Asthma Novel Medicines

Running Heading: ASTHMA NOVEL MEDICINES 1

Asthma Novel Medicines

Ahmed Abouelnour

ASTHMA NOVEL MEDICINES 2

Asthma Novel Medicines

Asthma is a disease that affects your lungs. It causes repeated episodes of

wheezing, breathlessness, chest tightness, and nighttime or early morning coughing.

Asthma can be controlled by taking medicine and avoiding the triggers that can cause an

attack. You must also remove the triggers in your environment that can make your

asthma worse. [‎1-]

According to WHO estimates, 235 million people suffer from asthma. Asthma is

the most common chronic disease among children. In USA, Asthma affected 25.7 million

people 2010 where 439,000 people were hospitalized because of asthma. In UK,

5.4 million people are currently receiving treatment for asthma, 1.1 million of who are

children .. The total costs in 2008 in U.S.dollars were high and varied widely Canada,

$654M; Switzerland, $1413M; Germany, $2740M; United States, $8256M .[see ‎2-‎3-‎4-]

Types of Asthma include Allergic (extrinsic) asthma (asthma symptoms triggered

by an allergic reaction) and Non-Allergic (intrinsic) asthma (asthma symptoms triggered

by factors not related to allergies).Current Medications of Asthma aim for the

management of acute and chronic conditions to achieve control of asthma and prevent

exacerbations.[see‎5-] Management of Asthma involves pharmacological and non-

pharmacological aspects. The non-pharmacological management involves avoiding

environmental and personal risk factors like (Allergen Avoidance, Wight reduction,

Microbial exposure protection, Smoking Avoidance, etc.).Pharmacological management

includes bronchodilators (Figure 1 Bronchodilators), Inhaled and oral Glucocorticoids

(Beclomethasone-Fluticasone), Leukotriene Receptors Antagonists (Motelukast) ,5-

Lipoxiginase inhibitors.(Zeluton), Mast cell Stabilizers (Cromoglycate) and Histamine 2

receptor antagonists (Loratidine) [‎6-]. (Figure 2 The Different Targets of Current Asthma

Management Medications in Asthma Pathophysiology)

Figure 1 Bronchodilators


Figure 2 The Different Targets of Current Asthma Management Medications in Asthma Pathophysiology

The above mentioned therapies included many limitation .The most important

was the wide variability in both efficacy and side effects attributed to a number of factors

as the interaction of genetic factors, individual patient characteristics like weight, gender,

and pregnancy and exposure to environmental insults, such as air pollution, allergens, and

cigarette smoke. Other limitations included the possible side effects may result from

systemic corticosteroids effect.[‎7-]

The listed limitations was the engine for drug development approaches in asthma

management therapies .The development went in 2 main pathways,(1) to enhance the

current medications via different approaches(Table 1 Illustrates Strategies Adopted to

Enhance the Current Medications) ‎6-‎8-], (2) to think about the genetic and heterogenetic

factors of asthma and try to develop more stratified and personalized treatments. The

development and recent details in 1990s of the asthma pathophysiology was the most

factors augmented the 2nd approach.[‎7-]

Table 1 Illustrates Strategies Adopted to Enhance the Current Medications


PDE4 Inhibition:

During 2000s, PDE4 inhibition was a promising target also, where Roflumilast

which got FDA approval on 2010 for treatment to reduce the risk of COPD exacerbations

in patients with severe COPD associated with chronic bronchitis and a history of

exacerbations [17]. A systematic review shown that PDE4 inhibitors offered benefit over

placebo in improving lung function and reducing the likelihood of exacerbations;

however, they had little impact on quality of life or symptoms. Gastrointestinal adverse

effects and weight loss were common, and safety data submitted to the US Food and

Drug Administration (FDA) have raised concerns over psychiatric adverse events with

Roflumilast. The optimum place of PDE4 inhibitors in COPD management therefore

remains to be defined. Longer-term trials are needed to determine whether or not PDE4

inhibitors modify FEV1 decline, hospitalization or mortality in COPD.[‎18-] Figure 3 The

MOA of Roflumilast

Figure 4 The Th2 Asthma Mechanism

Figure 3 The MOA of Roflumilast


First Step Personalized:

The first step in personalization was the discovery of IgE mediated mast cell

degranulation which could be inhibited by a monoclonal antibody toward the IgE binding

site to the high affinity receptor (FcER1)‎9-]. Anti-IgE (omalizumab) became the first

specific biologic to be used in the treatment of severe allergic IgE mediated

asthma.Omalizumab got the FDA approval on 2003 for adults and adolescents (12 years

of age and above) with moderate to severe persistent asthma who have a positive skin test

or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately

controlled with inhaled corticosteroids [‎10-] Figure 5 Omalizumab Mechanism of Action.

Omalizumab was well tolerated in effective in several dated Systimatic review on

2009,2012 and 2013 where recent update of National (NICE) guidance in 2013

recommended Omalizumab for use as add-on therapy in adults and children over six

years of age with inadequately controlled severe persistent allergic IgE-mediated asthma

who require continuous or frequent treatment with oral corticosteroids.‎11-‎12-‎13-]

Asthma Pathophysiology Development:

However asthma has traditionally been considered a Th2 process linked to atopy

and allergy, type I hyper-sensitivity reactions, eosinophilic inflammation, and response to

corticosteroids. [‎14-‎15-] The second level of personalization started then, where

biomarker approach helped to divide asthma into and Th2 high and Th2 low disease. In

2009, Gene expression analyses identified two evenly sized and distinct subgroups, "Th2-

high" and "Th2-low" asthma. These subgroups differed significantly in expression of IL-

