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