Dr. Jebin AbrahamDepartment of Pulmonary Medicine

GMC Patiala

ASTHMA STATISTICS• Asthma affects about 334 million people worldwide.*

• Burden of disability is high.

• Asthmatics in India -18 million.

• Approximately 489000 people die per year from the disease.**

*Global asthma report 2014

**Agarwal R, et al. Guidelines for diagnosis and management of bronchial asthma: Joint ICS/NCCP (I) recommendations. Lung India. 2015 Apr;32(Suppl 1)

May 16, 2017 2

OVERVIEW

• Asthma phenotypes• Biomarkers of Asthma• Newer Drugs• Advances in inhalation

therapy• Personalised Medicine

• Pharmacogenetics• Immunotherapy• Vaccination in Asthma• Bronchial Thermoplasty• Surgical Management of

Asthma

May 16, 2017 3

Asthma phenotypes

• Asthma is a heterogeneous disease, with different underlying disease processes.

• Recognizable clusters of demographic, clinical and/or pathophysiological characteristics are often called ‘asthma phenotypes’.

• In patients with more severe asthma, some phenotype-guided treatments are available.

*Definition, description and diagnosis of asthma, GINA 2016

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• Allergic asthma: -Often commences in childhood and is associated with a past and/or family history of allergic disease

-Induced sputum - Eosinophilic airway inflammation.

-Usually respond well to inhaled corticosteroid (ICS) treatment.

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• Non-allergic asthma: -Some adults have asthma that is not associated with

allergy.

-The cellular profile of the sputum of these patients may be neutrophilic, eosinophilic or contain only a few inflammatory cells (paucigranulocytic).

-Patients with non-allergic asthma often respond less well to ICS.

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• Late-onset asthma: - Some adults, particularly women, present with asthma for the first time in adult life.

- These patients tend to be non-allergic

- Often require higher doses of ICS or are relatively refractory to corticosteroid treatment.

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• Asthma with fixed airflow limitation: - Some patients with long-standing asthma develop

fixed airflow limitation that is thought to be due to airway wall remodelling.

• Asthma with obesity:

- Some obese patients with asthma have prominent respiratory symptoms and little eosinophilic airway inflammation.

*Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:71625./*GINA2016

May 16, 2017 8

Biomarkers of Asthma

Biomarkers are objectively measured and evaluated indicators of normal biological

processes, pathogenic processes or pharmacological responses to a therapeutic

intervention

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Exhaled Breath Condensate

• EBC is the exhalate from breath, that has been condensed, typically via cooling using a collection device.

• A matrix of biomarkers- Volatile and non volatile substances.

*Liu J, Conrad DH, Chow S, Tran VH, Yates DH, Thomas PS. Collection devices influence the constituents of exhaled breath condensate. Eur Respir J. 2007 Oct;30(4):807-8.

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Possibilities

• Determining host inflammatory responses

to injury in the lung

• Possible single noninvasive sampling

method for point-of-care real-time analysis

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H2O2 and TBAR• Hydrogen peroxide and Thiobarbituric acid- reactive

products: Increased levels in Asthma.• Increase in levels associated with a drop in FEV1. • Significant reduction with treatment with ICS which

remained stable for 2 weeks after discontinuation.• May be a good measure for monitoring improvement

with treatment.

* Dohlman AW, Black HR, Royall JA. Expired breath hydrogen peroxide is a marker of acute airway inflammation inpediatric patients with asthma. Am Rev Respir Dis. 1993 Oct;148(4 Pt 1):955-60.

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Nitrotyrosine

• A stable end product of peroxynitrite.

• Studied on three asthma groups:

- Mild (steroid naïve)

- Moderate (on ICS)

- Severe (on oral CS)

• Increased levels were found in the first Group

*Hanazawa T, Kharitonov SA, Barnes PJ. Increased nitrotyrosine in exhaled breath condensate of patients with asthma. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1273-6.

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Isoprostanes

• Compounds formed by non-enzymatic peroxidation of membrane phopholipids during oxidative stress

• Levels are elevated in all asthma with higher levels in more severe disease*

• However correlation with PFT is not good

• Recent Meta-analysis- Use in Asthma unclear**

*Montuschi P, Corradi M, Ciabattoni G, Nightingale J, Kharitonov SA, Barnes PJ. Increased 8-isoprostane, a marker of oxidative stress, in exhaled condensate of asthma patients. Am J Respir Crit Care Med. 1999 Jul;160(1):216-20.

**Peel AM, Crossman-Barnes CJ, Tang J, Fowler S, Davies G, Wilson A, Loke Y. Biomarkers in adult asthma: a systematic review of 8-isoprostane in exhaled breath condensate. J Breath Res. 2017 Jan 19.

