post graduate medicine teaching programme

1. EMERGING THERAPY IN
BRONCHIAL ASTHMA……….
Dr CHANDAN KUMAR
VMMC& Safdarjung,new delhi

2. INTRODUCTION
GENERAL SYMPTOMS
• Coughing, particularly if
aggravated at night
• Recurrent dry rales
• Recurrent difficulty in
breathing

3. Manifestation or aggravation of the symptoms:
• During physical exercises
• During viral infections
• After exposure to allergens (animal hairs, domestic dust
mites, tobacco smoke,and pollen)
• Changes of temperature
• Strong emotions (loud laugh or cry)
• Exposure to chemical sprays
• Certain medications (aspirin, beta-blockers)
• Reversible and temporary air flow obstruction, as

4. EMERGING THERAPY.
1.BRONCHIAL THERMOPLASTY:
Aprroved by FDA-April 27, 2010
• What is it?
• The Alair Bronchial Thermoplasty System is
composed of a catheter with an electrode that
delivers radiofrequency energy (a form of
electromagnetic energy) directly to the airways
of the lungs.
A controller unit generates and controls the energy.

5. BRONCHIAL THERMOPLASTY:
• How does it work?
• The Alair Bronchial Thermoplasty System
treats severe persistent asthma by delivering
thermal radiofrequency energy to the airway
wall to heat the tissue in a controlled manner
in order to reduce airway smooth muscle
mass (muscle thickness).
• Patients are treated in multiple sessions, each
targeting a different area of the lungs.

6. BRONCHIAL THERMOPLASTY:
Thermal energy is delivered to the airway wall in
a series of three bronchoscopies that take place
3 weeks apart:
1. Treats the airways of the right lower lobe;
2. The airways of the left lower lobe; and
3. the airways of both upper lobes (Duhamel
2010).

7. BRONCHIAL THERMOPLASTY:
When is it used?
• The Alair Bronchial Thermoplasty System is
indicated for the treatment of –
Severe persistent asthma in patients 18 years
and older whose asthma is not well-controlled
with inhaled corticosteroids and long-acting
beta-agonist medicines

8. 1.BRONCHIAL THERMOPLASTY
SIDE EFEECTS
• asthma attacks,
• wheezing,
• chest discomfort, chest pain,
• partial collapse of the lungs (atelectasis)
• lower airway bleeding (hemoptysis),
• anxiety, headaches, and nausea.

9. Patients with the following conditions
should not be treated:
• Presence of a pacemaker, defibrillator, or other
implantable electronic devices.
• Known sensitivity to medicines required to
perform an internal examination of the airways
(bronchoscopy55), including lidocaine, atropine,
and benzodiazepines.
• Patients previously treated with the Alair System
should not be retreated in the same area(s). No
clinical data are available studying the safety
and/or effectiveness of repeat treatments

10. Patients should not be treated while
the following conditions are present:
• Active respiratory infection.
• Severe asthma attacks or changing dose of
systemic corticosteroids for asthma (up or down)
in the past 14 days.
• coagulopathy
• As with other bronchoscopic procedures, patients
should stop taking anticoagulants, antiplatelet
agents, aspirin and non-steroidal anti-
inflammatory drugs (NSAIDS) before the
procedure with physician guidance.

11. MONOCLONAL ANTIBODIES THERAPY
Omalizumab
• Anti -IgE ab
• It is a recombinant humanized monoclonal antibody
(rhuMAb- -E25) developed by immunizing mice with with
human IgE.
• Then, a monoclonal antibody was selected that recognizes
IgE at the same site as the high same site as the high- -
affinity receptor affinity receptor for IgE (Fcε εRI).
• DOSE- 150 to 300 mg subcutaneously every 4 weeks or 225
to 375 mg every 2 weeks, depending on pretreatment IgE
levels and patient's weight.
• Milgrom H, et al. N Engl J Med 1999;341(26):1966 73.

12. MONOCLONAL ANTIBODIES THERAPY
Omalizumab
Omalizumab the only MAb to date that has been
found to be effective and approved by both the
FDA and European the FDA and European
Medicines Agency (EMEA) for the treatment of
difficult allergic asthma.
• Bousquet J, et al. Expert Opin Biol Ther
2008;8(12):1921 Bousquet J2008;8(12):1921- -
8

13. MONOCLONAL ANTIBODIES THERAPY
Mechanisms of Action of Omalizumab
• Reduces serum levels of free IgE
• Down- -regulates expression of IgE receptors (FceRI)
on mast cells and basophils
• In the airways of patients with allergic asthma, it
reduces Fc asthma, it reduces Fcε εRI+ and IgE+ cells and
causes a profound reduction in tissue and causes a
profound reduction in tissue eosinophilia, together with
reductions in submucosal T submucosal T- -cell and B cell
• Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y,
Reisner C J J Allergy Clin Immunol 2005;115(3):459
Allergy Clin Immunol 2005;115(3):459- -65. 65.

