WO2020172380A1

WO2020172380A1 - Treatment of asthma patients having high baseline feno levels

Info

Publication number: WO2020172380A1
Application number: PCT/US2020/018997
Authority: WO
Inventors: Hector Ortega
Original assignee: Gb001, Inc.
Priority date: 2019-02-22
Filing date: 2020-02-20
Publication date: 2020-08-27

Abstract

Methods of treating asthma by administration of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid to patients exhibiting a high baseline fractional exhaled of nitric oxide (FeNO) are disclosed. In some embodiments, such patients have be pre-selected prior to administration based on exhibiting a high FeNO, such as having FeNO equal to or greater than 25 ppb or 35 ppb. In some embodiments, the patient has mild atopic asthma, and other embodiments moderate to severe asthma.

Description

TREATMENT OF ASTHMA PATIENTS

HAVING HIGH BASELINE FeNO LEVELS

Technical Field

[0001] The present invention relates to methods of treating asthma by administration of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2- ethylquinolin-5-yl)oxy)acetic acid to patients exhibiting high baseline fractional exhaled of nitric oxide (FeNO).

Summary

[0002] 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5- yl)oxy) acetic acid is an oral antagonist of the prostaglandin D2 receptor 2 (DP2). DP2 is expressed on a variety of cells including eosinophils, mast cells, and basophils. DP2 antagonists may inhibit recruitment and activation of airway eosinophils, with consequent reduction in airway inflammation including effects on FeNO. Clinical studies in patients with asthma were performed to evaluate efficacy, safety, PK and biomarkers.

Brief Description of the Drawings

[0003] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

FIG. 1 represents a graph of mean reduction in FeNO at Day 28 in the overall population and by baseline FeNO subgroups (low <35ppb, high >35ppb) for Clinical Study 1.

Detailed Description

[0004] Asthma is a heterogeneous condition characterized by different phenotypes/endotypes related to specific biomarkers that may predict therapeutic response in selected patient populations (Neelamegan et al., “Clinical utility of fractional exhaled nitric oxide (FeNO) as a biomarker to predict severity of disease and response to inhaled corticosteroid (ICS) in asthma patients,” J Clin Diagn Res 10: 1-6, 2016). Previous research suggests that FeNO measurement facilitates identification of patients exhibiting Type 2 mediated airway inflammation. FeNO has been investigated as a surrogate marker of airway inflammation which is closely associated with eosinophilic inflammation (Dweik et al., “An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FeNO) for clinical applications,” Am J Respir Crit Care Med.184:60-75, 2011 ). FeNO could serve as a prognostic marker of disease progression and severity, as well as a biomarker of treatment effect (Matsunaga et al.,“Persistently high exhaled nitric oxide and loss of lung function in controlled asthma,”. Allergology Inter 65: 266-271 , 2016; Castro et al.,“Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma,” N Engl J Med 378:2486-2496, 2018).

[0005] DP2 is a G-protein-coupled receptor selectively expressed by Type 2 T lymphocytes (Th2 and Tc2), eosinophils (Eos), basophils, and Type 2 innate lymphoid cells (ILC2s). DP2 signaling promotes the recruitment and activation of eosinophils and basophils and stimulates Th2 cells and ILC2 cells to release Type 2 cytokines including IL-4, IL-5, and IL- 13, leading to the development, amplification and persistence of Type 2 inflammation (Singh et al., “CRTFI2 antagonists in asthma: current perspectives,” Clin Pharmacol 9:165- 173.5, 2017).

[0006] Asthmatic patients with high FeNO (> 33 ppb) and high blood Eos (> 300/pL) have been reported to have increased PGD2 levels (Fajt et al., “Prostaglandin D2 pathway upregulation: Relation to asthma severity, control, and TFI2 inflammation,” J Allergy Clin Immunol, 131 :1504-1512.6. 2013). Asthmatic patients with both high FeNO levels and high blood Eos compared with those with low levels of both had significantly increased PGD2 and CRTFI2 mRNA levels. These results support the association of PGD2 pathway activation with Type 2 inflammatory markers, despite the use of corticosteroids. [0007] 2-((8-Chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5- yl)oxy)-acetic acid is a potent and highly selective oral DP2 antagonist being developed as a once daily oral add-on maintenance treatment for moderate to severe eosinophilic asthma. The synthesis of 2-((8-chloro-3-(4-chlorobenzyl)-4- (difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid is disclosed in Example 39 of U.S. Patent No. 7,858,640 (incorporated herein by reference in its entirety).

