Recent Advances in the

Pharmacotherapy of Bronchial Asthma Dr Pritam Biswas

As we go along

• Introduction

• Pathophysiology

• Current Management Guidelines.

• Recent Advances

Pharmacotherapy

Monoclonals & Anti cytokines

Immunotherapy

Non Pharmacological

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.

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

Pathophysiology of Asthma

IMMEDIATE RESPONSE

Eliciting agent: allergen ornon-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:

BRONCHOSPASMReversed 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

responsiveness

Endothelial damage

& stimulation ofC Fibes and

irritant receptors

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

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

Current Management of Asthma .

Short acting beta 2 agonist for symptom relief Step

1

Mild

intermittent

asthma

Mild

Persistent

asthma

Moderate

Persistent

asthma

Severe

asthma

ICS+ Leukotriene modifier add onStep

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

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

Inhalational corticosteroids ICS Pharmacokinetics Safety

Triamcinolone Greater systemic side

effects Beclomethasone

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

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

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

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

Mapracorat ( SEGRA )

• Topical treatment of atopic dermatitis and

inflammation following cataract surgery.

• New frontier for asthma research .

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

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.

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.

Inhalers- Hydrofluroalkane HFA

Breath actuated pMDI

( AUTOHALERS )

Multiple Dose Devices DPI Ultrasonic Nebulizers

Single dose DPI

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

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

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

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

Montelukast

Zafirlukast

Pranlukast

Zileuton

Leukotriene Modulators

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.

Methyl xanthinesLow 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 apoptosisInterleukin-10 Inhibition of NF-KB

Indications

Low dose sustained release theophyline as a add on to ICS in severe asthma

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

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

Roflumilast

selective, long-acting inhibitor of the enzyme PDE-4

Reduces release of cytokines

Reduces migration and activation of immune cells

Advances in use of Anticholinergics

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

Novel classes of bronchodilators

Magnesium sulfate

MOA• Reduces cytosolic calcium in airway smooth

musclebronchodilatation

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

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

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 .

ANP & related peptide Urodilatin

- Activates membrane guanylyl cyclase cGMP

bronchodilatation

- Bronchodilator effects comparable to SABA.

- Useful for additional bronchodilatation in Acute severe

asthma

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

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

Anticytokines

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

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

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

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

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

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

Th1 directed

Serious infections

Neoplastic

disorders

TH2 directed

Autoimmune

diseasesRestricted to

phenotype

Needs evaluation of

cytokines &

markers

Expensive add to

the cost diagnosis

and treatment

Drawbacks

Toll like receptors

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”

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

Macrolides

Clarithromycin reported to be effective in many cases asthma.

Causation of asthma linked to Chlamydia pneumonia or mycoplasma pneumonia

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.

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

Bronchial thermoplasty

Gene therapy

T cell therapy

Immunotherapy

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

• 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

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

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.

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

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

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

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

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

Thank You