personalized medicine in asthma...what is personalized medicine? personalized medicine can be...
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Personalized Medicine in
Asthma
Alireza Shafiei
Allergist & Clinical Immunologist
Assistant Professor, Bahrami Hospital,
Tehran University of Medical Sciences
Introduction: Asthma clinical manifestations may be similar among patients.
Recent researches have shown that asthma consists of several distinct
clinical clusters or phenotypes.
Each phenotypes has different underlying molecular pathways yielding
different treatment responses.
The main “goal” of this personalized approach is to enable choosing a
treatment which will be more likely to produce a beneficial response in
the individual patient rather than a ‘one size fits all’ approach.A.I. Papaioannou et al. Respiratory Medicine 142 (2018) 15–22
What is personalized medicine?
Personalized medicine can be defined as an approach to treating and
preventing disease by taking into consideration the individual
variability in genes, environment and lifestyle for each subject.
By taking this approach, there is an increased likelihood of treating “the
right patient with the right drug at the right time”, because
preventive measures and therapies can be tailored for each individual
What is needed for the practice of personalized
medicine in asthma?
The recent need to phenotype asthma has been spurred by the realization
that a sizeable proportion of patients with asthma do not respond to
currently available treatments
The step-wise treatment course is recommended regardless of the
underlying cause of asthma or the pathology of the disease
Make available accurate and reliable diagnostics with the
identification of predictive and response biomarkers.
Asthma Pathology
The pathway of inflammation has been arbitrarily divided into T2 high
and non-T2.
T2 inflammation is characterized by a predominance of eosinophilic
inflammation
Non-T2 is marked by a neutrophilic cellular infiltrate or few cells e
paucigranulocytic.
Asthma Endotypes
The “traditional” distinction of asthma endotypes is mainly based on the
discrimination of Th-2 high and Th-2 low inflammatory responses.
The discovery of innate lymphoid cells (ILCs) and the fact that they are
also capable of releasing Th-2 cytokines, results in a better
discrimination of asthma into type-2 and non-type-2 endotypes.
A.I. Papaioannou et al. Respiratory Medicine 142 (2018) 15–22
Biomarker:
Biomarker is short for biological marker
Generally a biomarker is anything that can be used as an indicator of a
particular disease state or some other physiological state of an organism
Biomarkers can be specific cells, molecules, or genes, gene products,
enzymes, or hormones,….
A biomarker should be:
• Easy to obtain as possible.
• The detection method must be accurate, rapid and as easy to carry out.
• A biomarker for clinical use needs good sensitivity and specificity.
• Provide information about disease prognosis and clinical outcomes.
• “Normalize” with successful treatment.
Why Biomarkers?
Biomarkers are important in asthma in order to define the phenotypes
that constitute the whole range of asthma and to identify patients who
will respond to specific therapies
A limited number of biomarkers are currently available:
IgE
Peripheral blood eosinophils
Exhaled nitric oxide (FeNO
Why the need for Biologics?
Patients with severe asthma who are uncontrolled with maximum doses
of inhaled “conventional” therapies
Although only 5% of all asthmatic patients are severe and these patient
s represent ~50% of health care spending
In asthma, it is highly unlikely that we will find another “blockbuster”
drug that is as widely effective as steroids or beta-agonists, thus
future therapies will need to be tailored to particular subsets of
asthmatics
What steps need to be considered prior to the
addition of biologics to asthma treatment?
Confirm the diagnosis of asthma
Non-adherence to medications
proper inhaler procedures
Co-morbid conditions
Smoking
Anti-IgE :
Allergology International 68 (2019) 158e166
omalizumab
Omalizumab is approved by FDA in patients:
Age 6 and above with moderate-to-severe persistent allergic asthma
An IgE level of 30 to 700 IU/mL
Positive allergen skin or specific IgE tests to a perennial allergen
And incomplete symptom control with inhaled glucocorticoid treatment
Omalizumab is administered by subcutaneous injection every two to four
weeks in a dose that is determined by body weight and the levels of
serum IgE (0.016 mg/kg per IU/mL of IgE per month).
No more than 150 mg is administered at a single injection site, to prevent
local reactions.
Home-administration:
In the United States, home-administration of omalizumab using pre-filled
syringes is allowed temporarily during the coronavirus disease 2019
(COVID-19) pandemic, although supervised administration is preferred.
Criteria for home-administration include:
No prior history of anaphylaxis.