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Leukotrienes

• Airway smooth muscle contraction, microvascular leakage, mucus hypersecretion.

• Increased levels of LTB4 in asthma which

increase with severity

• No correlation with FEV1

*Becher G, Winsel K, Beck E, Neubauer G, Stresemann E. [Breath condensate as a method of noninvasive assessment of inflammation mediators from the lower airways]. Pneumologie.

1997 Apr;51 Suppl 2:456-9. May 16, 2017 15

pH

• Acute asthma associated with pH decline

of two-log

• Normalised with corticosteroid therapy

• Suggested that serial measures can help

titrate therapy

*Kostikas K, Papatheodorou G, Ganas K, Psathakis K, Panagou P, Loukides S. pH in expired breath condensate of patients with inflammatory airway diseases. Am J Respir Crit Care Med. 2002 May 15;165(10):1364-70. May 16, 2017 16

Future Prospects for EBC in asthma• Some markers persist despite ICS

• Leukotriene pathway is not suppressed by steroids

• Persistent elevation of leukotrienes may be used to initiate therapy with specific inhibitors

• If rise in markers precedes physiological changes greater utility is likely

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FeNO• The most studied biomarker of Asthma• Can be analyzed in a quick and easy way • Comfortable for school-age children • Correlate with bronchial hyper-responsiveness,

blood eosinophils, serum eosinophil cationic protein (ECP), and atopic status/ immunoglobulin E (IgE) levels in children

• Levels tend to be reduced by corticosteroid treatment .

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• If the fraction is high, patients are more likely to respond to ICS.

• Values > 50 ppb* in adults and >35ppb in children High eosinophilic inflammation.

• Conversely, values <25 ppb in adults and <20 ppb in children Low responsiveness to corticosteroids is less likely.

* Dweik RA, et al; An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011 Sep 1;184(5):602-15. May 16, 2017 19

May 16, 2017 20

• Use of FeNO to guide asthma therapy in children may be beneficial in a subset of children,but it cannot be universally recommended for all children with asthma.*

• Not recommended at present for deciding whether to treat patients with possible asthma with ICS.**

*Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev. 2016 Nov 9;11:CD011439.

** GINA 2016May 16, 2017 21

Volatile Organic Compounds

• Also known as e-Nose. • It involves the profiling of multiple metabolic compounds

originating from the lungs and upper airways. • The technique used – Gas chromatography coupled with

Mass spectrometry (GC-MS), • This method has been found to differentiate between adults

with asthma, COPD, and healthy controls.• In children with asthma, VOC analysis enables prediction of

subsequent exacerbations.

*Bos LD, Sterk PJ, Fowler SJ. Breathomics in the setting of asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2016 Oct;138(4):970-976.

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• Breath analysis by e-Nose has even been found to predict response to steroids in patients with asthma more accurately than sputum eosinophils or FeNO.*

* van der Schee MP et al. Predicting steroid responsiveness in patients with asthma using exhaled breath profiling. Clin Exp Allergy. 2013 Nov;43(11):1217-25.

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Induced Sputum• Induced sputum is a relatively safe, semi-invasive method• Can be performed even in school-age children.• Different cellular compositions have been described in

children (eosinophilic, neutophilic, mixed granulocytic, and paucigranulocytic), which may relate to different asthma phenotypes.

• It has been shown that sputum eosinophil numbers are higher in atopic as compared to non-atopic childhood asthma.

• Sputum IL-26 Biomarker of non Th2 mediated, non-eosinophilic type Asthma

*Konradsen JR et al., The cytokine interleukin-26 as a biomarker in pediatric asthma. Respir Res. 2016 Mar 31;17:32.

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Blood Eosinophil Counts

• In adults, high blood eosinophil numbers show associations with higher total IgE, lower FEV1, more exacerbations.

• A marker of response to corticosteroids.

• High eosinophil counts to be a potential biomarker capable of reflecting successful omalizumab treatment effects

*Busse W, Spector S, Rosén K, Wang Y, Alpan O. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J Allergy Clin Immunol. 2013 Aug;132(2):485-6.

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Immunoglobulin

• Serum IgE levels can provide important information for the clinical diagnosis of atopic asthma.

• Measuring allergen-specific IgE levels sensitizing allergens, enabling the avoidance of trigger factors.

• Total IgE levels general predisposition towards atopic asthma.

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Basophil allergen threshold sensitivity (CD-sens)

• A relatively new development • It may enable improved assessment of the degree of

response to a given allergen • Alternative to clinical allergen provocation tests,

performed in vitro.• Involves the detection of CD63 on basophils.• CD-sens is also possible biomarker of response to

treatment with Omalizumab.

