Advances in the pharmacotherapy of asthma

1. Recent Advances in the
Pharmacotherapy of Bronchial Asthma
Dr Pritam Biswas

2. As we go along
• Introduction
• Pathophysiology
• Current Management Guidelines.
• Recent Advances
 Pharmacotherapy
 Monoclonals & Anti cytokines
 Immunotherapy
 Non Pharmacological

3. Introduction
• Asthma represents a global public health issue due to high
prevalence rates in the general population( 1% to 18% of
the population in different Countries),
• Affects approximately 300 million people worldwide
• Rising prevalence in developing countries which is
associated with increased urbanization.

4. Asthma is defined as a chronic inflammatory disease
 Airway hyper responsiveness
 Recurrent symptoms such as wheezing, dyspnea
(shortness of breath), chest tightness and coughing.
 Episodes are associated with widespread ,variable,
airflow obstruction within the lungs that is reversible
spontaneously or with appropriate asthma treatment

5. Pathophysiology of Asthma

9. IMMEDIATE RESPONSE
Eliciting agent: allergen or
non-specific stimulus activates:
Mast cells, platelets, alveolar
macrophages, causing release of:
Spasmogens: H,
PAF, LTC4, LTD4,
causing:
Chemotaxins:
LTB4, PAF, MNC,
ECF-A which
cause:
BRONCHOSPASM
Reversed by 
agonists &
Theophylline
Aggregation & activation of
platelets, infiltration & activation of
neutrophils, eosinophils,
monocytes/macrophages :
PAF, LTB4,
LTD4, platelet
factors&
susbstance P
Neurotensin
ODEMA, MUCOUS
SECRETION &
BRONCHOSPASM
LATE-PHASE RESPONSE
Bronchial
hyper
responsiven
ess
Endothelial
damage
& stimulation of
C Fibes and
irritant
receptors

10. Inflammation
 IgE
 Histamine
 Tryptase
 Serotonin
 Leukotrienes (LTC4, LTD4 LTB4)
 Platelet activating factor (PAF)
 Prostaglandins (PGD2)
 Interleukins (IL-4, IL-5,IL- 9 ,IL- 13, IL-17 )
 Granulocyte-macrophage colony stimulating factor (GM-CSF)
 Tumor Necrosis Factor (TNF)
 Major Basic Proteases (MBP)
 Eosinophil Cationic Protein (ECP)
 Eosinophil neurotoxin
 Substance P
 Neurotensin

12. Controller Medications
 Inhaled Glucocorticosteroids
 Leukotriene modifiers
 Long acting inhaled β2 agonists
 low dose sustained release
Theophylline
 Cromones
 Long acting oral β2 agonists
 Anti – Immunoglobin E
 Systemic glucocorticosteroids
Reliever Medications
Rapid acting inhaled β2
agonists
Systemic glucocorticosteroids
 Anticholinergics
Theophylline imediate release
 Short acting oral β2 agonists

13. Current Management of Asthma .
Short acting beta 2 agonist for symptom reliefStep
1
Mild
intermittent
asthma
Mild
Persistent
asthma
Moderate
Persistent
asthma
Severe
asthma
ICS+ Leukotriene modifier add on
Step
2
Step
3 Low dose ICS +LABA
High dose ICS+ LABA
Leukotriene modifier
Step
4
Severe
Persistent
asthma
Step
5
Oral steroid+ high
dose ICS+ LABA

14. Inhalational corticosteroids &
Advances in Steroid resistance
Beta 2 agonists
Phosphodiesterase Inhibitors
Methyl xanthines
Anticholinergics
Anti IgE
Anti cytokines
Novel class of
bronchodilators
Immunomodulatory therapies
Newer anti-inflammatory
therapies
Miscellaneous approaches
CTRH
Toll like receptors
Marcolides
Endothelin antagonists

