Among the estimated 235 million people worldwide who have asthma,1 a sizable portion are unable to achieve adequate disease control without high doses of inhaled corticosteroids (ICS) and/or oral corticosteroids, or are generally unresponsive to these therapies. These individuals, comprising approximately 5% to 10% of the total asthma population,2 are considered to have severe asthma.
The clinical severe asthma phenotypes described by the National Heart, Lung and Blood Institute’s Severe Asthma Research Program (SARP) “provide a good ‘starting point’ for addressing disease heterogeneity in severe asthma in everyday practice. However, more efforts are needed to understand how these phenotypes relate to underlying disease treatment responses and underlying disease mechanisms,” wrote the authors of a 2017 review.3
Elucidating these factors will be necessary for the realization of precision medicine for the treatment of severe asthma. “The identification of inflammatory subsets and asthma endotypes holds promise to improve asthma management and guidance [with]… the most adequate targeted treatment for each individual patient,” as stated in a 2019 position paper from the European Academy of Allergy & Clinical Immunology (EAACI) Task Force on Biomarkers in Asthma.2
The recent and ongoing development of novel therapies – most of which target T2 inflammation – for patients with severe uncontrolled asthma further underscores the need for clinically applicable biomarkers to inform treatment selection and predict and monitor treatment response. In one part of the EAACI paper, the authors explored these various therapies together with biomarkers that could help to guide treatment for this patient group. Selected relevant findings are highlighted below.
IgE-targeted therapies. In a 2013 retrospective analysis of data from the EXTRA study of patients with uncontrolled severe allergic asthma (n=850), the authors reported that blood eosinophils, exhaled nitric oxide (FeNO), and serum periostin may predict response to treatment with omalizumab.4 The authors divided participants into 2 groups based on median baseline biomarker values (low or high) and found greater reduction in exacerbations in the groups with high vs low biomarker values as follows:
53% in the FeNO-high group (≥19.5 ppb) vs 16% in the FeNO-low group (<19.5 ppb)
32% in the group with high eosinophils (≥260 cells/μL) vs 9% in the group with low eosinophils (<260 cells/μL)
30% in the periostin-high group (≥50ng/ml) vs 3% in the periostin-low group (<50ng/mL)
IL-5-targeted therapies. In a 2017 systematic review (N=6000), treatment with anti-IL-5 led to an approximately 50% reduction in exacerbations in patients with uncontrolled eosinophilic asthma.5 Various study findings indicate that patients with >3% of eosinophils in sputum or ≥500 cells/μL blood eosinophils are more likely to show a response to anti-IL5 treatment.2
IL-4/IL-13-targeted therapies (dual blockade). In a phase 2 study of dupilumab, patients with moderate to severe asthma with ≥3% of eosinophils in sputum or blood eosinophils ≥300 cells/µL demonstrated significant reductions in exacerbations with dupilumab vs placebo (6% vs 44%), as well as improved forced expiratory volume in 1 second (FEV1) and improved scores on the Asthma Control Questionnaire following withdrawal from long-acting β-agonist treatment and ICS dose tapering and discontinuation.6 Another phase 2 study of dupilumab found improvements in FEV1 in patients with blood eosinophils ≥300 cells/µL; however, exacerbations decreased with nearly all dose regimens, regardless of eosinophil levels. This finding calls into question the utility of blood eosinophil count as a biomarker for treatment response.7
IL-13-targeted therapies. Phase 2 studies showed improvements in FEV1 and exacerbations among periostin-high patients with uncontrolled asthma, although this result was not observed in subsequent phase 3 trials.2
CRTH2 antagonists. Recent research has demonstrated improvements in multiple clinical outcomes in patients with allergic and/or refractory eosinophilic asthma.2 Results of a post hoc analysis of a study of patients with moderate asthma suggest that the CRTH2 antagonist OC000459 (timapiprant) is most effective in patients with uncontrolled atopic asthma who are aged ≤40 years and have blood eosinophilia (≥250 cells/μL).8 “Currently, several CRTH2 antagonists are moving into phase 3 studies which should help to consolidate phenotypes and adequate biomarkers responding to these targeted drugs,” the EAACI task force wrote.2
Although initial progress on the path to precision medicine for severe asthma seems promising, there are still many remaining research needs before such an approach can be fully utilized in clinical practice. In “order for molecular phenotypes to become endotypes, the associated pathways defined in the phenotype need to be proven to be the driving mechanism underlying the pathophysiological features of severe asthma,” according to a 2019 review published in Allergy.9 “The description of a range of severe asthma endotypes with distinct treatable driving mechanism(s) should become the future goal of asthma care.”