*Nilsson C, Nordvall L, Johansson SG, Nopp A. Successful management of severe cow's milk allergy

with omalizumab treatment and CD-sens monitoring. Asia Pac Allergy. 2014 Oct;4(4):257-60May 16, 2017 27

Periostin• Up-regulated by type 2 cytokines IL-4 and IL-13. • Serum periostin can predict the efficacy of anti-IL-13

antibodies (lebrikizumab) and anti-IgE antibodies (omalizumab)

• Periostin-high asthma patients have several unique characteristics, including eosinophilia, high fraction of nitric oxide, aspirin intolerance, nasal disorders, and late onset.

*Izuhara K, Ohta S, Ono J. Using Periostin as a Biomarker in the Treatment of Asthma. Allergy Asthma Immunol Res. 2016

Nov;8(6):491-8.

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YKL-40

• Biomarker of non-type 2 driven Asthma.• Elevated in the serum of both children and adults

with severe asthma. • Increased circulating YKL-40 consistently associates

with reduced lung function.• Associates with measures of airway remodeling such

as bronchial wall thickness and subepithelial fibrosis and increases the proliferation of bronchial smooth muscle cells.

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• Serum YKL-40 estimation may be done using ELISA, RIA or Real-Time Surface Plasmon Resonance Technology*

• Cord blood YKL-40 levels could already serve as potential biomarkers for milder forms of asthma.**

*Naglot S, Aggarwal P, Dey S, Dalal K. Estimation of Serum YKL-40 by Real-Time Surface Plasmon Resonance Technology in North-Indian Asthma Patients. J Clin Lab Anal. 2016 Sep 12.

**Usemann J, Frey U, Mack I, Schmidt A, Gorlanova O, Röösli M, Hartl D, Latzin P. CHI3L1 polymorphisms, cord blood YKL-40 levels and later asthma development. BMC Pulm Med. 2016 May 18;16(1):81.May 16, 2017 30

Serum CCSP level

• Club Cell Secretory Protein• Independently related to small airway

hyperresponsiveness.• Measured by Computed Tomodensitometry.

*Bommart S, Marin G, Molinari N, Knabe L, Petit A, Chanez P, Gamez AS, Devautour C, Vachier I, Bourdin A. CCSP Serum Level is A Surrogate Marker of Small Airway Involvment in Asthma. J Allergy Clin Immunol. 2017 Jan 17. pii: S0091-6749(17)30039-8.

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Urinary Eicosanoids• Different prostaglandins (PGs) both pro- (e.g.,

PGD2) and anti-inflammatory (e.g., PGE2) processes. • But measurement is difficult rapid metabolism• As an alternative to blood- Urinary metabolites

measured. • Liquid chromatography coupled to mass

spectrometry (LC-MS)- technique .• 11β-PGF2α-Reflects Mast cell activation• LTE4- Reflects eosinophil activation

*Balgoma D et al.,Quantification of lipid mediator metabolites in human urine from asthma patients by electrospray ionization mass spectrometry: controlling matrix effects. Anal Chem. 2013 Aug 20;85(16):7866-74.

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Eosinophil-Derived Neurotoxin

• Measured in the urine• Eosinophil protein X (EPX)• Advantage -Reflect eosinophil activation, rather than

eosinophil numbers.• Further studies required for relevance of use.

*James A, Hedlin G. Biomarkers for the Phenotyping and Monitoring of Asthma in Children. Curr Treat Options Allergy. 2016;3(4):439-52.

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Soluble L-Selectin

• L-Selectin is described to have important role in the development of allergic airway inflammation in asthma.

• Recently suggested to be an independent biomarker of Asthma.

• Levels measured in blood.

*Nadi E, Hajilooi M, Pajouhan S, Haidari M. Soluble L-Selectin as an Independent Biomarker of Bronchial Asthma. J Clin Lab Anal. 2015 May;29(3):191-7.

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Other biomarkers

• Thymic stromal lymphopoetin (TSLP)• 25-OH Vitamin D• Chemokine ligand 5 (CCL5)• Hematopoietic prostaglandin D synthase

(HPGDS)• Neuropeptide S receptor 1 (NPSR1)

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NEWER BRONCHODILATORSWhy the need for newer BD?• Once daily dosing convenient and hence improves compliance

and adherence• BDs that provide rapid relief provide patients with

reassurance after first dose and thus improve compliance• Once-daily agents may also affect stability of airway tone,

with reduced fluctuations in airway patency leading to increased morning FEV1

Murphy et al. Turning a Molecule into a Medicine: the Development of Indacaterol as a Novel Once-Daily Bronchodilator Treatment for Patients with COPD. Drugs (2014) 74:1635–57