Clinical Study 1

[0008] FeNO was evaluated as a baseline marker and an outcome following administration of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2- ethylquinolin-5-yl)oxy)acetic acid or placebo over 28 days in patients with mild to moderate symptomatic, partially controlled atopic asthma.

[0009] 36 subjects with mild to moderate, partly controlled atopic asthma receiving a total daily dose of fluticasone propionate <500 meg or equivalent were randomized (2:1 ) to receive 2-((8-chloro-3-(4-chlorobenzyl)-4- (difluoromethoxy)-2-ethylquinolin-5-yl)oxy)-acetic acid (N=24) or placebo (N=12) once daily for 28 days. The mean (SD) age was 34.6 (8.9) years, 92% were male, and 92% were Caucasian. No safety signals were identified. There were no serious treatment-emergent adverse events (TEAEs), severe TEAEs, or TEAEs leading to study drug discontinuation.

[0010] Safety, PK/PD parameters and markers of asthma control, determined by lung function (FEV1 ) and Asthma Control Questionnaire (ACQ- 7), were assessed. FeNO was collected at baseline and Day 28, using an ozone/N02 chemiluminescence-based analyzer, in accordance with ATS/ERS recommendations (see Dweik et al. , Am J Respir Crit Care Med. 2011 , 184:60- 75), at a target constant flow rate of 0.05 Us. Subjects refrained from eating/drinking for 1 hour before measurement. Mean (SD) FeNO levels at baseline were: Placebo = 34.53 (16.93) ppb, and 2-((8-chloro-3-(4- chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid = 31.53 (22.13) ppb. At the end of the treatment period FeNO decreased in both treated and placebo groups. The mean (SD) decrease from baseline was: Placebo = 4.62 (8.55) ppb, and 2-((8-chloro-3-(4-chlorobenzyl)-4-

(difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid = 9.08 (13.83) ppb.

[0011] A greater proportion of treated subjects experienced a decrease from baseline in FeNO that was >10 ppb at Day 28 (or >20% decrease if baseline FeNO was >50 ppb) relative to placebo (10 [42%] versus 2 [18%]).

[0012] Outcomes for subgroups based on low and high baseline FeNO were analyzed. In one analysis, the cut-off for low/high baseline FeNO was <25 ppb (low) and >25 ppb (high). In a different analysis, the cut-off for low/high baseline FeNO was <35 ppb (low) and >35 ppb (high). Of note, previously published data used a cutoff of 35 ppb (see Dweik et at.,“Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma,” Am J Respir Crit Care Med 181 :1033-1041 , 2010).

Analyses Using baseline FeNO 35ppb Cut-off

[0013] Baseline characteristics were generally similar between the low and high baseline FeNO subgroups, with the exception of total IgE and blood eosinophils, which were greater in the high baseline FeNO subgroup (see Table 1). While lung function was normal in the majority of the subjects, FEVi was slightly lower in the high baseline FeNO subgroup.

Table 1

Baseline demographic and clinical characteristics for low (<35 ppb) and high (>35 ppb) baseline FeNO subgroups and overall study population

Low FeNO High FeNO Overall

Characteristics (<35 ppb) (>35 ppb) Population

(N=22) (N=14) (N=36)

Age (years) 33.5 (8.43) 36.4 (9.65) 34.6 (8.90)

Male 20 (91 ) 13 (93) 33 (92)

BMI (kg/m²) 28.02 (4.62) 26.42 (3.94) 27.40 (4.38)

Former Smoker 6 (27) 3 (21 ) 9 (25) ACQ-7 score 0.82 (0.51 ) 0.86 (0.41 ) 0.84 (0.46)