Successful administration of three separate doses of omalizumab in the
office
Ability to recognize and treat symptoms of anaphylaxis
Ability to follow the prescribed dosing regimen
Utilize proper injection technique for omalizumab
response to treatment:
The response to omalizumab therapy is variable and difficult to predict,
with overall response rates (reduced inhaled fluticasone dose, rescue
medication use, asthma symptoms) in patients with moderate to severe
asthma averaging 30 to 50 percent .
A minimum of 12 weeks of treatment is needed to determine the efficacy
of anti-IgE therapy
we typically use a three to six month trial before concluding benefit or
lack thereof.
Administration:
SubQ:
For SubQ injection only; doses >150 mg should be divided over more
than 1 injection site.
Each injection site should be separated by ≥1 inch.
Do not inject into moles, scars, bruises, tender areas, or broken skin.
Injections may take 5 to 10 seconds to administer (solution is slightly
viscous).
Administer only under direct medical supervision and observe patient for
2 hours after the first 3 injections and 30 minutes after subsequent
injections
Pricing: US
Solution (reconstituted) (Xolair Subcutaneous)
150 mg (per each): $1,394.81
Solution Prefilled Syringe (Xolair Subcutaneous)
75 mg/0.5 mL (per 0.5 mL): $697.40
150 mg/mL (per mL): $1,394.81
Eosinophilic phenotype: The eosinophilic phenotype is generally characterized by ≥ 2–3% sputum
eosinophils although there are no universally accepted thresholds.
FeNO≥42ppd and absolute blood eosinophil count ≥400/μL are both able
to detect a sputum eosinophil count of ≥3% with acceptable accuracy.
Patients with corticosteroid-resistant eosinophilic airway inflammation
qualify for targeted (biologic) therapies which have been shown to
improve asthma control
Anti-IL-5 therapy:
Interleukin (IL)-5 is a pro-eosinophilic cytokine that is a potent mediator
of eosinophil hematopoiesis and contributes to eosinophilic inflammation
in the airways.
Mepolizumab and Reslizumab are anti-IL-5 monoclonal antibodies
Benralizumab is an anti-IL-5 receptor alpha antibody
Mepolizumab:
FDA and the National Institute for Health and Care Excellence (NICE)
for add-on, maintenance treatment of severe asthma in patients who are
age 12 or older and have an eosinophilic phenotype.
While the FDA did not set a specific threshold, NICE recommends a
threshold of an absolute blood eosinophil ≥300/microL. Clinical trial
data suggest that efficacy requires an absolute blood eosinophil count
≥150/microL
Administration:
Mepolizumab is administered subcutaneously into the upper arm, thigh,
or abdomen, 100 mg every four weeks.
Hypersensitivity reactions have been reported with mepolizumab.
In addition, Herpes zoster infections have occurred in a small number of
patients receiving mepolizumab.
Mepolizumab: Drug information
Brand Names: Nucala
FDA approves Nucala to treat severe asthma November 4, 2015
Dosing: Children ≥12 years, Adolescents and Adult
Asthma: Add-on maintenance treatment of severe asthma with an
eosinophilic phenotype who have a history of severe asthma attacks
(exacerbations) despite receiving their current asthma medicines.
SubQ: 100 mg once every 4 weeks
Adverse Reactions: Headache (19%), Injection site reaction (8%),
Immunogenicity (6%); Fatigue (5%),….hypersensitivity reaction and
herpes zoster
Mepolizumab: Drug information
• Asthma: Not indicated for the treatment of acute asthma symptoms or
acute exacerbations
Patients with preexisting helminth infections should undergo treatment
of the infection prior to initiation of mepolizumab therapy.
Patients who become infected during mepolizumab treatment and do
not respond to anti-helminth therapy should discontinue mepolizumab
until the infection resolves
Mepolizumab: Drug information
• Corticosteroids: Do not discontinue systemic or inhaled
corticosteroids abruptly upon initiation of mepolizumab.
Clinicians should note that a reduction in corticosteroid dose may be
associated with withdrawal symptoms and/or unmask conditions
previously suppressed by systemic corticosteroid therapy.
We typically assess response in terms of symptoms, steroid-sparing
effect, and exacerbation frequency at three and six months to determine
whether to continue therapy.
Pricing: US
Solution (reconstituted) (Nucala Subcutaneous)
100 mg (per each): $3,744.23
Solution Auto-injector (Nucala Subcutaneous)
100 mg/mL (per mL): $3,744.23
Solution Prefilled Syringe (Nucala Subcutaneous)
100 mg/mL (per mL): $3,744.23
Reslizumab:
Reslizumab, a monoclonal anti-IL-5 antibody, has been approved by the
FDA for add-on, maintenance therapy of severe asthma in patients who
are age 18 or older and have an eosinophilic phenotype.