14. Omalizumab
•The reductions in circulating levels of IgE resulting from
omalizumab treatment leads to reductions in FceRI expression
on mast cells, reductions in FceRI expression on mast cells,
basophils and dendritic cells.
•This combined effect results in attenuation of several
markers of inflammation, peripheral and bronchial tissue
eosinophilia, levels of GM levels of GM- -CSF, IL- -2, IL- -4,IL- -5
and IL- -13.
•It may also reduce allergen presentation to T- - cells and the
production of Th2 cytokines. cells and the production of Th2
cytokines.
Holgate S, et al. Allergy 2009:64(12):1728 Holgate S, et al.
Allergy 2009:64(12):1728– –36.

15. MONOCLONAL ANTIBODIES THERAPY
Omalizumab Safety
•The most common adverse reaction from
omalizumab is injection- -site pain, bruising but
the package insert contains warnings regarding
1.malignancies,
2.geohelminth infections and
3. a "black box" warning about anaphylaxis.
• Cox LS, et al. Allergy Asthma Clin Immunol
2009;5(1):4.

16. MONOCLONAL ANTIBODIES THERAPY
Omalizumab in allergic patients at risk
of geohelminth infection
•A RDBPC trial from Brazil, conducted in 137
subjects (conducted in 137 subjects ,12– 30
years), revealed that 50% of the omalizumab
group experienced at least one intestinal
geohelminth infection infection compared with
41% of the placebo subjects.
Cruz AA, et al. Clin Exp Allergy 2007; 37 : 197– –
207. 207.

17. MONOCLONAL ANTIBODIES THERAPY
Omalizumab and Malignancy •
•Current clinical trial data do not support an
increased risk of malignant neoplasia or
thrombocytopenia with omalizumab. omalizumab.
Corren J, et al. Clin Exp Allergy 2009;39(6):788- -97.
97.
• The majority of cases (60%) were diagnosed
within 6 months of treatment
Cox LS, et al. Allergy Asthma Clin Immunol
2009;5(1):4.

18. MONOCLONAL ANTIBODIES THERAPY
Churg- Strauss syndrome in patients
treated with omalizumab
• Omalizumab treatment may unmask CSS in
patients who have an underlying eosinophilic
disorder due to withdrawal of corticosteroids
in favor of omalizumab, or may delay
corticosteroid treatment allowing for CSS to
manifest
• Wechsler ME, et al. Chest 2009;136;507-
18.http://chestjournal.chestpubs.org/content/
136/2/507.full.html

19. MONOCLONAL ANTIBODIES THERAPY
ANTI IL-5 THERAPIES are undergoing
premarket analysis.
1.Mepolizumab
2. Reslizumab
3. Benralizumab

20. MONOCLONAL ANTIBODIES THERAPY
ANTI IL-5 THERAPIES
1.Mepolizumab
• under investigation and in preclinical
development byGlaxoSmithKline,
• Mechanism of action:
a) reduces the production, activation, and
proliferation of eosinophils (Smith 2011).
Mepolizumab

21. MONOCLONAL ANTIBODIES THERAPY
ANTI IL-5 THERAPIES
1.Mepolizumab
• Decreases exacerbation rates and the eosinophil counts
in both blood and sputum (Halder 2009
• Reductions in oral corticosteroid dosage without the risk
of exacerbations (Parameswaran 2009).
• Reduces the number of asthma exacerbations
experienced per year (Pavord 2012).
• Appears to be a safe and effective option that could lead
to withdrawal of oral corticosteroids

22. MONOCLONAL ANTIBODIES THERAPY
ANTI IL-5 THERAPIES
2.Reslizumab
Reslizumab (SCH55700; Teva Pharmaceuticals,
Petah Tikva, Israel) is a humanised IL-5
monoclonal antibody that has been previously
investigated in the treatment of nasal polyps
and is currently in clinical development for the
treatment of asthma.