Blood eosinophils (cells/pL) 175 (84) 330 (276) 235 (196) FeNO (ppb)

54.44 (13.48)

Total IgE (klU/L) 355 (341 ) 772 (1 ,295) 517 (857)

FEVi % predicted 100 (19) 91 (18) 97 (19) FEVi (mL) 3,951 (943) 3,534 (852) 3,789 (920) BMI = body mass index; ACQ-7 = Asthma Control Questionnaire, 7-item; FEVi = forced expiratory volume in one second. Values are mean (SD) for continuous parameters and n (%) for categorical parameters. There were 6 placebo and 16 treated subjects (22 total) in the low baseline FeNO subgroup, and 6 placebo and 8 treated subjects (14 total) in the high baseline FeNO subgroup.

[0014] The difference (95% confidence interval (Cl)) in mean change (baseline to Day 28) for treated vs placebo in lung function and asthma control (FEVi and ACQ-7) for low and high baseline FeNO subgroups and the overall study population are presented in Table 2. Difference in mean change from baseline and 95% Cis were calculated using two-sample t-tests and assuming equal variances in both treatment groups.

Table 2

Low FeNO High FeNO Overall

Outcome (<35 ppb) (>35 ppb) Population

(N=22) (N=14) (N=36)

0.02 -0.13 -0.05

ACQ-7 score

(-0.42, 0.46) (-0.85. 0.59) (-0.40, 0.31 ) FEV₁ (ml_) 34 207 102

(-184, 253) (-283, 698) (-110, 314)

FEV₁ % predicted 0.8 6.5 3.0

(-4.8, 6.4) (-5.3, 18.2) (-2.2, 8.3)

[0015] Table 2 shows the treatment group demonstrated greater numeric improvements in lung function and asthma control (FEVi and ACQ-7) relative to placebo in the high baseline FeNO subgroup compared to the low baseline FeNO subgroup.

[0016] The difference (95% Cl) in mean change (baseline to Day 28) for treated vs placebo in FeNO (ppb) for low and high baseline FeNO subgroups and the overall study population are presented in Table 3. Values were calculated using two-sample t-tests and assuming equal variances in both treatment groups.

Table 3

Low FeNO High FeNO Overall

Outcome (<35 ppb) (>35 ppb) Population

(N=22) (N=14) (N=36) -1.26 -13.42 -4.47

FeNO (ppb)

(-9.08, 6.56) (-29.55, 2.72) (-13.70, 4.77)

[0017] Table 3 shows the treatment group demonstrated greater numeric reductions in FeNO relative to placebo in the high baseline FeNO subgroup compared to the low baseline FeNO subgroup. In the overall population, treated subjects demonstrated slightly greater mean reductions in FeNO at Day 28 relative to placebo (mean [SE]: 9.08 [2.82] vs 4.62 [2.58]). Treatment had minimal effect relative to placebo on FeNO reduction in the low baseline FeNO subgroup. FeNO reduction was greater in magnitude in the high versus low baseline FeNO subgroup (see Figure 1).

Analyses Using Baseline FeNO 25ppb Cutoff

[0018] The difference (95% Cl) in mean change (baseline to Day 28) for treated vs placebo in lung function and asthma control (FEVi and ACQ-7) for low and high baseline FeNO subgroups and the overall study population are presented in Table 4. Difference in mean change from baseline and 95% Cis were calculated using two-sample t-tests and assuming equal variances in both treatment groups.

