3. Pathogenesis in a glimpse…
• Asthma has traditionally been described as a Th2
lymphocyte mediated condition in which allergen
presentation by antigen presenting cells to naïve T cells
results in Th2 cell differentiation.
• The Th2 lymphocytes produce IL-4, IL-5, and IL-13 cytokines
that then drive B cells to secrete immunoglobulin E.
4. Available classes of biologicals…
Omalizumab Anti IL5 mab
Primary mechanism of
action
Anti IgE Anti IL5
Other potential MOA Anti rhinoviral
Bio-marker for patient
selection
IgE to indoor aero-
allergens
Eosinophils
Children ≥6yrs ≥12yrs
Patient selection Total IgE and BMI BMI for reslizumab
ROA s.c. Mepolizumab: s.c.
Reslizumab: I.V.
5. The drugs…
• Omalizumab, a monoclonal antibody against
immunoglobulin E (anti-IgE), was the first biologic
developed for the treatment of severe allergic asthma. It
binds to free IgE, which lowers free IgE levels and causes
FcεRI receptors on basophils and mast cells to be
downregulated.
• Mepolizumab or reslizumab, anti-interleukin-5 (anti-IL-5)
mAbs or benralizumab, an anti-IL-5 receptor mAb, are
effective in reducing exacerbations in patients with severe
eosinophilic asthma.
6. Anti IL-5 MOA…
• Mepolizumab specifically binds to the α-chain of IL-5 and disrupts
its interaction with the α-subunit of the IL-5 receptor, which is
present on the eosinophils and their early precursors.
• Reslizumab binds to the alpha chain of the IL-5 receptor on the
eosinophil surface.
• Benralizumab binds to the amino acid isoleucine-61 present
within the domain 1 of human IL-5Rα, thus interacting with the
extracellular IL-5Rα epitope. As a consequence, benralizumab
inhibits hetero-dimerization of IL-5 receptor α/βc subunits and the
following signal transduction mechanisms.
7. Severe Eosinophilic disease diagnosis..
Major Minor
Diagnosis of severe asthma Late onset of disease
Evidence of high load of eosinophilic
disease (persistent blood or sputum
eosinophilia detected on ≥2 occasions.
Upper airway disease
Frequent exacerbations (≥2 per yr.) Role of other biomarkers
Dependence on OCS to achieve asthma
control
Fixed airflow obstruction
Air trapping/presence of mucus plugs.
9. When to use what???
Omalizumab for treating severe persistent allergic asthma
A positive skin test or in vitro reactivity to a perennial aeroallergen
Reduced lung function (FEV1 <80% in adults and adolescents)
Frequent daytime symptoms or night-time awakenings
Multiple documented severe exacerbations despite daily high-dose plus LABA
10. Mepolizumab, as an add-on to optimised standard therapy, is recommended as an
option for treating severe refractory eosinophilic asthma in adults, only if:
The blood eosinophil count is ≥300 cells per μL or more in the previous 12 months, and
The person has agreed to and followed the optimised standard treatment plan, and
Has had four or more asthma exacerbations needing systemic corticosteroids in
the previous 12 months, or
Has had continuous oral corticosteroids of at least the equivalent of prednisolone
5 mg per day over the previous 6 months.
T
11. At 12 months of treatment:
Stop mepolizumab if the asthma has not responded adequately, or
Continue treatment if the asthma has responded adequately and assess response
each year
An adequate response is defined as:
At least 50% fewer asthma exacerbations needing systemic corticosteroids in those
people with four or more exacerbations in the previous 12 months, or
A clinically significant reduction in continuous oral corticosteroid use while
maintaining or improving asthma control
12. Reslizumab, as an add-on therapy, is recommended as an option for the treatment of
severe eosinophilic asthma that is inadequately controlled in adults despite
maintenance therapy with high-dose ICS plus another drug, only if:
The blood eosinophil count has been recorded as ≥400 cells per μL
The person has had three or more asthma exacerbations in the past 12 months, and
At 12 months:
Stop reslizumab if the asthma has not responded adequately, or
Continue reslizumab if the asthma has responded adequately and assess response
each year
An adequate response is defined as:
A clinically meaningful reduction in the number of severe exacerbations needing
systemic corticosteroids, or
A clinically significant reduction in continuous oral corticosteroid use while
maintaining or improving asthma control
13. Dosing…
• Omalizumab is administered subcutaneously every 2–
4 weeks at doses 75-375mg based on baseline total IgE level
and body weight.
• Reslizumab is administered intravenously every 4 weeks
based on body weight (3 mg·kg−1). The corresponding
volume must be injected slowly into a 50-mL bag of 0.9%
sodium chloride. It is then injected over 20-50min.
• Mepolizumab is administered as a fixed dose subcutaneous
injection (100mg) every 4 weeks.
15. • Benralizumab is given as 30 mg SC q4weeks for the first 3
doses, then q8weeks thereafter
16. If not IL5, then??...
• IL-4 and IL-13 expressed by Th2 cells, mast cells, basophils,
and innate lymphoid cells are key cytokines in the
pathogenesis of allergic asthma and atopic disease.
• IL-4 is responsible for many features of asthma, including
Th2 differentiation, mucus production, and B cell isotype
switching. Both IL-4 and IL-13 signal through two different
but overlapping heterodimeric receptors that share the
alpha subunit of the IL-4 receptor (IL-4Rα).
17. Drugs in the pipeline….
Drug MOA
Pascolizumab Anti IL4
Altrakincept Recombinant human IL-4Rα antagonist
Pitrakinra Antagonist against IL-4/IL-13 cytokine
heterodimeric receptor, composed of IL-
13Rα1 and IL-4Rα subunits
Dupilumab Humanized monoclonal antibody to the
IL-4Rα subunit
Lebrikizumab Anti IL-13
Tralokinumab Anti IL-13