23. MONOCLONAL ANTIBODIES THERAPY
ANTI IL-5 THERAPIES
3.Benralizumab (MEDI-563; Kyowa Hakko
Kirin/AstraZeneca) is a humanised anti-IL-5Ra
monoclonal
antibody .
• Benralizumab targets the effector cells that are
driven by IL-5 (eosinophils/basophils) which
produce IL-5.
• In vitro experiments demonstrated that
benralizumab
directly targets eosinophils for antibody-dependent
cell-mediated cytotoxicity .

24. MONOCLONAL ANTIBODIES THERAPY
ANTI IL-5 THERAPIES
.Benralizumab
A single dose of benralizumab administered
intravenously to 44 subjects with mild atopic
asthma has been shown to induce dose-
dependent peripheral blood eosinophil count
depletion for at least 8–12 weeks [in phase two
trial]

25. MONOCLONAL ANTIBODIES THERAPY
A mutated interleukin- -4 (pitrakinra) that binds the IL
binds the IL- -4R 4Rα αand blocks the effects of IL- -4 and
IL 4 and IL- -13 has been developed.
•A small RDBPC phase II trial in mild- -to to- - moderate
asthmatics showed that inhaled moderate asthmatics
showed that inhaled pitrakinra reduced the late phase
decline in lung function in response to inhalational
allergen challenge with no serious adverse allergen
challenge with no serious adverse events. events.
Wenzel SE, et al. Lancet 2007;370:1422 Wenzel SE, et al.
Lancet 2007;370:1422– –3

26. MONOCLONAL ANTIBODIES THERAPY
Chemoattractant Receptor-
Homologous Molecule
• Researchers have identified chemoattractant
receptor-
homologous molecule (CRTH2) as a marker for
human Th2 cells (Chevalier 2005).
• New evidence is mounting surrounding the role
of prostaglandin D2,
which is thought to elicit actions through the D-type
prostanoid receptor.
The prostaglandin binds to CRTH2
(Schuligoi 2010) and indomethacin.

27. MONOCLONAL ANTIBODIES THERAPY
• Scientists have used indomethacin, a CRTH2
agonist, as a starting block andhave prepared
novel CRTH2 DP2-selective
antagonists(Birkinshaw 2006).
• Both CRTH2 and prostaglandin D2are
promising targets for antiasthma drug therapy.

28. MONOCLONAL ANTIBODIES THERAPY
• A novel CRTH2 antagonist, MK-7246, is reversible
and highly selective for the human CRTH2
receptor (Gervais 2011).
• An oral CRTH2 antagonist (OC0000459) showed
a 7.4% improvement in FEV1 at 28 days (p=0.037).
• The OC0000459 agent also led to a reduction in
total IgE concentration and a trend toward
decreasing sputum eosinophils (Barnes 2012).

29. MONOCLONAL ANTIBODIES THERAPY
TNF-α Blockade
A phase 2 study of Golimumab in patients with severe
persistent asthma was ended early at week 24 because
of safety concerns that included
1.increased incidence of
malignancies (8 reported out of 231 patients) and
2.infections
such as pneumonia (Wenzel 2009).

30. MONOCLONAL ANTIBODIES THERAPY
TNF-α Blockade
Subgroup analysis revealed a trend toward a lower risk of
asthma
exacerbations with golimumab versus placebo in the following
subgroups: (1) patients 49 years or older,
(2) patients with more than one ED visit or hospitalization
in the year before the study,
(3) patients with baseline
prebronchodilator FEV1s less than 60% predicted, and
(4) patients with asthma onset at 12 years of age or older
(Wenzel 2009).

31. NEWER DRUGS UNDER TRIAL

32. CLASSIFICATION DRUGS MECHANISM EFFICACY BENEFIT

34. MONOCLONAL ANTIBODIES THERAPY
Limitations of Use of MAbs in Asthma
•Expense
•Parenteral administration
•Adverse effects •
•Host anti -drug responses limiting ongoing
therapy

35. ROFILOMILAST
• Roflumilast, an oral (250 and 500 μg) , once-daily
phosphodiesterase 4 inhibitor, attenuates
allergen-induced asthmatic reactions
• Roflumilast is an oral, once-daily
phosphodiesterase type 4 (PDE4) inhibitor in
clinical development
• Phosphodiesterases hydrolyze the second
messenger cyclic adenosine monophosphate
(cAMP) to 5′-adenosine monophosphate,
rendering it inactive

36. ROFILOMILAST
• cAMP blocks proliferation and chemotaxis of
inflammatory cells (eg, lymphocytes), inhibits
proinflammatory cell activity (eg, phagocytosis
and respiratory burst).
• Adverse effects, such as nausea and
headache, diarrhea.

37. • THANK U