Table 4

Low FeNO High FeNO Overall

Outcome (<25 ppb) (—25 ppb) Population

(N=18) (N=18) (N=36)

-0.06 0.00 -0.05

ACQ-7 score

(-0.68, 0.56) (-0.54, 0.54) (-0.40, 0.31 )

FEV₁ (mL) 31 194 102

(-0.284, 0.222) (-0.189, 0.576) (-0.110, 0.314)

FEV₁ % predicted -0.3 5.5 3.0

(-7.2, 6.7) (-3.6, 14.6) (-2.2, 8.3)

[0019] Table 4 shows the treatment group demonstrated greater numeric improvements in lung function (FEVi) relative to placebo in the high baseline FeNO subgroup compared to the low baseline FeNO subgroup. [0020] The difference (95% Cl) in mean change (baseline to Day 28) for treated vs placebo in FeNO (ppb) for low and high baseline FeNO subgroups and the overall study population are presented in Table 5. Differences in mean change from baseline and 95% Cis were calculated using two-sample t-tests and assuming equal variances in both treatment groups.

Table 5

Low FeNO High FeNO Overall

Outcome (<25 ppb) (>25 ppb) Population

_ (N=18) (N=18) _ (N=36)

n -0.13 -15.20 -4.47 e^NU (-9.22, 8.95) (-28.23, -2.16) (-13.70, 4.77)

[0021] Table 5 shows the treatment group demonstrated greater numeric reductions in FeNO relative to placebo in the high baseline FeNO subgroup compared to the low baseline FeNO subgroup.

[0022] There was a marked difference in both the treatment effect and the magnitude of FeNO reduction relative to placebo for subjects with high versus low baseline FeNO. These results demonstrate that administration of 2-((8- chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid reduces airway inflammation (FeNO) and that administration to asthma patients having high baseline FeNO provides a more beneficial clinical outcome.

Clinical Study 2

[0023] A Phase 2 randomized double-blind, placebo-controlled, parallel- group, explanatory study in adults patients with bronchial asthma was performed to evaluate the efficacy, as related to "uncontrolled asthma" or "asthma worsening" (including asthma exacerbations), and safety of once-daily oral administration of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2- ethylquinolin-5-yl)oxy)acetic acid.

[0024] Prior to the study, patients were using Long-Acting Beta Agonists (LABA) and/or medium-dose inhaled corticosteroids (ICS) to control their disease. Patients on LABA discontinued its use upon entry to the study, and all patients were brought to a standardized medium dose of ICS for a four-week lead-in period. Patients were then randomized (1 :1 :1 ) to one of two dose arms (5mg, 20mg) of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2- ethylquinolin-5-yl)oxy)acetic acid, or to placebo administered once daily, in combination with a low dose of ICS for four weeks. Following this period of combination with low-dose ICS, use of ICS was discontinued, and patients continued taking 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2- ethylquinolin-5-yl)oxy)acetic acid or placebo for 12 weeks.

[0025] Demographic and baseline characteristics are presented in Table 6, and were generally similar across the treatment groups.

Table 6

Placebo 5 mg 20 mg Total

Characteristics

(N = 53) (N = 52) (N = 53) (N = 158)

Age (years) 50.2 (12.2) 49.9 (12.4) 48.8 (13.3) 49.7 (12.6) Female 31 (59) 30 (58) 34 (64) 95 (60) BMI (kg/m²⁾ 23.17 (2.79) 23.37 (2.84) 23.14 (3.21 ) 23.22 (2.93)

ACQ5 score 0.562 (0.663) 0.486 (0.617) 0.528 (0.626) not available Blood eosinophils

349.8 (322.2) 265.6 (180.3) 341.0 (290.2) 319.0 (272.4) (cells/uL)

Non-specifc IgE

432.2 (467.5) 525.5 (916.1 ) 699.4 (2475.6) 552.5 (1545.1 ) (lll/mL)

FeNO (ppb) 30.57 (25.51 ) 26.48 (21.03) 27.71 (24.20) 28.28 (23.60)

FEV1 (L) 2.150 (0.606) 2.219 (0.616) 2.190 (0.486) 2.186 (0.568)

AM PEF (L/min) 346.3 (109.8) 343.1 (103.2) 344.4 (83.4) 344.6 (98.8)

BMI = body mass index; ACQ5 = Asthma Control Questionnaire (questions 1-5); AM PEF = morning peak expiratory flow; FeNO = fractional exhaled nitric oxide; FEVi = forced expiratory volume in 1 second; IgE = immunoglobulin E; Values are mean (SD) for continuous parameters and n (%) for categorical parameters.

