Potential new treatments for asthma

Written by N Tangney 1, DM Murphy 1

1 The Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland

Asthma overview

Asthma is a heterogenous condition characterised by airway obstruction and hyper-responsiveness with chronic inflammation and subsequent bronchial remodelling. Genetic make-up may predispose people to developing asthma after exposure to certain triggers, e.g. viruses, allergens, aspirin.1

There are two typical phenotypes – Th2-high (‘type 2’) and Th2- low. This refers to whether or not the disease process is driven by T-helper type 2 cells (Th2). Th2 cells promote eosinophilic airway inflammation by the generation of interleukin (IL)-4, IL-5, and IL-13 which manifests as a high eosinophils, high fractional exhaled nitric oxide (FeNO), high immunoglobulin E (IgE), or allergic phenotype (Figure 1). These individuals make up approximately 50% of asthma patients.2 This is clinically relevant as certain therapeutics in severe asthma are aimed at theses targets in this group.

Current treatments

Asthma therapy has evolved over centuries.3 The Ebers Papyrus from 1550 BC mentions inhalations from heated henbane (Hyoscyamus niger, a plant from which hyoscine is extracted) used as treatment for a condition likely to be asthma. In China circa 1000 BC Ma Huang, a plant from which ephedrine was eventually extracted, was used. Moses Maimonides, a Spanish physician of the 12th century, advised dry air, an even temper, and chicken soup for asthma. Atropa belladonna (deadly nightshade) was used in 1869 by Henry Salter which eventually led to the isolation of ipratropium, an ingredient in some modern inhalers (Figure 2). Medicines such as cortisone and antihistamines are relatively recent products of the 20th century.

Modern asthma guidelines focus on a process of shared decision-making depending on the patient’s own views, goals, and capabilities. The Global Initiative for Asthma (GINA) guidelines involve a step-wise approach depending N Tangney on symptom frequency.4 Over the last number of years the importance of early introduction of inhaled corticosteroids (ICS) in the asthma treatment paradigm has been increasingly emphasised. Treatment with inhaled corticosteroids is now recommended at all stages of treatment on either a regular or as required basis. The treatment paradigm is based on achieving control with escalating levels of therapy to attempt to achieve this goal.

Severe asthma is defined as “uncontrolled despite adherence with maximal optimized high dose ICS-long-acting beta agonist treatment and management of contributory factors”. These individuals should be referred for specialist assessment where phenotype and appropriate treatment options are assessed. Patients with Th2-high phenotypes may be considered for targeted biologic therapy while advanced options for Th2-low asthmatics are limited, as fewer biological targets have been identified to date. Though only a minority of patients has severe asthma (5-10%), this group make up the majority of the associated healthcare costs and so there is a pressing need to improve therapeutics for this group, particularly for the Th2-low patients.

Alongside pharmacological methods, it is crucial to address other elements which may be corrected such as inhaler technique, adherence, triggers (beta-blockers, non-steroidal anti-inflammatories) and weight.5 One should always consider comorbidities and optimise these issues as they can often contribute to symptoms under the guise of asthma, e.g. rhinosinusitis, gastrooesophageal reflux, anxiety.

Smart inhalers

The prevalence of poor inhaler technique ranges from 14 – 90% depending on the device and context.6 Smart inhalers are a new technology capable of assessing inhaler technique and tracking compliance. These can be linked to phones and send reminders when medications are due. Some can detect high pollution or pollen in the area. Given compliance can be a major issue in asthma treatment, these may provide a solution for some users which could have a positive effect on overall symptom management.

Anti-IgE

Omalizumab (Xolair) is a monoclonal anti-IgE antibody which is currently indicated in severe allergic asthma as a 2 – 4 weekly subcutaneous injection. It is indicated in patients >6 years old with proven IgEmediated, severe asthma. Higher blood eosinophils and FeNO and childhood-onset asthma may predict a better response to treatment. It can also be considered for use in pregnancy thanks to its favourable safety profile. It has been shown to reduce severe exacerbations by 44% and significantly improve quality of life.7

Anti-IL5

Three anti-IL5 biologics are currently available for use in severe asthma – benralizumab (Fasenra), mepolizumab (Nucala), and reslizumab (Cinqaero). They are indicated in patients with high blood eosinophils and frequent exacerbations. Higher blood eosinophils, adult-onset asthma, and nasal polyposis may predict a better response. Benralizumab and mepolizumab are given as subcutaneous injections while reslizumab is administered as an intravenous infusion. Anti-IL5 use has been shown to significantly reduce both hospital and nonhospital exacerbations, GP visits, and oral corticosteroid (OCS) use.8 Switching to IL5 inhibitors in patients who are not fully controlled on omalizumab has been associated with a significant reduction in hospital and community exacerbation rates with a non-significant reduction in asthma control questionnaire (ACQ) score.9

