1. NEW TREATMENT OPTIONS IN ASTHMA
Prof. Ferah Ece, MD, FCCP
Istinye University School of Medicine
Department of Chest Diseases
Liv Hospital

2. I have no financial or other conflicts of interest to report

3. Asthma is one of the most common chronic diseases worldwide with more than 300 million affected individuals
with enormous socioeconomic impact
with approximately 10% having severe or uncontrolled asthma
When asthma is well-controlled, patients can
Avoid troublesome symptoms during the day and night
Need little or no reliever medication
Have productive, physically active lives
Have normal or near-normal lung function
Avoid serious asthma flare-ups (also called exacerbations, or severe attacks)

4. Asthma treatment is planned in 3 ways:
1) Assess
2) Adjust treatment (pharmacological and non-pharmacological)
3) Review the response
After assessing the patient with asthma, regular daily controller treatment should be initiated. After starting initial treatment response should be reviewed within 1-3 months. If asthma has been well controlled for 3 months, decreasing the dose should be considered

5. Stepwise approach
Step 1 ) as-needed inhaled short-acting beta2-agonist (SABA)
This option should be reserved for patients with infrequent symptoms (less than twice a month) of short duration, and with no risk factors for exacerbations
Step 2 ) low-dose controller + as-needed inhaled SABA
Low dose ICS reduces symptoms and reduces risk of exacerbations and asthma-related hospitalization and death
Step 3 ) one or two controllers + as-needed inhaled reliever
preferred options are either combination low dose ICS/LABA maintenance with as-needed SABA, OR combination low dose ICS/formoterol maintenance and reliever regimen
Step 4 ) two or more controllers + as-needed inhaled reliever
preferred option is combination low dose ICS/formoterol as maintenance and reliever regimen, or combination medium dose ICS/LABA with as-needed SABA
Step 5 ) higher level care and/or add-on treatment
Add-on tiotropium for patients ≥12 years with history of exacerbations, Add-on anti-IgE (omalizumab) for patients with severe allergic asthma, Add-on anti-IL5 (mepolizumab (SC) or reslizumab (IV)) for severe eosinophilic asthma (≥12 yrs)
Step 1: Consider adding regular low dose inhaled corticosteroid (ICS) for patients at risk of exacerbations
Step 2: Other options: a) Leukotriene receptor antagonists (LTRA) with as-needed SABA, b) Combination low dose ICS/long-acting beta2-agonist (LABA) with as-needed SABA, c) Intermittent ICS with as-needed SABA for purely seasonal allergic asthma with no interval symptoms
Step 3: Other options: Adults/adolescents: Increase ICS dose or add LTRA or theophylline (less effective than ICS/LABA), Adults: consider adding SLIT
Step 4: Other options: Tiotropium by mist inhaler may be used as add-on therapy for patients aged ≥12 years with a history of exacerbations; consider adding SLIT; Trial of high dose combination ICS/LABA, but little extra benefit and increased risk of side-effects; Increase dosing frequency (for budesonide-containing inhalers); Add-on LTRA or low dose theophylline

6. SALFORD Trial
open-label, randomised, controlled, two-arm effectiveness trial
ICS/vilanterol improved asthma control

7. Management of severe asthma
Optimize dose of ICS/LABA
Complete resistance to ICS is rare
Consider therapeutic trial of higher dose
Consider low dose maintenance oral corticosteroids
Monitor for and manage side-effects, including osteoporosis
Add-on treatments without phenotyping
Tiotropium - reduces exacerbations (history of exacerbations, age ≥12 years)
Theophylline, LTRA – limited benefit
Phenotype-guided treatment
Severe allergic asthma: add-on omalizumab (anti-IgE)
Severe eosinophilic asthma: add-on mepolizumab or reslizumab (anti-IL5)
Sputum-guided treatment to reduce exacerbations and/or steroid dose
Aspirin-exacerbated respiratory disease: consider add-on LTRA
Non-pharmacological interventions
Consider bronchial thermoplasty for selected patients
Comprehensive adherence-promoting program

8. Why the search for new drugs
• Asthma has a complex pathogenesis
• Patients who aren’t controlled even by oral steroids need an alternative
• Need a drug which can reduce the dose of steroid or replace it

9. New approaches to treatment
• Novel class of bronchodilators
• New antiinflammatory therapies
•Immunomodulatory therapies

10. Novel class of bronchodilators
1) Magnesium sulphate
• Reduces cytosolic calcium in airway smooth muscle
bronchodilation
• Can be given by iv/nebulisation
• Not suitable to be employed alone as clinical benefit is small

11. 2) Atrial natriuretic peptide (ANP) and related peptide Urodilatin
• Urodilatin is paracrine regulator for sodium and water homeostasis
• Bronchodilator effect comparable to SABA
• Useful for additional bronchodilation in severe asthma
3) Vasoactive Intestinal Peptide (VIP) analogs
VIP binds to VIP receptor type-1 (VPAC1) (smooth muscles of blood vessels) and VIP receptor type-2 (VPAC2) (airway smooth muscle), stimulates adenyl cyclase smooth muscle relaxation
•Potent bronchodilator but is rapidly metabolised, SE high
• More stable analog of VIP (RO ) selectively stimulates VPAC2 but effect is not prolonged