May 16, 2017 36

Ultra long acting Beta 2 Agonists

• Indacaterol

• Vilanterol

• Olodaterol

• Carmoterol

• Milveterol

• Abediterol

• GSK-642444

• PF-610355May 16, 2017 37

Indacaterol

• Rapid onset and sustained bronchodilation• It is delivered as an aerosol formulation through

a dry powder inhaler.• It is licensed only for the treatment of chronic

obstructive pulmonary disease (COPD).• Long-term data in patients with asthma are lacking.• Not effective as LAMA in preventing exacerbations• Side effects- nausea, fainting, chest pain, palpitations

etc

May 16, 2017 38

Vilanterol• Rapid onset• Approved in may 2013 in combination with Fluticasone

furoate (DPI)• May be used both in Asthma or COPD as once

daily medication• Flu Fu + Vil comparable in efficacy to Salmeterol + FP in

both asthma and COPD• Studies comparing them with LAMA are required

*Woodcock A et al. Efficacy and safety of fluticasone furoate/vilanterol compared with fluticasone propionate/salmeterol combination in adult and adolescent patients with persistent asthma: a randomized trial. Chest. 2013 Oct;144(4):1222-9

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Olodaterol• Rapid onset of action• Long duration of action ~ 24 hrs• Dose 5-10 mcg via Respimat® breath actuated

inhaler• May also have anti-inflammatory and antifibrotic

effects• In asthma, evidence of bronchodilator efficacy of

Olodaterol was demonstrated with statistically and clinically significant improvements over placebo.

*O'Byrne PM et al., Dose-finding evaluation of once-daily treatment with olodaterol, a novel long-acting β2-agonist, in patients with asthma: results of a parallel-group

study and a crossover study. Respir Res. 2015 Aug 18;16:97. May 16, 2017 40

Long Acting Muscarinic Agonist

•There are emerging data from key clinical trials to

show that LAMA may confer bronchodilator effects and

improved control when used in addition to inhaled

corticosteroid (ICS) alone or in conjunction with long

acting β-adrenoceptor agonists (LABA).

* Lipworth BJ. Emerging role of long acting muscarinic antagonists for asthma. Br J Clin Pharmacol. 2014 Jan;77(1):55-62.

May 16, 2017 41

Newer LAMA

• Aclidinium bromide

• Glycopyrronium bromide

• Umeclidinium bromide

• CHF-5407

• TD-4208

• AZD8683

• V-0162

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Aclidinium bromide

• Aclidinium is a quaternary ammonium; Hence low systemic exposure

• May be used od or bd

• Dose 400 mcg BD approved by FDA

• Delivered via Genuair® DPI

• Rapid onset of action compared to tiotropium

• Side effects- Urinary retention, blurring of vision, allergic reactions etc

May 16, 2017 43

Glycopyrronium

• Fast onset of action, IV/inhalation/oral• Used 50 mcg od• Delivered via Breezhaler® DPI device• 3 major trials – GLOW 1, 2, 3• Better than placebo as well as tiotropium in some

studies• Side effects: Hyperthermia, dry mouth etc

Watz H et al., Fast onset of action of glycopyrronium compared with tiotropium in patients with moderate to severe COPD - A randomised, multicentre, crossover trial. Pulm Pharmacol Ther. 2017 Feb;42:13-20.

May 16, 2017 44

Umeclidinium

• Novel LAMA with strong affinity to M3 Receptors• Faster and longer acting compared to Tiotropium• Approved in combination with Vilanterol as DPI

(125/25 mcg or 62.5/25 mcg)• Improvement in FEV1 when compared with

monotherapies for both doses.• No difference in exacerbation rates or dyspnea

scores

*Lee LA, Briggs A, Edwards LD, Yang S, Pascoe S. A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma. Respir Med. 2015 Jan;109(1):63-73.

May 16, 201745

MABA therapy

• Combination of LABA and LAMA in a single

fixed dose system

• Synergistic effect as they act via diff pathways

• Batefenterol, AZD2115 and AZD8871- in clinical trials

• Predominance of either LAMA or LABA activity

*Cazzola M, Lopez-Campos JL, Puente-Maestu L. The MABA approach: a new option to improve bronchodilator therapy. Eur Respir J. 2013 Oct;42(4):885-7.

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QVA 149• Fixed dose combination of 110 μg indacaterol

+ 50 μg glycopyrronium• DPI administered OD via Breezhaler®• Series of 8 Phase III trials done as part of

IGNITE program• Approved in Europe, FDA approval pending• QVA149 - better in reducing exacerbations than

Glycopyrronium/Tiotropium alone, but similar to LABA+ICS

*Metzdorf N, Hallmann C, Disse B. Impact of tiotropium on exacerbations versus glycopyrronium and QVA149. Expert Rev Respir Med. 2015;9(6):675-6.