5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood

and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P <

0.03). The lung function improvements expected with inhaled corticosteroids were

restricted to Th2-high asthma, and Th2 markers were reproducible on repeat

evaluation.[‎19-]Figure 4 The Th2 Asthma Mechanism

Figure 5 Omalizumab Mechanism of Action


Recent Approaches:

Actually, Researchers now understand that asthma is heterogeneous and,

particularly for strategies targeting specific mediators, careful selection of patients is

necessary to fully understand the therapeutic potential of new drugs. Recent approaches

to the treatment of asthma include the following [‎16-] Figure 6: Personalized Targets for

Asthma:

Cytokine inhibition—for example, anti-IL5 (mepolizumab), anti-tumor necrosis

factor alpha (TNFα) (etanercept, soluble TNFR), anti-Interleukin 13 (IL13)

(lebrikizumab, tralokinumab)

Chemokine receptor antagonists—for example, chemokine (CXC motif) receptor

2 (CXCR2) (SCH527123).

Targeting IL5,

Targeting IL5

Targeting IL5, was the most successful pathway till now where, Mepolizumab got

FDA approval on 4th of November 2015 to be an add-on maintenance treatment of

Figure 6: Personalized Targets for Asthma


patients with severe asthma aged 12 years and older, and with an eosinophilic

phenotype.[‎20-] Eosinophilic asthma was defined as persistent sputumeosinophilia of

greater than 3% at least once in the previous year. In a randomized, double-blind,

placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic

asthma and a history of recurrent severe exacerbations, intravenous mepolizumab for 1

year reduced asthma exacerbations by approximately 48% compared with placebo, with a

modest effect on asthma quality of life, accompanied by a marked decrease in blood and

sputum eosinophil counts. FEV1, symptoms, and FENO levels were not affected.

However, on computed tomographic imaging, there was a decrease in airway wall

thickening.[‎21-]

Targeting IL-13

Targeting IL13, Two molecules under current investigation lebrikizumab and

tralokinumab. In a randomized, double-blind, placebo-controlled studies, evaluating

multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of

medium-to-high-dose inhaled corticosteroid and a second controller, Treatment with

lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in

the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients

(all doses: 5% reduction); no dose-response was evident. Lung function also improved

following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high

patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low

patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well

tolerated and no clinically important safety signals were observed.[‎22-] It highlights the

conclusion that Periostin level may be an ideal biomarker for the efficacy of

Lebrikizumab.Figure 7:Lebrikizumab Response in High and Low Periostin

Figure 7:Lebrikizumab Response in High and Low Periostin Patients


For Tralokinumab , in a randomized, double-blind, placebo-controlled, parallel-group,

multicenter, phase 2b study at 98 sites in North America, South America, Europe, and

Asia, Tralokinumab had an acceptable safety and tolerability profile but did not

significantly reduce asthma exacerbation rates in patients with severe uncontrolled

asthma. Improvement in FEV1 with Tralokinumab given every 2 weeks and results of

post-hoc subgroup analyses suggested a possible treatment effect in a defined population

of patients with severe uncontrolled asthma.

Targeting IL-4/IL-13

Targeting IL-4/IL-13, Pitrakinra is a mutant IL-4 molecule that blocks the ability

of human IL-4 or IL-13 to bind to IL-4Ra. Nebulized pitrakinra for 4 weeks in patients

with mild atopic asthma reduced the late asthmatic response 3.7-fold compared with

placebo [‎23-].On the other hand, Two studies evaluated a broader blockade, inhibiting

IL-4Ra without any additional benefit. Pitrakinra did not decrease induced asthma

exacerbations compared with placebo when background medication was withdrawn in a

population with moderate-to-severe asthma.[‎24-]

Targeting Thymic Stromal Lymphopoietin TSLP:

Targeting Thymic Stromal Lymphopoietin, The cytokine thymic stromal

lymphopoietin (TSLP) promotes differentiation of Th2 T cells and secretion of

chemokines which preferentially attract them. Both asthma and COPD are associated

with elevated bronchial mucosal expression of TSLP and the same Th1- and Th2-

attracting chemokines. Thus TSLP blockade in an allergen challenge model appeared to

more broadly affect physiologic and inflammatory pathways than targeting either IL-

4/IL-13 or IL-5[‎25-].In a double-blind, placebo-controlled study AMG 157 is a human

anti-TSLP monoclonal immunoglobulin G2λ that binds human TSLP and prevents

receptor interaction. Treatment with AMG 157 reduced allergen-induced

bronchoconstriction and indexes of airway inflammation before and after allergen

challenge.[‎26-].

Future Approach:

Looking over the personalized biological pathway, I can expect that the IL-13,

and TSLP will be highly important pathways. For IL-13 pathway, More researches over

the IL-13 receptors and IL-13 subtypes may be important to produce much more

personalization of medicine as the current trials shown some variability specially in that

of Periostin [‎22-].For TSLP, The current experiments and trials are promising where can

lead to mAb that blocks the TSLP but still there is some other targets within this cycle


where the receptors of TSLP on Th2 cells should be studied and also if there is any other

active receptors for TSLP on other cells that can be a more specific target.

In my opinion, personalized approach for the treatment of asthma will be the successful

where it is:

Designed actually to deliver the medicines to the targeted patient.

It goes parallel with the fact that asthma is a heterogenic disease.

Current safety and efficacy data are promising.

Whatever, the main challenges remain:

Long term safety over prolonged use.

Reproducibility of efficacy.

Biological personalized medicines for asthma is still having a lot to do where researches

should be on continuous research over discovering and validating biomarkers which are

considered as the key for that secret.

ASTHMA NOVEL MEDICINES

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