15. Inhalational corticosteroids
ICS Pharmacokinetics Safety
Triamcinolone Greater systemic side
effectsBeclomethasone
Fluticasone High first Pass
Metabolism (liver )
Fewer systemic side
effects
Safe at higher doses
Budesonide
Momethasone
Ciclesonide Prodrug
High First Pass
metabolism
High plasma protein
binding
Minimal systemic side
effects

16. Ciclesonide
Prodrug, converted to active ingredient
des-ciclesonide by lung esterases
Oral Bioavailability <1 %
Highly Plasma protein bound 99%
Half-life: 0.71 hr (ciclesonide); 6-7 hr
(des-ciclesonide)
Clearance: 152 ML/hr high
Lipid Binding to fatty acids in lung
Decreased
systemic toxicity
Increased Local
action

18. Soft steroids
They have improved local, topical selectivity and have
much less steroid effect outside target area.
Lactone GCS conjugate
Glucocorticoid with a lactone ring
Stable in the lung , not metabolized by lung esterases
Metabolized quickly by plasma paraoxonase
Soft steroids
Loteprednol
Approved for ophthalmic use
Phase 2 development in Germany
Lactone GCS
Butixocort/ Tipredane Lack clinical efficacy
Rofleponide Preclinical phase

19. SEGRA- Selective Glucocorticoid
receptor agonist
Desirable anti-inflammatory and immuno suppressive properties of classical
glucocorticoids drugs but with fewer side effects .
Transactivation
annexin
A1, angiotensin-
converting
enzyme, neutral
endopeptidase
Transrepression
COX,NO
synthase, TNF, TG
F BETA, ICAM-1

20. Mapracorat ( SEGRA )
• Topical treatment of atopic dermatitis and
inflammation following cataract surgery.
• New frontier for asthma research .

21. Advances in Steroid resistance
About 5-10% of asthmatics are resistant to steroids
Definition
Failure to improve baseline FEV1by more than 15% after treatment with
prednisolone (30– 40 mg daily) for 2 weeks
Type I Steroid Resistant Asthma
Reduction in glucocorticoid receptor‐binding affinity
High concentrations of IL‐2 and IL‐4 or by IL‐13 alone
Type II Steroid Resistant Asthma
Due to low numbers of glucocorticoid receptors

24. IV immunoglobulins:
Steroid-sparing effect appears to be present but is not used, as it is
prohibitively expensive.
IL-2 & IL-4 levels can be lowered by IV immunoglobulins: 2-3 mg / kg /
wk / 4wks
Methotrexate:
Methotrexate causes inhibition of T cell proliferation through inhibition
of enzyme Amidophosphoribosyltransferase.
Concomitant weekly methotrexate therapy causes clinically
significant reduction in oral prednisolone doses 15mg/day to
5mg/day.
Methotrexate therapy also increases peripheral blood T cell sensitivity
to prednisolone inhibition.

25. Cyclosporine:
selectively inhibits T lymphocyte proliferation, IL-2 and other cytokine
production and response of inducer T cells to IL-1.
It is used as a second line immunomodulator drug in steroid resistant
asthma.
Gold:
Has been used in Japan, and isolated studies in
Europe and America have shown decreased use of steroids,
improved symptoms but no change in FEV 1
Leflunomide:
A disease modifying agent for rheumatic diseases, it also causes selective
suppression of Th cytokine expression. They have a steroid sparing effect.

26. Inhalers- Hydrofluroalkane HFA
Breath actuated pMDI
( AUTOHALERS )
Multiple Dose Devices DPIUltrasonic Nebulizers
Single dose DPI

27. SIT - Single Inhaler therapy
• LABA monotherapy has been associated with an
increased risk of asthma-related morbidity and mortality,
• Should only be used along with an ICS
Combination therapy
Inhalational corticosteroid +LABA
Maintenance

28. Rational of ICS + LABA
Common combinations
Beclomethasone+ salmeterol
Fluticasone + salmeterol
ICS
1. Prevents down regulation of Beta receptors
2. Prevents desensitization
LABA
Helps In enhancing the binding of Glucocorticoids to GCR
Maintenance Levosalbutamol