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Novel class of Bronchodilator

• Recently, agonists of Bitter taste receptors (TAS2R), including Quinine, Chloroquine and Saccharine, have been identified as a novel class of Bronchodilator.

• Calcium sensing receptor(CaSR) blockers- bronchodilator effect

*Deshpande DA, Wang WC, McIlmoyle EL, et al. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat Med 2010;16(11):1299–1304

May 16, 2017 48

PDE4 Inhibitors

• PDE4 inhibition leads to elevated levels of intracellular cAMP

• It leads to suppression of inflammatory cell influx and function.

• Also inhibits of mucin production from airway epithelial cells and alterations in airway smooth muscle tone

• Dual PDE3/4 Inhibitor- RPL554nebulization in asthma

May 16, 2017 49

Cilomilast

• It is orally active, second-generation PDE4 inhibitor

• Currently FDA approved for use in COPD.

Roflumilast• Orally active, Long-acting PDE4 inhibitor• Its primary clinical use is in the prevention of

exacerbations in severe COPD.• Has an inhibitory effect on allergen-induced

responses in asthma• Side effects: Nausea, diarrhea, weight loss etcMay 16, 2017 50

CRTh2 antagonists

• Prostaglandin (PG)D2 is released from mast cells, Th2 cells, and dendritic cells and activates DP2-receptors, also known as chemoattractant homologous receptor expressed on Th2 cells (CRTh2), which mediate chemotaxis of Th2 cells and eosinophils.

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Setipiprant• A selective, orally available antagonist of

the Prostaglandin D2 receptor 2 (DP2)

• Initially researched as a treatment for allergies and inflammatory disorders, particularly asthma.

• No sufficient advantages over existing drugs.

Fevipiprant• Acts as a selective, orally available antagonist of

the prostaglandin D2 receptor 2 (DP2 or CRTh2).

• As of 2016, it is in phase II clinical trials for the treatment of asthma

May 16, 2017 52

Ciclesonide

• A new ICS that is locally activated in the lower airway epithelium.

• Consequently with very low systemic bioavailability.• Negligible risk of local or systemic side effects even

for long-term high-dose treatment.• Cleaved by Esterases in bronchial epithelium.• Available as inhaler/nasal spray alone or in

combination• Side effects: head ache, nose bleeds etc

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Ramatroban

• A thromboxane receptor antagonist.

• It is also a DP2 receptor antagonist.

• It has also been used for the treatment of asthma.

*Endo S, Akiyama K. [Thromboxane A2 receptor antagonist in asthma therapy]. Nihon Rinsho. 1996 Nov;54(11):3045-8.

May 16, 2017 54

Mapracorat

•Anti-inflammatory drug belonging to the experimental class of selective glucocorticoid receptor agonists (SEGRAs)

•In clinical trials for the topical treatment of atopic dermatitis, allergic conjunctivitis etc

May 16, 2017 55

FLAP inhibitors

• The enzyme 5-lipoxygenase (5'-LO) works through 5'lo-activating protein (FLAP).

• Several novel 5'-LO and FLAP inhibitors are currently in clinical development.

• Drugs like Meclofenamate Sodium and Zileuton.

May 16, 2017 56

Cytokine Blockade

• Involves blockade of cytokines involved in TH2 responses or their receptors

• IL-4 & IL-13 - Regulates immunoglobulin E (IgE) formation, particularly in severe asthma.

May 16, 2017 57

Pitrakinra

• A mutated form of IL-4 that blocks IL-4Rα.• Reduces the late response to inhaled allergen in mild

asthmatics when given by nebulization.• Clinical trials are currently in progress.*

• Anti IL-13 Ab- Dupilumab- Reduced exacerbations• Anti IL-17Rα Ab- Brodalumab-Ineffective in asthma

*Antoniu SA. Pitrakinra, a dual IL-4/IL-13 antagonist for the potential treatment of asthma and eczema. Curr Opin Investig Drugs. 2010 Nov;11(11):1286-94.

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Antisense Oligonucleotides

•Inhaled antisense oligonucleotides that block the common β chain of IL-5 and GM-CSF (granulocyte-macrophage colony-stimulating factor) receptors together with the chemokine receptor CCR3 (TPI ASM8) has effect in reducing allergen responses and airway inflammation.

