Table 2.

Pharmacologic treatments for non-eosinophilic asthma under development

Name	Via	Mechanism of action	Asthma severity	Reference	Variables	Relevant findings
SCH527123	Oral	CXCR1/2 receptor antagonist	Asthma and COPD in animal models	85	Regulates pulmonary neutrophilia and mucus hypersecretion	Anti-inflammatory activity also via endothelial and epithelial cells
SCH527123	Oral	Selective CXCR2 receptor antagonist	Severe uncontrolled asthma	91	Safety and change in ACQ score, minor and major exacerbations, spirometry, and sputum neutrophil activation markers	Mean reduction of 36.3% in sputum neutrophil percentage
AZD5069	Oral	CXCR2 antagonist	Severe uncontrolled asthma	92	Number of severe asthma exacerbations in 6 months	No dose reduced the rate of severe exacerbations
Golimumab	SC	Human monoclonal antibody against TNF-α	Severe uncontrolled asthma	93	Change from baseline through week 24 in prebronchodilator predicted FEV1 Number of severe asthma exacerbations through week 24	No significant differences from placebo; 1 death and 8 malignancies
Anti-IL-6	No data	Inhibition of IL-6 pathway	Not available	95	Human and animal data. Mice exposed to HDM in the presence/absence of endogenous IL-6. Intensity and nature of lung inflammation, levels of progranulocytic cytokines and chemokines were analyzed	Elevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss of function of IL-6 signaling (knockout or antibody-mediated neutralization), abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice
Brodalumab (AMG827)	SC	IgG2 anti-IL-17RA Inhibits IL-17a, IL- 17F, IL-25	Moderate-to-severe asthma	98	Change in ACQ in week 12 FEV1, symptom scores, and symptom-free days	Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma
Anakinra	SC	IL-1 receptor antagonist	Healthy volunteers	99	One hour after the second treatment dose, subjects underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 4 hours after inhaled LPS. The effect of anakinra compared with placebo on airway neutrophil counts and airway proinflammatory cytokine levels after LPS challenge was compared by using a linear mixed-model approach	Anakinra pretreatment significantly diminished airway neutrophilia compared with placebo. LPS-induced IL-1β, IL-6, and IL-8 levels were significantly reduced during the anakinra treatment period compared with those seen after placebo
p38MAPK inhibitor		p38MAPK inhibitor	Severe asthma	102	Effects of a p38MAPK inhibitor in corticosteroid sensitivity in PBMCs from severe asthmatics and the profile of its responders	p38MAPKα/β is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPKα/β inhibitor in the future
Losmapimod	Oral	p38MAPK inhibitor	Severe asthma	103	Effect of losmapimod in reducing the rate of moderate/severe exacerbations in patient subgroups with ≤2% and>2% blood eosinophils at baseline. Lung function, fibrinogen, and hsCRP were also evaluated	Exposure-related reduction in the rate of moderate/severe exacerbations with losmapimod relative to placebo
PI3Kδ (PIK- 294) and JAK (tofacitinib) inhibitors	In vitro	Anti-inflammatory effects	Assessment of cytokines from bronchoalveolar lavage and PI3Kδ in bronchial biopsies (asthma)	104	Suppression of cytokine production from asthma and healthy BAL cells and reduction of T-cell activation	Suppression of TCR stimulated IFN-γ, IL-13, and IL-17 production. Tofacitinib + dexamethasone additive effect on the inhibition of IL-13 and IFN-γ production. PI3Kδ can enhance the effects of corticosteroids
Roflumilast	Oral	PDE4 inhibitor	COPD and asthma	105,106	Exacerbations rate, time to first and next severe exacerbation, change in postbronchodilator FEV1 and change in CAT score, adverse events. Extent of the late allergic response after an allergen challenge, change in sputum cell eosinophil counts or FeNO, FEV1, and exercise- induced bronchoconstriction. Early allergic response and measurements of TNF-α, sputum cells and inflammatory markers	No significant difference between roflumilast and placebo in time to a first severe exacerbation in patients not hospitalized for a COPD exacerbation in the previous year. Post-bronchodilator FEV1 increased significantly with roflumilast over the 52 weeks; no changes in total CAT score; no differences in adverse events. Attenuation of allergen-induced bronchoconstriction (FEV1) in patients with asthma. Significant reductions in allergen-induced airway inflammation, including a reduction in both eosinophil and neutrophil counts
Azithromycin	Oral	Antimicrobial antibiotic immunomodulation	Add-on therapy in patients with uncontrolled, persistent asthma on medium-to- high ICS plus LABA	108	Rate of total (severe and moderate) asthma exacerbations over 48 weeks and asthma quality of life. Data were analyzed on an intention-to- treat basis	The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 [61%] patients in the placebo group vs 94 [44%] patients in the azithromycin group, P<0.0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0.36 [95% CI 0.21–0.52]; P=0.001)
Azithromycin	Oral	Antimicrobial antibiotic immunomodulation	CF	109	Viral RNA, IFN, IFN-stimulated gene, and pattern recognition receptor expression were measured by real-time quantitative PCR	Azithromycin pre-treatment reduces rhinovirus replication in CF bronchial epithelial cells, possibly through the amplification of the antiviral response mediated by the IFN pathway
Statins	Oral	Potential regulation of Th17 response	Asthma	112	In vitro effects of the combination of simvastatin and FP on the numbers of Treg and Th17 cells in asthmatic patients after co-incubation with mDCs	Significantly increased Treg and concomitantly reduced Th17 cell numbers to a greater extent than FP or statin treatment alone. The enhancing effects of simvastatin on FP effects were mediated through the up-regulation of indoleamine 2, 3-dioxygenase and IL-10, together with down-regulation of IL-6 and IL-23 expression in mDCs

Abbreviations: SC, subcutaneously; TNF-α, tumor necrosis factor-α; IL, interleukin; JAK, Janus-activated kinases; LPS, lipopolysaccharide; PI3Kδ, phosphatidylinositol 3-kinase delta; PBMC, peripheral blood mononuclear cell; PDE4, phosphodiesterase 4; CAT, COPD assessment test; TNF-α, tumor necrosis factor α; ICS, inhaled corticosteroids; CF, cystic fibrosis; IFN, interferon; FP, fluticasone propionate; mDC, monocyte-derived DC; FeNO, fractional exhaled nitric oxide; ACQ, asthma control questionnaire; HDM, house dust mites; GR, glucocorticoid receptor; hsCRP, high sensitive C-reactive protein; LABA, long-acting beta-2 agonists; mDC, monocyte-derived dendritic cells; TCR, T-cell receptor.