29. SMART – Single Inhaler Maintenance
and reliever therapy
Formoterol has a fast onset of action <1min compared to
other LABA like salmeterol with a onset of 30min
Therefore ICS+ LABA Combinations that contain
formoterol
Budesonide + formoterol
Fluticasone + formoterol
Maintenance and
reliever

30. Advances in Beta 2 agonists
Ultra LABA’s
Ultralong acting LABA . Duration > 24 hrs.
Indacaterol
Bambuterol
carmoterol,
vilanterol
olodaterol,
Indacaterol
Initial trials
Safe
Improvements in FEV1 at 4 weeks ,
Long term studies – Not established the effect
on asthma disease control
Asthma exacerbations

31. Montelukast
Zafirlukast
Pranlukast
Zileuton
Leukotriene Modulators

32. CysLT 2 Receptor antagonists
• Studies have revealed that Cyst LT2 mRNA is
abundantly expressed on activated eosinophils.
• Raised the possibility that Cyst LT2 antagonists
would be more effective in ameliorating the LT’s
response explaining the relative failure of the
existing Cyst LT1 antagonists.

33. Methyl xanthines
Low dose Sustained release theophylline
Plasma values 5 to 10 mg/l – Anti-inflammatory / Less side effects .
Mechanisms :
Histone deacetylase activation- Steroid resistant asthma
Effects on apoptosis
Interleukin-10
Inhibition of NF-KB
Indications
Low dose sustained release theophyline as a add on to ICS in severe asthma

34. Doxofylline
• Novel xanthine bronchodilator
Mechanism of action
• Inhibition of phosphodiesterase 4,
• Decreased affinities towards adenosine A1 and A2
receptors,
Comparative Safety Profile
No CNS stimulation
No cardiac arrhythmias

35. Phosphodiesterase Inhibitors
PDE4 inhibition is thought to lead to elevated levels of
intracellular cAMP,
• suppression inflammatory cell function
• inhibition of mucin production epithelial cells
• alterations in airway smooth muscle tone
Selective PDE inhibitors
Roflumilast , Cilomilast, Rolipram, Ibudilast,
Piclamilast, Luteolin

36. Roflumilast
selective, long-acting inhibitor of the enzyme PDE-4
Reduces release of cytokines
Reduces migration and activation of immune cells

37. Advances in use of Anticholinergics

38. Results
Long acting Muscarinic Agonists ( Tiotropium )
1. In moderate to severe asthma , as a add on when no response to
ICS+ LABA
2. In mild persistent asthma as a add on to ICS .
Important outcomes that are not evaluated in all studies published until
now are the reduction of exacerbations and the anti-inflammatory
effects of tiotropium
Currently available data on the efficacy of tiotropium in asthmatic patients are
not sufficient to recommend the use of this drug

39. Novel classes of bronchodilators
Magnesium sulfate
MOA
• Reduces cytosolic calcium in airway smooth
musclebronchodilatation
USES :
Useful as an additional drug to SABA in A/c severe asthma
can be given by IV/nebulisation
Side effects
Include flushing and nausea
Not suitable to be employed alone as clinical benefit is small

40. Potassium channel openers
Potassium channel openers that open calcium activated
large conductance K+ channels in smooth muscle
Calcium channel blockers Nifedipine, verapamil
-Prevent calcium entry into smooth muscle
-Inhibit stimuli induced bronchoconstriction

41. VIP analogs
- VIP binds to VPAC1(smooth muscles of blood vessels) &
VPAC2(airway smooth muscle)couple to Gs
adenylyl cyclase stimulated-smooth muscle
relaxation
- VIP potent bronchodilator in vitro studies but in patients
it is rapidly metabolized and also has vasodilator Side
effects
Stable analog of VIP (RO 25-1533) selectively stimulate
VPAC2-produces rapid bronchodilatation but effect is
not prolonged .