May 16, 2017 59

Anti IL-5 Therapy• Mepolizumab and Reslizumab• Reduce exacerbations in refractory eosinophilic

inflammation• For Step 5 treatment, add-on treatment options for

patients with severe asthma uncontrolled on Step 4 treatment now also include Mepolizumab for patients aged ≥12 years with severe eosinophilic asthma*

• An antibody against the IL-5 receptor (IL-5Rα) Benralizumab is also being studied in clinical trials.**

*GINA 2016 Guidelines

*Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, doubleblind, placebo-controlled trial. Lancet 2012;380:651-9.

**Wang B, Yan L, Yao Z, Roskos LK. Population Pharmacokinetics and Pharmacodynamics of Benralizumab in Healthy Volunteers and Patients With Asthma. CPT Pharmacometrics Syst Pharmacol. 2017 Jan 21. May 16, 2017 60

Lumiliximab

• A monoclonal antibody that targets CD23.

•Is well tolerated and reduces IgE concentrations in patients with mild asthma.

•Clinical efficacy has not been reported.

*Reichert JM. Technology evaluation: lumiliximab, Biogen Idec. Curr Opin Mol Ther. 2004 Dec;6(6):675-83.

May 16, 2017 61

Anti-TNF therapies• Several uncontrolled or small studies suggested that

anti-TNF therapies (TNF blocking antibody Infliximab or soluble receptor Etanercept) may be useful in reducing symptoms, exacerbations, and airway hyper-responsiveness in patients with severe asthma.

Chemokine Receptor Antagonists• CCR3 and CXCR2 antagonists• CXCR2 antagonists- In neutrophilic asthma, disappointing

results*Nair P et al., Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum

neutrophils: a randomized, placebo-controlled clinical trial. Clin Exp Allergy2012;42:1097–1103.

May 16, 2017 62

PPARγ AGONISTS

•Peroxisome proliferator-activated receptor gamma agonists have a wide spectrum of anti-inflammatory effects, including inhibitory effects on macrophages, T cells and neutrophilic inflammation.•Polymorphisms of the PPARγ gene increased risk of asthma.

• Rosiglitazone small improvement in lung function in smoking asthmatic patients.

May 16, 2017 63

SCF and c-kit blockers• Stem cell factor (SCF) is a key regulator of mast cell survival in

the airways.• Acts via the receptor c-kit on mast cells.• Blockade of SCF or c-kit is very effective in animal models of

asthma• Suggesting that this pathway may be a good target for new

asthma therapies. • Masitinib is a potent tyrosine kinase inhibitor that blocks c-kit

(as well as platelet-derived growth factor receptors) and provides some symptomatic benefit in patients with severe asthma.

• More selective c-kit inhibitors are in developmentMay 16, 2017 64

Kinase Inhibitors• SPLEEN TYROSINE KINASE (SYK) that is involved in activation

of mast cells and other immune cells and several small molecule SYK inhibitors are in development.

• p38 MAPK (Mitogen- Activated protein kinase) Inhibitors- Effective in steroid resistant inflammation (Eg. Losmapimod)

• JANUS ACTIVATED KINASE (JAK) inhibitors- Anti inflammatory,

Under development.

• PHOSPHOINOSITIDE -3- KINASE (PI3K) Inhibitors- Possible role in steroid resistant asthma.

Barnes PJ. Kinases as novel therapeutic targets in asthma and COPD. Pharmacol Rev2016;68:788–815.May 16, 2017 65

Inflammasome Inhibitors

• NLRP3 Inflammasome- mediate pro-inflammatory cytokines

• NLRP3 Inhibitors like CRID-3 recently discovered- May be useful in severe asthma

Anti-oxidants• NOX-4 Inhibitors: Inhibit Reactive Oxygen Species

formation

*Gross NJ, Barnes PJ. New Therapies for Asthma and Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2017 Jan 15;195(2):159-166.

May 16, 2017 66

Advances in Inalation Therapy

• New technology for delivering inhaled drugs by metered dose inhaler.

• Using the new hydrofluoroalkane propellant instead of the old chlorofluorocarbon propellant.

• Maintains the drug in a solution- better nebulised in ultrafine particles

• Improvement in the device - slow plume speed and better lung penetration.

• Effectively reaching the smaller airways, especially in more severe asthmatics.

May 16, 2017 67

No clinically significant differences in efficacy or safety were observed comparing small and standard

particle size ICS medications for the treatment of asthma.

*El Baou C, Di Santostefano RL, Alfonso-Cristancho R, Suarez EA, Stempel D, Everard ML, Barnes N. Effect of inhaled corticosteroid particle size on asthma efficacy and safety outcomes: a systematic literature review and meta-analysis. BMC Pulm Med. 2017 Feb 7;17(1):31.

