Recent Advances in the Management of Asthma

  • Asthma is a chronic lung disease characterized by inflammation and narrowing of the airways causing recurring periods of wheezing, chest tightness, shortness of breath, and coughing.
  • Worldwide, the economic costs associated with asthma are estimated to exceed those of TB and HIV/AIDS combined
  • India accounts for 10% of the asthma cases

Need for newer drugs

  • Concern about the long-term safety of ICS and that they must be taken by inhalational route
  • Poor adherence with ICS
  • Concern about the long-term safety of LABAs, although when administered in combination with ICSs there does not seem to be a problem
  • Approximately 5 to 10% of patients are not controlled despite taking effective inhaled therapy
  • Different phenotypes or endotypes of asthma
  • The types of new drugs needed for asthma include new classes of drug that are –
  • Effective in severe, poorly controlled asthma;
  • An oral treatment that is as effective as ICSs but without any side effects;
  • Drugs that modify the course or even cure the disease.+
  • There are at least 2 major types of asthma—Th2-high and Th2-low—dependent on the presence of selected Th2 molecular signatures
  • periostin and high levels of sputum and blood eosinophils in response to Th2 cytokines such as IL-4, IL-5, and IL-13.
  • Asthmatic patients with the uncontrolled severe disease despite high doses of ICSs and having high eosinophils à respond to anti–IL-5 and anti–IL-13 therapy.
  • There is a negligible clinical response to anti–IL-1, anti–IL-4, anti–IL-17, or TNF-α treatment.
  • Non-Th2 patients à more mixed lymphocyte profile involving Th1 and Th2 cells.
  • respond to anti-CXCR2 antagonists but not to anti–IL-1, anti–IL-8, or TNF-α treatment. Studies using anti–IL-17 or other antineutrophil approaches are yet to be completed.

Th 2 Mediated Asthma

Anti IL-5 Ab

  • Interleukin (IL)-5 is specifically focused on the development, differentiation, recruitment, activation, and survival of eosinophils
  • Approximately 50% of severe asthma exacerbations are eosinophilic in nature

Mepolizumab (2015) and Reslizumab (2016)

  • Reduce exacerbation rates and eosinophil counts in both blood and sputum             
  • Mepolizumab reduces oral steroid requirement by 50%, exacerbations by 50 %, given once a month

Benralizumab (Nov 2017)

  • Add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype
  • FDA approval based on the Phase III program demonstrating up to 51% reduction in asthma exacerbations, significant improvement in lung function and a 75% reduction in daily oral steroid use.

Anti IL-13 Ab

  • IL-13 à mediate airway hyperresponsiveness, inflammation, mucus hypersecretion, and subepithelial fibrosis.
  • Interleukin-13 à induces bronchial epithelial cells to secrete Periostin à Can be used as a biomarker for eosinophilia
  • Tralokinumab failed its two Phase III trials in severe, uncontrolled asthma.
  • Lebrikizumab failed to show efficacy in two Phase III studies.
  • May not be sufficient to provide clinically meaningful improvements in reducing asthma exacerbations.

IL-4 Targeted Pathway

Pitrakinra

  • A soluble IL-4 receptor (sIL-4R) that acts as an IL-4R antagonist is in Phase II

Dupilumab

  • Fully humanized anti–IL-4Ra Mab
  • Reduced asthma exacerbations in moderate-to-severe asthma, and who had a blood eosinophil count >300 cells/mL or a sputum eosinophil level >3%.
  • Improved lung function and reduced levels of Th2-associated inflammatory markers. (Liberty Asthma Quest Trial)

Prostaglandin D2 receptor antagonist

  • Chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTh2), is a high-affinity prostaglandin D2 receptor that is expressed on major human cell types that mediate asthma pathogenesis.
  • Fevipiprant à Phase II completed
  • Reduced eosinophilic airway inflammation and was well tolerated in patients with persistent moderate-to-severe asthma and raised sputum eosinophil counts despite inhaled corticosteroid treatment.