In pivotal trials, an eosinophil phenotype was defined as a peripheral
blood absolute eosinophil count of 400/microL or greater.
In these studies, reslizumab reduced asthma exacerbations by
approximately 50 percent .
Administration:
Reslizumab is administered 3 mg/kg by intravenous infusion over 20 to
50 minutes in a setting prepared to handle anaphylaxis.
Based on a frequency of anaphylaxis of 0.3 percent, the FDA has
placed a boxed warning recommending a period of observation after
dosing.
The most common adverse reaction was oropharyngeal pain (incidence
≥2 percent).
Pricing: US
100 mg/10 mL (per mL): $114.12
Benralizumab:
Benralizumab is a cytotoxic monoclonal antibody directed against IL-5
receptor alpha that is approved by the FDA as add-on therapy in
patients (≥12 years) with severe asthma and an eosinophilic phenotype
(eg, peripheral blood eosinophil count ≥300 cells/microL)
Benralizumab depletes IL-5 receptor-bearing cells (eosinophils and
basophils) via enhanced antibody-dependent cytotoxicity and also
blocks IL-5 binding to its receptor.
It appears to be more effective than anti-IL-5 antibodies in reducing
eosinophil numbers.
Administration:
Benralizumab is given subcutaneously, 30 mg every four weeks for the
first three doses, and then 30 mg every eight weeks.
It is supplied in a prefilled syringe and should be brought to room
temperature prior to use.
It should be administered in a setting prepared to handle anaphylaxis.
Pre-existing helminth infections should be treated prior to initiating
benralizumab.
Pricing: US
Solution Auto-injector (Fasenra Pen Subcutaneous)
30 mg/mL (per mL): $6,234.04
Solution Prefilled Syringe (Fasenra Subcutaneous)
30 mg/mL (per mL): $6,234.04
Anti-lL-4 receptor alpha subunit antibody:
Dupilumab is a fully human monoclonal antibody that binds to the alpha
subunit of the IL-4 receptor.
Dupilumab inhibits the activity of both IL-4 and IL-13, type 2 cytokines
that play a key role in allergy and asthma.
Dupilumab is approved by the FDA for the treatment of moderate-to-
severe, eosinophilic asthma (eg, peripheral blood eosinophils
≥150/microL) in patients age 12 years and older.
Administration:
The recommended dose of dupilumab is an initial 400 mg (two 200 mg
subcutaneous injections), followed by 200 mg given every other week
OR an initial dose of 600 mg (two 300 mg injections) followed by 300
mg given every other week.
The higher dose is suggested for patients with oral glucocorticoid-
dependent asthma or comorbid moderate-to-severe atopic dermatitis.
Pre-existing helminth infections should be treated prior to initiation.
Adverse effects with dupilumab include injection site reactions (in about
15 percent) and transient eosinophilia.
Pricing: US
Solution Pen-injector (Dupixent Subcutaneous)
300 mg/2 mL (per mL): $961.02
Solution Prefilled Syringe (Dupixent Subcutaneous)
200MG/1.14ML (per mL): $1,686.00
300 mg/2 mL (per mL): $961.02
Bronchial thermoplasty:
Bronchial thermoplasty (BT) refers to a technique of applying heat (via
a device that delivers localized controlled radiofrequency waves) to the
airways during bronchoscopy, which reduces the increased mass of
airway smooth muscle associated with asthma.
Due to the risk of the procedure and modest degree of improvement,
additional data are needed regarding long-term effects and
morphologic changes in the airways in order to determine the ideal role
for BT in asthma.
Bronchial thermoplasty:
Bronchial thermoplasty has been
approved by the FDA in April 27th 2010
as a therapy for severe asthma not
controlled by inhaled corticosteroids
and long-acting beta agonists
Bronchial thermoplasty:
The FDA has approved marketing of Alair Bronchial
Thermoplasty System for the treatment of adults (≥18 years
old) with severe asthma not well-controlled with inhaled
glucocorticoids and long-acting beta agonists.
Bronchial thermoplasty is also approved in the European
Union. However, all of the trials excluded subjects with more
than three exacerbations per year or an FEV1 <50 percent
of predicted.
BREITENEDER et al. Allergy. 2020;75:3039–3068.
NAEPPCC EXPERT PANEL WORKING GROUP 2020 ,JACI
** The AHRQ systematic reviews that informed this report did not include studies that examined the role of asthma biologics (e.g. anti-IgE, anti-
IL5, anti-IL5R, anti-IL4/IL13). Thus, this report does not contain specific recommendations for the use of biologics in asthma in Steps 5 and 6.
Thank You