12. New anti-inflammatory drugs
NF-kB inhibitors
• NF is a transcription factor regulating inflammatory genes in asthma
• When NF is inhibited susceptibility to infections
2) Mitogen activated protein kinase inhibitors
• MAP kinase pathways are involved in inflammation
• Inhibit synthesis of inflammatory mediators but severe toxicity

13. Others
1) Anticholinergics
2) Bronchial thermoplasty
3) Antibiotics

14. Spiriva Respimat Inhalation Spray
Tiotropium (Spiriva)
Long-acting muscarinic antagonist (LAMA)
In use for over decade as one of the mainstays of COPD therapy
Asthma approved as a second indication by the FDA
Included in the GINA guidelines as a possible add-on at step 5
Spiriva Respimat Inhalation Spray
Once daily 2.5 mcg dose

15. When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma.

16. The study was designed to compare the effectiveness of
tiotropium + ICS vs LABA + ICS in delaying time to first exacerbation
The findings do not support the superiority of LABA + ICS
Compared with tiotropium + ICS for black patients with asthma.

17. Bronchial thermoplasty
It is a potential treatment option for adult patients whose asthma remained uncontrolled despite optimal therapy regimens
Bronchoscopic procedure in which bronchial smooth muscle mass is reduced by (essentially) RF ablation
Series of 3 procedures
Carries an increased risk of asthma exacerbation immediately after the procedure

18. Randomized 109 patients on highdose ICS/LABA (step 4 or 5 per GINA guidelines) to maintenance therapy with azithromycin or placebo

19. Overall, there was no benefit seen with azithromycin therapy
However, subgroup analysis showed that patients with noneosinophilic asthma had fewer exacerbations
this result suggests azithromycin may be an effective option for the neutrophilic/Th-1 phenotype (COPD is also neutrophilic)
Non-eosinophilic asthma was defined as a peripheral eosinophil count less than 200 cells/microliter

20. Immunomodulatory therapies
Immunosuppressive therapy (methotrexate, cyclosporine, gold salts, etc.)
Not employed any more (greater SEs and lesser efficacy)
2) Specific immunotherapy
subcutaneous immunotherapy (SCIT)
sublingual immunotherapy (SLIT)
3) Anti IgE therapy

21. Omalizumab (Xolair)
Applies to a more discrete patient population
Anti-IgE mAb
Criteria:
Skin or serum allergen testing positive for a year-round allergen such as dust mites, molds, animal dander, etc
An elevation in total serum IgE

22. 4) Interleukin-5 Antagonists Monoclonal Antibody Add on for maintenance treatment of poorly controlled moderate to severe eosinophilic asthma

23. The future treatments for asthma is based on the essential idea of personalized medicine
Personalised medicine involves seeking the best ratio between efficacy and feasibility using
clinical characteristics (called “phenotypes”) or guided by biomarkers (called “endotypes”) relevant to the underlying pathogenesis of asthma

24. Endotype-based strategies Phenotype-based strategies
Atopic status
Th2-orientated therapies
Non-Th2-dedicated drugs
Cough/sputum
Low-dose azithromycin regimen
Chronic airway obstruction
IL-5
IL-13
GATA3
Aspirin sensitivity

25. The classification of asthma into phenotypes and endotypes allows for the use of targeted therapies
Interleukin-5 is the most important growth, differentiation, and activating factor for human eosinophils
, including three biologics which target interleukin 5 (IL-5) signaling in eosinophilic asthma. Areas covered: As of December 2016, two monoclonal antibodies, mepolizumab and reslizumab, are approved by U.S. Food and Drug Administration and one, benralizumab, is in clinical development.
Varricchi G, et al. Curr Opin Allergy Clin Immunol (2016) 16:186–200

26. Phenotyping
The only significant exception is the broad division of patients based on the presence or absence of significant eosinophilia
The currently available novel/targeted therapies are essentially all directed at the eosinophilic phenotype

27. Mepolizumab (Nucala) Humanized monoclonal antibody against interleukin-5 (IL-5) Subcutaneous injection Every 4 week dosing 12 years and older Reduces • severe asthma attacks • hospitalization • prednisone usage
GSK May 2016

28. 135 adults with severe eosinophilic asthma on oral glucocorticoids
SIRIUS trial
135 adults with severe eosinophilic asthma on oral glucocorticoids
Compared to placebo:
Reduction in steroid dose (50%)
Reduced exacerbation rate (32%)
ACQ score improvement was statistically significant
 In the phase III MENSA trial in patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high-dose inhaled glucocorticoid therapy, mepolizumab significantly reduced the annualized exacerbation rate. In the phase III SIRIUS trial, mepolizumab had an oral glucocorticoid-sparing effect in patients with severe eosinophilic asthma requiring systemic glucocorticoid maintenance therapy.