42. ANP & related peptide Urodilatin
- Activates membrane guanylyl cyclase cGMP
bronchodilatation
- Bronchodilator effects comparable to SABA.
- Useful for additional bronchodilatation in Acute severe
asthma

43. Anti IgE
Omalizumab
Humanized monoclonal
antibody
MOA:
•Neutralizes IgE in circulation
•Inhibits activation of IgE bound
to mast cells
•Down regulates IgE receptors
on mast cells

44. Route : S/c or IV every 2- 4 weeks
Use :
severe persistent extrinsic asthma who are resistant to
other forms of treatment.
Reduces exacerbations and requirement of oral and
inhaled steroids in them
Drawback : high cost
S/E : local reaction at inj. Site
urticarial, rash, flushing
rarely anaphylactic reaction

45. Anticytokines

46. Anti IL-5
IL-5
Anti IL-5 Antibodies
Mepholizumab
Humanized Monoconal antibody
Phase 3 trials
Reduced Eosinophil entry in the airways
Decrease asthma exacerbation
Reslizumab
Phase 2
Pronounced in a subgroup
of patients with highest blood &sputum
eosinophils,
IL5 Receptor antibodies
Benralizumab
Pre-clincial stage
Decrease of circulating eosinophills

47. Anti IL-4
IL-4
Th2 differentiation
Switching of B cells to IgE synthesis
Eosinophil recruitment
Development of mast cells
Anti IL4
Pitrakinra ( s.c / inhaled )
Pascolizumab
Dupilumab decrease in asthma exacerbation rate during
withdrawal of inhaled therapy with
corticosteroids and long-acting 𝛽2-
adrenergic agonists,
marked improvement of respiratory function
TH2

48. Anti IL-13
Lebrikizumab ( PHASE 3)
Improvement of lung function in patients
with moderate-to severe asthma
Improvement of FEV1 from baseline
Tralokinumab ( s.c) -- Phase 3
Decrease need for rescue medication
Anti IL-9
MEDI -528
Improved Asthma Symptom scores
In Trial for exercise induced asthma
TH2

49. Anti TNF alpha Th1 TNF alpha
Recruitment neutrophils and eosinophils via upregulation of
epithelial and endothelial adhesion molecule
Anti TNF alpha Evidence from phase 2
trials
Concern
infliximab circadian oscillations in
peak expiratory
flow
active tuberculosis,
pneumonia, sepsis, and
several different
malignancies
(breast cancer, B-cell
lymphoma, metastatic
melanoma, cervical
carcinoma, renal cell
carcinoma, basal cell
carcinoma,
and colon cancer)
golimumab Not conclusive
etanercept improve lung function,
airway hyper-
responsiveness, and
quality of life

50. Anti IL-17
TH1 IL-17
Neutrophilic inflammation, airway remodeling, Steroid resistant
Secukinumab Humanized anti IL17 antibody
Brodalumab Il-17 receptor antibody
On Going Phase 2 trials in severe asthma that is not adequately
controlled by ICS+LABA
IL-17 is also involved in immune protection against infectious and
carcinogenic agents

51. In vitro studies human anti-GM-CSF monoclonal
IgG1 antibody (MT203) has been developed,
capable of significantly decreasing survival and activation
of peripheral human eosinophils
Anti GM-CSF
GM-CSF is a growth factor over expressed in asthmatic
airways

52. Th1 directed
Serious infections
Neoplastic
disorders
TH2 directed
Autoimmune
diseases
Restricted to
phenotype
Needs evaluation of
cytokines &
markers
Expensive add to
the cost diagnosis
and treatment
Drawbacks

53. Toll like receptors

54. CRTH2
CRTH2 (Chemo attractant Receptor-homologous
molecule expressed on Th2 cells)
G-protein coupled receptor expressed by Th2
lymphocytes, eosinophils, and basophils.
The receptor mediates the activation and chemotaxis of
these cell types in response to prostaglandin D2 (PGD2),
produced by mast cells.
Contributes to the so-called “Th2 polarization”