Anti – IgE antibody

Ligelizumab

  • binds IgE with higher affinity than omalizumab
  • Head to head comparisons suggests it may be more efficacious than omalizumab with respect to both inhaled and skin allergen responses in patients with mild allergic asthma.
  • Completed phase II

Omalizumab for allergic asthma in children 6 to 11years of age (July 2016)

  • Indication
  • patients with moderate to severe persistent asthma and sensitization to perennial aeroallergens who are inadequately controlled on inhaled glucocorticoids
  • US-FDA has now lowered the approved age range from 12 to 6 years of age.
  • Black Boxed warning related to anaphylaxis has been added
  • Patients should be observed for 2 hrs after the first three injections & for 30 mins after each subsequent dose because 75% of anaphylaxis cases occurred within those periods

Th 17 Mediated Asthma

  • A subset of patients with severe disease that do not respond well to ICS.
  • These patients may have a Th-17 predominate disease with high levels of IL-17
  • Leading to more neutrophil predominance and inflammation, less reversible airflow obstruction, and less bronchial hyper-responsiveness with methacholine challenge testing.

IL- 17 Antagonists

Brodalumab,

  • an anti–IL-17Rα Mab
  • Despite good results in preclinical studies, had no effect on asthma control questionnaire score, FEV1, symptom scores, or a number of symptom-free days in 302 subjects with inadequately controlled moderate-severe asthma taking regular ICSs.
  • Secukinumab – Phase 2 terminated

Thromboxane A2 receptor antagonist

  • Thromboxane A2 (TXA2) is a bronchoconstrictor prostanoid
  • Involved in the pathogenesis of acute and chronic inflammatory processes of asthma

Seratrodast

  • thromboxane A2 (TXA2) receptor antagonist
  • Has shown to exhibit better control on asthma than that of cysteinyl leukotriene receptor antagonists
  • Global Initiative for Asthma (GINA) guidelines has recommended seratrodast as a controller of asthma in step 1 for long term management.

PDE-4 Inhibitor – Roflumilast

  • Clinical trials were being conducted with Roflumilast for Asthma and COPD.
  • Anti-inflammatory effects of roflumilast observed in COPD are also seen in asthma.
  • Roflumilast attenuated allergen-induced bronchoconstriction (FEV1) in patients with asthma. Significant reductions in allergen-induced airway inflammation, including a reduction in both eosinophil and neutrophil counts, were also observed and physiologic responses to the allergen-induced challenge were confirmed by a significant reduction in TNFα. Side effects were similar to COPD but did not include weight loss.
  • However, it received FDA approval only for COPD in 2011.

Bronchial thermoplasty

  • Controlled radiofrequency energy is delivered to the intra-parenchymal airways during a series of bronchoscopies
  • Resulting in a prolonged reduction of airway smooth muscle mass.
  • Approved by FDA in 2010
  • Included in step 5 of GINA guidelines
  • First BT performed in India in June 2017

New strategies:

  • SMART (Single inhaler maintenance and reliever therapy).
  • Budesonide/formoterol is better than CS/short-acting b2 agonist.
  • Rationale: ICS used as rescue therapy prevents the buildup of inflammation that precedes an acute exacerbation. Since formoterol is long-acting, even if the patient forgets a few of his maintenance dose, no harm is done. This addresses the problem of poor compliance.

New corticosteroids. (Mapracorat)

•            To decrease systemic side effects

•            Steroids rapidly metabolized when it enters the systemic circulation

Steroids metabolized after its action (soft steroid S/E are due to binding of steroid to DNA receptors, while anti-inflammatory effects are d/t transrepression through non-genomic effects.

•            Hence dissociated steroids are being developed. (SEGRAs) Selective Glucocorticoid receptor agonist

•            Limitation: Some anti-inflammatory activity might be d/t transactivation of anti-inflammatory genes.

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