For additional perspectives about precision medicine for severe asthma, Pulmonology Advisor interviewed Fan Chung, MD, DSc, FRCP, professor of respiratory medicine, head of experimental studies at the National Heart & Lung Institute at Imperial College London, and one of the authors of the Allergy review; and Tara F. Carr, MD, FAAAAI, associate professor of medicine and otolaryngology, director of the adult allergy program, and scientist at the Asthma and Airway Disease Research Center at the University of Arizona College of Medicine. Dr Carr co-wrote a paper on the topic that was published in 2018 in the Annals of Allergy, Asthma & Immunology.10
Pulmonology Advisor: What are some of the most common challenges in treating severe asthma?
Dr Chung: Common challenges in severe asthma include reaching the diagnosis and providing proper management, diagnosis and treatment of comorbidities, determining whether patients will be suitable for available biologics, and monitoring their response to biologics.
Dr Carr: First, physicians need to differentiate between difficult-to-treat asthma and severe asthma. Difficult-to-treat asthma requires higher doses of inhaled steroids and other medications to gain control, but often there are contributing factors that, when properly addressed, can help to control asthma. These factors include medication nonadherence, poor inhaler technique, and comorbidities such as allergen exposures, cigarette smoking, obesity, reflux, vocal cord dysfunction, and sinusitis. When the asthma still requires high doses of controller therapy to maintain control despite addressing these factors, or is uncontrolled despite high-dose therapies, this is considered to be severe asthma.
With the various biologics now available to treat asthma, we have multiple treatment options for our patients who have characteristics of type 2 inflammation, which represents half or more of severe asthma patients. However, some patients do not qualify for these medications due to lack of T2 inflammation or they fail to improve significantly despite these therapies. Therefore, the alternative therapies in development are still relevant and important.
Pulmonology Advisor: What does the evidence suggest thus far about the potential role of precision medicine in the management of severe asthma?
Dr Chung: Precision medicine has yet to reach the practice of severe asthma; we are using a blood eosinophil count and FeNO to guide phenotyping patients who will respond to the currently available biologics. The potential role of precision medicine is great, and evidence would suggest that it is likely to provide better biomarkers than the ones we are using now.
Dr Carr: The dramatic fast and sustained improvement in clinical outcomes – including lung function, symptoms, and inflammatory markers – upon initiating a biologic therapy speaks directly to the importance of these pathways and chemical/cellular targets in the pathobiology of asthma. However, since there is variability in response – for example, not all patients with 300 blood eosinophils derive benefit from the anti-IL-5 therapies – we also must recognize that precision therapies require tools for precision application.
Pulmonology Advisor: What are remaining needs in this area in terms of research or otherwise?
Dr Chung: There is a need to conduct proof-of-concept studies regarding the value of applying currently well-defined molecular phenotypes in the management of severe asthma, and to define those targets that will be valuable for patients who cannot receive the eosinophilic-targeted or allergy-targeted biologics available currently.
Dr Carr: While the label indication for each available T2 biologic is slightly different, some patients technically qualify for more than one treatment. Therefore, we need improved markers indicating likely response to therapy – those precision tools to select precision therapies. Also not yet known is the potential benefit for combining biologics. Finally, non-T2 inflammation-targeted therapies are in development, and the benefit of these drugs for non-T2 asthma patients is yet to be fully understood.
Pulmonology Advisor: Are there additional clinical takeaways or any other points you would like to note about the topic?
Dr Chung: There have been significant advances in the management of severe asthma of late, with the introduction of biologic therapies for a subgroup of these patients. Therefore, for the clinician, it is important that this condition be appropriately diagnosed and managed. If necessary, patients could be referred to specialized centers for severe asthma.
Dr Carr: Severe asthma is a disease that causes significant morbidity for our patients. The challenges related to starting advanced therapies, including the biologics – such as cost and paperwork – are far outweighed by the potential benefits.
References
1. World Health Organization. Chronic respiratory diseases – asthma. https://www.who.int/respiratory/asthma/en/ Accessed June 5, 2019.
2. Diamant Z, Vijverberg S, Alving K, et al. Towards clinically applicable biomarkers for asthma – An EAACI position paper [published online April 6, 2019]. Allergy. doi:10.1111/all.13806
3. Fitzpatrick AM, Moore WC. Severe asthma phenotypes — how should they guide evaluation and treatment? J Allergy Clin Immunol Pract. 2017;5(4):901-908.
4. Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187(8):804-811.
5. Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017;9(9):CD010834.
6. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-2466.
7. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44.
8. Pettipher R, Hunter MG, Perkins CM, et al. Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459. Allergy. 2014;69(9):1223-1232.
9. Chung KF, Adcock IM. Precision medicine for the discovery of treatable mechanisms in severe asthma [published online March 13, 2019].Allergy. doi:10.1111/all.13771
10. Carr TF, Kraft M. Use of biomarkers to identify phenotypes and endotypes of severe asthma. Ann Allergy Asthma Immunol. 2018;121(4):414-420.