29. Statistically significant:
MENSA trial
576 patients with history of frequent exacerbations randomized to mepolizumab or placebo
Statistically significant:
Reduction in significant exacerbations (ED/hospitalization)
Increase in FEV1 (~100mL), SGRQ and ACQ scores
 In the phase III MENSA trial in patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high-dose inhaled glucocorticoid therapy, mepolizumab significantly reduced the annualized exacerbation rate. In the phase III SIRIUS trial, mepolizumab had an oral glucocorticoid-sparing effect in patients with severe eosinophilic asthma requiring systemic glucocorticoid maintenance therapy.

30. Reslizumab (Cinqair) IV over 20-50 minutes every 4 weeks
18 years and older
Severe asthma w/ eosinophilic phenotype
Teva Pharmaceuticals / 2016 

32. interleukin-5 (iL-5) plays a fundamental role in the growth, maturation, and activation of human eosinophils. Group 2 innate lymphoid cell (ILC2), Th2 cells, mast cells, natural killer cells (NK T cells), and eosinophils themselves produce IL-5. This cytokine specifically binds to IL-5 receptor α (IL-5Rα) and recruits the βc subunit on the membrane of eosinophils. The βc subunit is the signal-transducing molecule shared with IL-3 and granulocyte-macrophage colony-stimulating (GM-CSF). This IL-5Rα/βc interaction leads to a series of biochemical events that control eosinophil differentiation and maturation in the bone marrow, cell migration to the site of allergic inflammation, the release of pro-inflammatory mediators, and inhibition of apoptosis. IL-3 and presumably GM-CSF, through binding to the βc of IL-5 receptor, can also function as eosinophil survival factors. Reslizumab binds with high affinity (Kd of approximately 50 pM) to amino acids 89–92 of human IL-5 that are critical for binding to IL-5Rα, resulting in inhibition of eosinophil maturation and activation.

33. Targeted therapy with reslizumab appears to be effective and safe in the treatment of adults with severe eosinophilic asthma and represents one step closer to precision medicine.

34. Reslizumab reduces exacerbation rates and improves lung function and patient-reported outcomes in
patients with eosinophilic asthma receiving therapy per Steps 4 and 5 of the GINA guidelines.

35. Other noteworthy mAb
Benralizumab (Benra/AstraZeneca)
It is a humanized, anti-eosinophilic
monoclonal antibody against IL-5 receptor alfa, which is
expressed on the surface of eosinophils and basophils
No FDA app.

36. Change from baseline in FEV1 for patients receiving benralizumab + high-dose ICS/LABA

37. N Engl J Med Jun 22;376(25):
Benralizumab showed significant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT )

38. Compared to mepolizumab and reslizumab,
the possible advantages of benralizumab are
• less frequent dosing and
• a potential to reduce exacerbations irrespective of the blood eosinophil count 

39. PLoS ONE 11(11): e0166833. doi:10.1371/journal. Nov 22, 2016
20 RCTs investigating the effect of anti-interleukin 5 monoclonal antibodies in
patients with asthma.
The results suggest that anti-interleukin 5 therapy was well tolerated and
could significantly improve AQLQ score, FEV1, FEV1% of predicted value, and decrease asthmatic exacerbation, blood and sputum eosinophil levels

40. For asthma, currently available anti-inflammatory agents (GCs and the biological therapeutics anti-IgE, IL-5 or IL-13) target pro-inflammatory mediator pathways
Common lung diseases such as asthma and COPD are characterized by unrestrained and chronic inflammation that fails to resolve.
Resolution is an active process with highly regulated cellular and biochemical events that terminates acute inflammation.
Levy BD, et al. Clin Chest Med September ; 33(3): 559–570

41. inhibition of neutrophil migration,
Specialised pro-resolving mediators (SPM) (such as lipoxins, protectins, resolvins and maresins) play main role in inflammation resolution including
inhibition of neutrophil migration,
enhancement of macrophage phagocytosis of apoptotic neutrophils,
suppression of pro-inflammatory cytokines and chemokines
The majority of individuals with asthma have chronic inflammation of the airways that does not resolve.
There is still limited understanding of why the asthmatic airway
inflammation fails to resolve.
The reduction in pro-resolving activity may be the cause.
Duvall MG, et al. Eur J Pharmacol August 15; 785: 144–155

42. currently under phase I/II study
Insights into these chemical mediators and their signaling pathways provide an opportunity to develop agonists of resolution as a potential novel class of therapeutics.
Thus, bioactive stable analog mimetics of these mediators may offer new therapeutic strategies for asthma and airway inflammation associated diseases.
currently under phase I/II study

43. Further trials are necessary
to determine the most effective asthma treatment drug
to distinguish which patients will respond to particular treatment
Further studies in the context of inflammation resolution is likely to inform potential new avenues for therapeutic intervention in asthma

44. THANK YOU

45. it has been suggested that “targeted anti-eosinophilic strategies may unmask or even accelerate progression” of certain tumors in few patients with hypereosinophilic syndrome (71). Therefore, future surveillance and “real-life” studies will be needed to further confirm the safety of reslizumab in long-term treatment of patients with severe eosinophilic asthma.