Anti-IL4

Dupilumab (Dupixent), an anti-IL4 biologic, is another new addition to the 2022 GINA guidelines though for Th2-high asthmatics only. It is a two-weekly subcutaneous injection. Randomised control trials (RCT) have shown it reduces the rate of severe asthma exacerbations to a greater extent than those receiving placebo. In a study of 1,902 patients, the annual rate of severe exacerbations was 0.46 in the dupilumab group compared to 0.87 in the placebo group.10 There was a 0.32 L increase in forced expiratory volume (FEV1) compared to 0.14 L in the placebo group and ACQ-5 and asthma quality of life questionnaire (AQLQ) scores were lower in the treatment arm. A greater effect was seen with higher baseline eosinophils. A subsequent post hoc analysis showed similar outcomes in both allergic and non-allergic phenotypes (based on IgE).11 A study by Rabe et al showed that dupilumab had a significant reductive effect on OCS dose with 48% no longer requiring OCS vs 25% with placebo, regardless of eosinophil levels.12 Its use is further supported by a phase 2 trial which showed increased lung function and reduced severe exacerbation rate (53.7 – 70.5% depending on dose) in 611 patients treated with dupilumab irrespective of baseline eosinophil count.13

Anti-TSLP

Tezepulumab (Tezspire), a four-weekly subcutaneous injection, inhibits thymic stromal lymphopoeitin (TSLP) which acts further upstream in the inflammatory cascade than most biologics and as a result affects both Th2-low and Th2-high asthmatics. It is the first such biologic to be approved in the EU and is included in the 2022 GINA guidelines. Evidence is based largely on two RCTs – NAVIGATOR and SOURCE. The NAVIGATOR study consisted of 1,061 patients with severe, uncontrolled asthma (including those with low eosinophils).14 Compared to placebo, treatment with tezepulumab resulted in an overall rate ratio of 0.44 for asthma exacerbation rates and also had a greater improvement in prebronchodilation FEV1 and scores on ACQ-6, AQLQ, and asthma symptom diary (ASD). The SOURCE trial evaluated its OCS-sparing effect, however there was no significant reduction in OCS dose compared with placebo.15 WAYFINDER is an ongoing study which aims to build on these results16 and DESTINATION is an extension from NAVIGATOR and SOURCE examining long term safety and asthma exacerbations.17 PASSAGE is a phase 4 trial underway that will examine tezepulumab’s effectiveness in a real world population.18

OTHER TARGETS:

GATA-3 inhibitor

GATA3 is a transcription factor that controls the production of certain Th2 cytokines such as IL-4, 5 and 13 whose overexpression has been observed in severe asthma. A GATA3-specifc DNA enzyme, SB010, has been developed as an oral inhaler that cleaves GATA3 mRNA thus reducing cytokine production.19 A phase 2 RCT investigating the efficacy of SB010 in patients with mild, allergic type asthma (as per GINA guidelines) showed clinical potential and the GIANT-1 (GATA3 Inhibition in Asthmatics Not controlled on standard medication with Type-2) trial is a follow on study for patients with moderate to severe type-2 asthma that is currently underway.

Tyrosine kinase inhibitors

Mast cells are activated by stem cell factor (SCF) binding to the c-kit receptor (a tyrosine kinase receptor (TKR)). It has been shown that inhibition of the SCF/c-kit pathway leads to a reduction in histamine and mast cells, as well as eosinophil infiltration, IL-4 and airway hyper-responsiveness in vivo20, revealing a potential therapeutic pathway. Another TKR which may be of value is that of platelet-derived growth factor (PDGF) receptor which has been shown to play a role in chronic tissue remodelling in asthma. Oral masitinib has demonstrated clinical efficacy in early studies with a phase 3 trial underway for masitinib treatment in patients with severe uncontrolled, eosinophilic asthma which will hopefully yield positive results.21, 22 Imatinib illustrated some potential benefit in patients with severe, refractory asthma but these early results have yet to be replicated in large clinical trials.23

Anti-IL13/Anti-IL33

There have been numerous trials investigating therapies targeting IL-13 and IL-33. These are two cytokines thought to play a complex role in signalling cascades in asthma, particularly type 2 inflammation. Unfortunately, to date, there have not been any significantly positive results from trials of anti-IL13 or anti-IL33 therapies.24, 25, 26, 27

Th2-low options

There is a paucity of treatment options available in severe, Th2-low asthma as fewer feasible therapeutic targets have been identified to date. One option to consider in this group is the addition of maintenance azithromycin, a macrolide antibiotic that can also act as an immunomodulator in respiratory conditions such as asthma, bronchiectasis, or COPD. This is given either three times per week or once daily and should be trialled for at least six months. The AMAZES trial has shown a significant reduction in exacerbations from 64% to 49% along with a significant improvement in quality of life with the addition of azithromycin.28 Another possible option for the refractory Th2-low group is bronchial thermoplasty. This is a bronchoscopic technique which uses heat to reduce smooth muscle in the airway in order to decrease its bronchoconstrictive capabilities. In patients with severe asthma this procedure has been shown to improve AQLQ score and reduce severe exacerbations in the following year29 while also maintaining efficacy at 10 years post-procedure.30

Conclusion

Treatment advances in asthma have come a long way since the days of henbane inhalation. The illness still however places a major burden on healthcare systems and treatment in particular groups, such as the Th2-low asthmatics, has not kept pace. With the introduction of targeted monoclonal therapies, treatment for eligible patients has been revolutionised. The optimal therapies and switches between these agents are still being elucidated. Thankfully, continued research across the globe resulting in new treatment avenues casts a promising light for asthma therapy in the future.

References available on request

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