May 16, 2017 68

• ‘Co- suspension technology’*

• Dose- counters- User friendly• The 'Single-inhaler Maintenance And Reliever

Therapy' (MART) has been developed.• A rapid-onset bronchodilator (e.g., Formoterol) and

an ICS (e.g., Budesonide) at the time of the occurrence of asthma symptoms allows the delivery of higher doses of ICS at very beginning stages of exacerbations.

*Fabbri LM et al. Dose-response to inhaled glycopyrrolate delivered with a novel Co-Suspension™ delivery technology metered dose inhaler (MDI) in patients with moderate-to-severe COPD. Respir Res 2016;17:109.May 16, 2017 69

PERSONALISED MEDICINE IN ASTHMA MANAGEMENT

• There is heterogeneity in patient responses to current asthma medications.

• Significant progress has been made identifying genetic polymorphisms that influence the efficacy and potential for adverse effects to asthma drugs.

• Pharmacogenetics holds great promise to maximise clinical outcomes and minimize adverse effects.

• Genome-wide association studies have begun to identify genes underlying asthma (e.g., IL1RL1), which represent future therapeutic targets.

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PHARMACOGENETIC EFFECTS OF CURRENT THERAPIES

• 1. Beta2 –adrenergic receptor agonists (e.g., salbutamol and salmeterol)

-Act by binding to the b2 -adrenergic receptor, a G-protein-coupled receptor encoded by an intron-less gene (ADRB2) located on chromosome 5q31.32.

-Most studies have focused on the role of nonsynonymous coding-region polymorphisms Arg16Gly, Gln27Glu, Val34Met and Thr164Ile

May 16, 2017 71

-Arg16 variant has been associated with an enhanced acute response to b2 -adrenergic receptor agonist.

-But it also showed a decline of asthma control following prolonged use.

May 16, 2017 72

2.Leukotriene modifiers (e.g., montelukast, zarfirlukast and zileuton)

• Evidences suggests that polymorphisms spanning the ALOX5 gene influence clinical responses to LTRAs and LTSIs;

-OATP2B1 polymorphism- Reduced morning plasma concentrations of Montelukast

-Resulting in lack of clinical benefit• MRP1 polymorphism Causes a differential response

to zileuton and montelukast therapy (FEV1 change)

May 16, 2017 73

• CYSLT2 polymorphism- Associated with morning PEF variations in subjects taking montelukast

• LTC4S A plymorphism- Associated with LTRA and LTSI (Zileuton) response (FEV1 change)

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3.Corticosteroids (e.g., prednisolone and beclomethasone)

• CRHR1 and STIP1- Associated with corticosteroid response (FEV1 change)

• TBX21 - Improvements in BHR with corticosteroid treatment

• FCER2 - Associated with asthma exacerbations in the presence of corticosteroids

Michael Portelli & Ian Sayers (2012) Genetic basis for personalized medicine in asthma, Expert Review of Respiratory Medicine, 6:2, 223-36

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Immunotherapy in Asthma

Administration of gradually increasing quantities of specific allergens to patients with IgE-mediated conditions till a dose is reached which is effective in reducing disease severity from natural exposure.

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Indications in Asthma

• Demonstration that disease is due to IgE mediated allergy• Insufficient response to environmental control or

pharmacotherapy• Environmental control not feasible • Significant side effects of pharmacotherapy• Poor compliance to therapy• Both nasal and bronchial symptoms

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Mechanism of immunotherapy

• Allergen→Th2stimulation→IgE• Later exposure →immediate mediator release

→eosinophilic & basophilic inflammation• IT Allergens →T regulatory cells (CD4+CD25+)

→IL-10 Th1↑ IFN-γ↑, Th2↓

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• Blocking AntibodyNatural allergen exposure after IT

↓

IgG4 instead of IgE

↓

blocks Ag

↓Immediate mediators ↓late phase

Less mast cells altered TH1/TH2 ratio

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Routes of Immunotherapy

• Subcutaneous, Oral, Sublingual, Nasal or Bronchial Routes

Rush IT: Can provide hypo-sensitization in short time

IT or Inhaled Steroids ?• Immunotherapy resulted in slow but steady

improvement which did not decline as rapidly as budesonide on cessation

*W.A. Shaikh. Clinical & Experimental Allergy 1997May 16, 2017 80

Recommendations• Allergen-specific immunotherapy may be an

option if allergy plays a prominent role, e.g. asthma with allergic rhinoconjunctivitis.*

• Indian guidelines do not recommend multiple allergen immunotherapy

• Single allergen therapy may be considered in demonstrated skin allergy by trained personnel at higher centres**

*GINA 2016

**Agarwal R, et al. Guidelines for diagnosis and management of bronchial asthma: Joint ICS/NCCP (I) recommendations. Lung India. 2015 Apr;32(Suppl 1)

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Vaccination in Asthma• Influenza contributes to some acute asthma

exacerbations.• Patients with moderate-severe asthma are advised

to receive an influenza vaccination every year.*

• However, vaccination is not expected to reduce the frequency or severity of asthma exacerbations.