55. CRTH2 antagonists
Using indomethacin, a CRTH2 agonist, as a starting block
and have prepared novel CRTH2 DP2-selective
antagonists
An oral CRTH2 antagonist (OC0000459) showed a 7.4%
improvement in FEV1 at 28 days (p=0.037).
led to a reduction in total IgE concentration and a trend
toward decreasing sputum eosinophils

56. Macrolides
Clarithromycin reported to be effective in many cases
asthma.
Causation of asthma linked to Chlamydia pneumonia
or mycoplasma pneumonia

57.  Statins are now under evaluation in asthma therapy by
AAAAI
 It was observed that asthmatics with co-morbidities who
are on statins have 30% lower risk for ER visits &
hospitalizations due asthma than controls.

58. Miscellaneous approaches
Endothelin antagonists may improve structural changes in asthma.
However not tested.
Antioxidants more potent than Vit C&E, N-Acetyl cysteine in development
as oxidative stress important in asthma.
Bitter taste receptors agonists ---chloroquine,saccharine

59. Bronchial thermoplasty
Gene therapy
T cell therapy
Immunotherapy

60. Bronchial thermoplasty
 Concept:
Passing RF pulses
through the airway
tissues generates heat
due to tissue resistance
debulking of ASM
 Devices :
thermoplasty apparatus
and RF compatible FOB

62. • In a double-blind, randomized, sham-controlled
clinical study of bronchial thermoplasty
• Improved Qol
• Reduction in asthma attacks
• Reduction in emergency room visits for
respiratory symptoms
• Reduction in days lost from work, school,
• Reduction in hospitalizations for respiratory
symptoms
FDA approved 2010

63. Immunotherapy
• Administration of increasing doses of allergen extracts to
induce persistent immune tolerance in patients with
allergen-induced symptoms
• Recently SubLingual immunotherapy (SLIT) is preferred
and claimed to be more effective in asthma

64.  Benefits include: ↓ in symptom scores, ↓ in
medication usage and ↓ airway reactivity
 Mechanism:
 Increased regulatory T cell activity
 Restoration of Th1- Th 2 balance
 Switching of allergen-specific B
cells towards IgG4 production.
 Usual course:
 3-5 years on maintenance therapy.

65. Allergen peptides:
The active peptides of allergens are used → down
regulation of T cells without co-stimulatory signals
1. Short T cell epitope peptides: induce tolerance without
mediator release (no IgE binding)
2. B cell epitope derived peptides: stimulate B cells to
produce blocking IgG 1 without IgE binding
Recombinant allergens:
Reconstructed with reduced allergenic activity

66. CpG-DNA based immunotherapy:
• Giving cytosine guanine plasmid DNA with allergen
extract produce a strong Th-1 response with increase of
mucosal IF-ϒ and decrease IgE production

68. Is the insertion of a functional gene in a target cell
to exert the gene function
 Genes transferred to target cells by a viral vector
or a liposome (? nanocarrier)
 Target cells in the lungs are respiratory epithelium

69. Cytokine encoding genes:
 Genes encoding for IL-12, IF-ϒ, IL-18:
Cause marked reduction in eosinophilic inflammation, IgE
production and airway hyper responsiveness
 Genes encoding for IL-10 and TGF-β:
Cause suppression of both Th-1&Th-2 response
 β2 receptors encoding genes:
To over express β2 receptors and potentiate bronchodilation
 Glucocorticoid R genes:
Over expression overcomes GCR resistance and decrease systemic
SEs

70. Cloned Th -1 cells are now under Phase 2 trials
Aim: correction of Th1-Th2 imbalance in
asthma with correction of cytokine profile:
↑↑ IL-12, IF-ϒ & ↓↓ IL-4, IL-5, IL-13
T cell Therapy

71. Thank You