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Targeted treatment for severe eosinophilic asthma

Prof. Peter Howarth
University of Southampton
UK
08 Dec 2020
Elevated levels of blood eosinophils are strongly associated with and predictive of poor disease control and future risk in patients with severe asthma already on optimal therapy with inhaled and oral medications. At a recent webinar, Professor Peter Howarth of the University of Southampton, Southampton, UK, who is also the Global Clinical Scientific Lead (Biologics) at GSK, provided updates on the role of eosinophils in eosinophilic diseases, particularly severe asthma, and the efficacy of targeted therapy, such as the interleukin 5 (IL-5) inhibitor mepolizumab, in disease control.  

Role of eosinophils in heath and disease

“In healthy individuals, eosinophils are present in a number of sites, such as the throat, gastrointestinal [GI] tract, adipose tissue and the thymus glands,” said Howarth. (Figure 1) [Annu Rev Immunol 2006;24:147-174; Nat Rev Immunol 2017;17:746-760; Nature metabolism 2020;2:688-702; Eur Respir J 2020;55:1901874]

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“Eosinophils play a central pathophysiological role in many diseases, such as asthma, eosinophilic granulomatosis polyangiitis [EGPA] and chronic rhinosinusitis with nasal polyps [CRSwNP]. The presence of too many eosinophils is associated with increased tissue damage. On the other side of the coin, eosinophils are paradoxically important in maintaining the immune system and have other potential roles in health, in protecting the airway against infection, in mucosal barrier defense in the GI tract, and in improving survival rate of GI cancer patients,” he noted. [Mucosal Immunol 2015;8:464-475; J Asthma Allergy 2015;8:105-14; Allergol Int 2019;68:430-436; Biomed Res Int 2018, doi: 10.1155/2018/9095275; Rheum Dis Clin North Am 2010;36:527-543; Frontiers in Immunology 2018, doi: 10.3389/fimmu.2018.02763; Microbiol Spectr 2016, doi: 10.1128/microbiolspec.MCHD-0020-2015; Nat Rev Immunol 2017;17:746-760; Oncoimmunology 2017;7:e1393134]

“Eosinophils present in the GI tract may also be important in maintaining a healthy gut microbiome, which has been identified as a key modulator of human health, playing key roles in obesity, hypertension, cardiovascular disease, diabetes, cancer, inflammatory bowel disease, depression, and ageing,” he stated. [World J Gastroenterol 2019;25:3503-3526; Immunology 2019;158:194-205; Nature Reviews Genetics 2017; 18:690-699; J Food and Drug Analysis 2019;27:623-631]

“Therefore, anti-eosinophil therapies indicated for treatment of eosinophilic-related disorders should strike a balance between reducing eosinophils and maintaining their normal levels, which will allow their recruitment to tissue sites in times of need for maintaining health and fighting infection,” noted Howarth.

Anti-IL-5 therapies

IL-5 is chiefly involved in eosinophil development and activation, and is a key cytokine generated in type 2 inflammation, sending the signal to the bone marrow to generate more eosinophil progenitors and to increase the number of circulating eosinophils that can be recruited to sites of tissue inflammation. This makes IL-5 a key target in modifying eosinophil levels and eosinophilic inflammation,” said Howarth. [Mucosal Immunol 2015;8:464-475]  

Blood eosinophil count reduction

“Mepolizumab, an anti-IL-5 antibody, effectively reduces asthma exacerbations in patients with severe eosinophilic asthma [SEA] by reducing blood eosinophil count [BEC] to the normal range, while benralizumab, an IL-5α receptor-directed cytolytic antibody, depletes peripheral blood eosinophils by depleting bone marrow eosinophils,” noted Howarth. “The biological impact of mepolizumab appears to be the removal of abnormal inflammatory eosinophils while preserving the IL-5–independent ‘normal’ eosinophils.” (Figure 2) [J Allergy Clin Immunol 2019;143:1742-1751; Lancet Respir Med 2019;7:46-59; J Allergy Clin Immunol 2010;126:175-177]

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“On the other hand, complete depletion of eosinophils by benralizumab has not been shown to offer additional advantage over normalization of eosinophil count by mepolizumab,” said Howarth.

For example, a matching-adjusted indirect comparison (MAIC) of benralizumab vs mepolizumab, which took into account baseline characteristics of patients (given that higher baseline BECs have been associated with more beneficial responses) and treatment study methods across asthma trials among other factors to reduce bias in treatment comparisons, found comparable efficacy between benralizumab and mepolizumab in improving pre-bronchodilator forced expiratory volume in 1 second (FEV1) and in reducing the annual rate of clinically significant exacerbations and exacerbations leading to emergency department visits or hospitalization. (Figure 3) [Eur Respir J 2018;52:1801393]

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Another MAIC similarly found that mepolizumab and benralizumab treatments at their approved doses significantly reduced the rate of clinically significant exacerbations and improved asthma control vs placebo in patients with SEA, regardless of BEC. Mepolizumab, however, was associated with significantly greater improvements in clinically significant exacerbations compared with benralizumab in patients with similar BECs (rate ratio [RR] for BEC >400 cells/µL: 0.55; 95 percent confidence interval [CI], 0.35 to 0.87) (RR for BEC >300 cells/µL: 0.61; 95 percent CI, 0.37 to 0.99) (RR for BEC >150 cells/µL: 0.66; 95 percent CI, 0.49 to 0.89) (all p<0.05) as well as better asthma control (p<0.05 in all subgroups). (Figure 4) [J Allergy Clin Immunol 2019;143:190-200]

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OCS reduction

Patients with severe asthma requiring maintenance or intermittent treatments with oral corticosteroids (OCS) to manage exacerbations may be at increased risk of comorbidities such as diabetes, osteoporosis, and metabolic and GI complications due to long-term or cumulative exposure to systemic corticosteroids. [Clin Exp Allergy 202050:442-452] Reduction of OCS exposure is therefore an important treatment goal for patients with severe OCS-dependent asthma.

A recent MAIC found that mepolizumab and benralizumab have similar OCS-sparing potential. The mean difference between benralizumab and mepolizumab for OCS reduction was 6.08 percent (95 percent CI, 22.22 to 34.38; p=0.67) by week 24, and the odds ratio of OCS elimination was 2.32 (95 percent CI, 0.48 to 11.15; p=0.29). [Clin Exp Allergy 2020;50:442-452]

Potential indications for mepolizumab

“More data are emerging on the potential use of mepolizumab beyond SEA, in other eosinophilic conditions such as EGPA, CRSwNP and hypereosinophilic syndrome,” said Howarth.

“In patients with EGPA, a study found a significant 50 percent reduction in annualized relapse rate with mepolizumab vs placebo, as well as a significantly longer accrued time in remission [both p<0.001], while the SYNAPSE [Effect of Mepolizumab in Severe Bilateral Nasal Polyps] study found that adding mepolizumab [vs placebo] to standard of care significantly reduced nasal polyp size and obstruction in adults with CRSwNP,” he continued. [N Engl J Med 2017;376:1921-1932; Hopkins C, et al, ERS 2020, abstract 4616; J Allergy Clin Immunol 2020;146:1713-1715; J Allergy Clin Immunol 2020, doi: 10.1016/j.jaci.2020.08.037]

“Mepolizumab’s ability to reduce eosinophil levels to normal range allows maintenance of the right balance for health and defense against potential insults,” he concluded. 

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Most Read Articles
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