[0026] 224 subjects who satisfied the inclusion criteria and did not infringe the exclusion criteria were provisionally enrolled and received medium-dose ICS and placebo of the study drug (in a single blind fashion) in Period I. In Period II, a total of 158 of those met enrollment criteria and were randomized to double-blind treatment (placebo n = 53, treated-5 mg n = 52, treated-20 mg n = 53). Study treatment was completed by 20 (37.7%) patients in the placebo group, 31 (59.6%) in the 5 mg group, and 40 (75.5%) in the 20 mg group.

[0027] Table 7 shows the proportion of subjects with asthma exacerbations by baseline FeNO levels (25 ppb and 35 ppb cut-offs).

Table 7

95% Cl based on Binomial (Clopper-Pearson) exact method.

[0028] A statistically significant difference was seen in the change in morning peak expiratory flow (AM PEF) at the last assessment between placebo and both arms of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2- ethylquinolin-5-yl)oxy)acetic acid (p = 0.015, 5mg; p = 0.027, 20mg). Treatment of patients with either dose resulted in significant reduction in worsening of morning peak expiratory flow versus placebo over the 16-week treatment period.

[0029] Withdrawal of ICS may result in elevated FeNO values. Flowever, FeNO values increased less in the treatment groups than the placebo group (66.2%, 75.0%, and 83.6% increases for 20 mg, 5 mg, and placebo, respectively).

[0030] In addition to being a marker of airway inflammation, FeNO may be a useful marker for treatment response to 2-((8-chloro-3-(4-chlorobenzyl)-4- (difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid.

[0031] Accordingly, in one embodiment, a method is provided for treatment of asthma by administering to a patient in need thereof an effective amount of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5- yl)oxy)acetic acid wherein the patient exhibits a high level of FeNO prior to administration

[0032] In other embodiments, a method is provided for treatment of asthma by administering to a patient in need thereof an effective amount of 2-((8- chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid as an add-on maintenance treatment in patients with moderate-to-severe asthma aged 12 years and older with elevated FeNO.

[0033] In other embodiments, a method is provided for treatment of asthma by administering to a patient in need thereof an effective amount of 2-((8- chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid as an add on maintenance treatment of patients with severe asthma aged 12 years and older, with elevated FeNO.

[0034] In other embodiments, a method is provided for treatment of asthma by administering to a patient in need thereof an effective amount of 2-((8- chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid for the maintenance treatment of asthma in patients 12 years of age and older with elevated FeNO whose asthma is not controlled with their current asthma medicines.

[0035] In other embodiments, 2-((8-chloro-3-(4-chlorobenzyl)-4- (difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid is indicated as an add-on maintenance treatment in patients with asthma, aged 12 years and older, with elevated FeNO. In some embodiments the patient is aged 18 and older. In some embodiments, the patient is an adult. In some embodiments, the asthma is moderate asthma. In some embodiments, the asthma is moderate-to-severe asthma. In some embodiments, the asthma is severe asthma. In some embodiments, the asthma is mild atopic asthma. In some embodiments, the asthma is mildly symptomatic asthma. In some embodiments, the asthma is partially controlled atopic asthma. In some embodiments, the maintenance treatment is an asthma controller medication. In some embodiments, the maintenance treatment is prednisolone, fluticasone, a long-Acting Beta Agonist (LABA), a corticosteroid, a glucocorticoid, or the like.

[0036] In other embodiments, 2-((8-chloro-3-(4-chlorobenzyl)-4- (difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid is indicated for the maintenance treatment of asthma in patients 12 years of age and older with elevated FeNO whose asthma is not controlled with their current asthma medicines. In some embodiments the patient is aged 18 and older. In some embodiments, the patient is an adult. In some embodiments, the asthma is moderate asthma. In some embodiments, the asthma is moderate-to-severe asthma. In some embodiments, the asthma is severe asthma. In some embodiments, the asthma is mild atopic asthma. In some embodiments, the asthma is mildly symptomatic asthma. In some embodiments, the asthma is partially controlled atopic asthma. In some embodiments, the maintenance treatment is an asthma controller medication. In some embodiments, the maintenance treatment is prednisolone, fluticasone, a long-Acting Beta Agonist (LABA), a corticosteroid, a glucocorticoid, or the like.

