofinflammatory
genesinasthma
KinaseInhibitors:p38mitogen-activatedproteinkinaseand
inhibitorofBkinase2
IdentifiedandevaluatedinmodelsofarthritisandotherTh1-
mediatedinflammatorydiseases
Roleinasthmaremainstobedetermined
Eur J Pharmacol 2006;533:118 –132

49. Peroxisome proliferator-activated receptor
gamma agonists
ThiazolidinedionesarePPAR-gagonistscurrentlyapprovedforNIDDM
PPAR-gagonistshaveanti-inflammatoryeffectsinadditiontoinhibitionof
GATA-3levelsthatcouldbetargetedfortreatmentofasthma
Severalsmallclinicaltrialsongoing
Anecdotally,diabeticpatientswithasthmastartedtakingthiazolidinediones
fordiabeteshadimprovementinasthmamanifestedbydecreasedsymptoms
andimprovedpulmonaryfunctionvalues
Clin Exp Allergy 2006;36:1494-504.
Diabetes Care 2002;25:401.

50. Toll-like receptor (TLR) agonists
TLRsplayakeyroleinactivatingantigen-presentingcellsforbothinnateand
adaptiveimmuneresponses
AgonistsorTLR4andTLR9havebeendevelopedandusedinclinicaltrials
TLR4agonist
Evaluatedasapotentialtherapyforseasonalallergicrhinitis
TLR9agonists(immunostimulatoryoligonucleotides)
Tolamba:currentlybeinginvestigatedforallergicrhinitis
N Engl J Med 2006;355:1445-55.
J Allergy Clin Immunol 2004;113:235-41

51. Targeted

52. Pharmacogenetics: The Future of Asthma
Therapeutics?
Gene Species Full name
C5 mouse Complement factor 5
TIM1 mouse T-cell immunoglobulin and mucin-domain 1
ADAM3
3
human A disintegrin and metalloproteinase 33
DPP10human dipeptidylpeptidase 10
PHF11human plant homeodomainfinger protein 11

53. Summary
Airwayinflammation,aprominentfeatureinasthma,needstobetargeted
witheffectivemedicationtoachieveasthmacontrol
Amajorunmetneedistotreatpatientswith
severeasthmawhoarerelativelycorticosteroid-resistantmoreeffectively
Anumberofapproachescurrentlyinclinicaldevelopment,showpromisein
targetingspecific
cytokines,inflammatorycells,orinflammatory
mechanisms,maybecomeavailableforclinicaluseinthefuture
Long-term,multicenterclinicaltrialsaccuratelyassessingrisksandbenefits
areneeded

54. THANK YOU