• Indian guidelines- Not recommended• Others- Pneumococcal vaccine

*GINA2016 May 16, 2017 82

Role of Vit D

• Several cross-sectional studies have shown that low serum levels of Vitamin D are linked to impaired lung function, higher exacerbation frequency and reduced corticosteroid response.

• However, to date, Vitamin D supplementation has not been associated with improvement in asthma control or reduction in exacerbations.

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Bronchial Thermoplasty

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Short-acting Beta2-agonists

Low-dose Inhaled Corticosteroids (ICS)

Low-dose ICS + Long-acting Beta2-agonists (LABA)

or Medium-dose ICS

Medium-dose ICS + LABA

High-dose ICS + LABAand Consider Omalizumab

High-dose ICS + LABA + Oral Corticosteroids

and Consider Omalizumab

Adapted from National Asthma Education and Prevention Program (NAEPP) Guidelines. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute, NIH Publication No. 07-4051, Revised August 2007.

1

22

3

4

5

6AlternativesNeeded

Stepwise Approach

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Asthmatic Airway

Role of Airway Smooth Muscle in Asthma

Normal Airway Asthma Attack

Bronchial Thermoplasty ASM Treatment Approach

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Reduces Airway Smooth Muscle (ASM)

Reduces Bronchoconstriction

Reduces Asthma Exacerbations

Improves Asthma Quality of Life

• A procedure that delivers thermal energy to the airways via a bronchoscope to reduce excess airway smooth muscle and limit its ability to constrict the airways

• Outpatient hospital procedure - 3 treatment sessions, routinely under moderate sedation

• Complementary treatment, and not a replacement, to current asthma reliever and controller medications

• Shown to increase the level of asthma control and improve quality of life in patients with severe asthma

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The Alair® Bronchial Thermoplasty System

• Alair Catheter – a flexible tube with an expandable wire array at the tip (introduced into the lungs through a standard bronchoscope)

• Alair Radiofrequency (RF) Controller – supplies energy via the Catheter to heat the airway wall

Recommendations

• Bronchial thermoplasty may be considered for some adult patients with severe asthma.*

• Not recommended in India, as good quality evidence is lacking **

*GINA 2016

**Agarwal R, et al. Guidelines for diagnosis and management of bronchial asthma: Joint ICS/NCCP (I) recommendations. Lung India. 2015 Apr;32(Suppl 1):S3-S42.

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Surgical Management Laryngeal Nerve Resection

• Unilateral resection of the internal branch of the superior laryngeal nerve

• Helped prevent/cure asphyxias in chronic severe asthma

• Cough reflex, respiratory control and phonation not affected.

• This approach is of interest for patients with severe and/or uncontrolled bronchial asthma in settings with limited access to drug treatment.

Kurbon U, Dodariyon H, Davlatov A, Janobilova S, Therwath A, Mirshahi M. Surgical treatment of bronchial asthma by resection of the laryngeal nerve. BMC Surg. 2015 Oct 8;15:109.

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Asthma and Palm Dermatoglyphs

• Single nucleotide polymorphisms (SNPs) in the IL-4 (IL-4R) gene close association with asthma severity.

• A close association between asthma and a distinctive palm dermatoglyphic pattern was observed

• Thus, genetic variation in IL-4R may be associated with the development of asthma and the distinctive palm pattern

*Sun L, Xue W, Li J, Zhou Z, Han W. Palm dermatoglyphs and interleukin-4 receptor polymorphisms in asthma. Biomed Rep. 2017 Jan;6(1):21-26.

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Asthma Action Plans

• Smartphone AAP* • Adolescents - satisfied users• Possible clinical benefit in uncontrolled asthma.• Asthma Management Mobile App for Adolescents-

under assessment**

*Perry TT, Marshall A, Berlinski A, Rettiganti M, Brown RH, Randle SM, Luo C, Bian J. Smartphone-based vs paper-based asthma action plans for adolescents. Ann Allergy Asthma Immunol. 2017 Jan 19. pii: S1081-1206(16)31362-X.

**Sage A, Roberts C, Geryk L, Sleath B, Tate D, Carpenter D. A Self-Regulation Theory-Based Asthma Management Mobile App for Adolescents: A Usability Assessment. JMIR Hum Factors. 2017 Feb 1;4(1):e5.

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