[0037] In other embodiments, 2-((8-chloro-3-(4-chlorobenzyl)-4- (difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid is indicated for add on maintenance of patients with asthma aged 12 years and older, and with elevated FeNO. In some embodiments the patient is aged 18 and older. In some embodiments, the patient is an adult. In some embodiments, the asthma is moderate asthma. In some embodiments, the asthma is moderate-to-severe asthma. In some embodiments, the asthma is severe asthma. In some embodiments, the asthma is mild atopic asthma. In some embodiments, the asthma is mildly symptomatic asthma. In some embodiments, the asthma is partially controlled atopic asthma. In some embodiments, the maintenance treatment is an asthma controller medication. In some embodiments, the maintenance treatment is prednisolone, fluticasone, a long-Acting Beta Agonist (LABA), a corticosteroid, a glucocorticoid, or the like.

[0038] In an alternative embodiment, a method is provided for treating asthma, comprising administering to a patient in need thereof an effective amount of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2-ethylquinolin-5- yl)oxy)acetic acid, wherein the patient has been pre-selected prior to administration based on exhibiting a high level of FeNO.

[0039] In one embodiment, a patient exhibiting a high level of FeNO (also referred to herein as elevated FeNO) prior to administration has a baseline FeNO equal to or greater than 25 ppb, 30 ppb, 35 ppb, 40 ppb, 45 ppb, or 50 ppb.

[0040] In one embodiment, a patient exhibiting an elevated or high level of FeNO prior to administration has a baseline FeNO of equal to or greater than 25 ppb.

[0041] In one embodiment, a patient exhibiting an elevated or high level of FeNO prior to administration has a baseline FeNO of equal to or greater than 35 ppb.

[0042] In one embodiment, the asthma patient has mild atopic asthma.

[0043] In one embodiment, the asthma patient has moderate to severe asthma.

[0044] All publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein.

[0045] This application claims the benefit of priority to U.S. Provisional Application No. 62/809,255, filed February 22, 2019, which application is hereby incorporated by reference in its entirety.

Claims

1. A method for treating asthma, comprising administering to a patient in need thereof an effective amount of 2-((8-chloro-3-(4-chlorobenzyl)- 4-(difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid, wherein the patient prior to treatment exhibits a high level of FeNO.

2. A method for treating asthma, comprising administering to a patient in need thereof an effective amount of 2-((8-chloro-3-(4-chlorobenzyl)- 4-(difluoromethoxy)-2-ethylquinolin-5-yl)oxy)acetic acid, wherein the patient has been pre-selected prior to administration based on exhibiting a high level of FeNO.

3. A method for treating asthma, comprising administering an effective amount of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2- ethylquinolin-5-yl)oxy)acetic acid to a patient having a high level of FeNO.

4. A method for treating asthma, comprising administering an effective amount of 2-((8-chloro-3-(4-chlorobenzyl)-4-(difluoromethoxy)-2- ethylquinolin-5-yl)oxy)acetic acid to a patient as an add-on maintenance treatment, wherein the patient has asthma with a high level of FeNO.

5. The method of any one of claim 1 -4 wherein the patient is 12 years and older.

6. The method of any one of claims 1-5, wherein the high level of FeNO is equal to or greater than 25 ppb.

7. The method of any one of claims 1 -5, wherein the high level of FeNO is equal to or greater than 30 ppb.

8. The method of any one of claims 1 -5, wherein the high level of FeNO is equal to or greater than 35 ppb.

9. The method of any one of claims 1 -8, wherein the asthma patient has mild atopic asthma.

10. The method of any one of claims 1 -8, wherein the asthma patient has moderate-to-severe asthma.

11. The method of any one of claims 1 -8, wherein the asthma patient has severe asthma.