Predictors of response to mepolizumab for severe asthma: a REDES study post hoc analysis

Abstract

Objective

To identify predictors of treatment response to help target mepolizumab to patients with severe asthma with type 2 inflammation (SA-T2) who are most likely to respond to therapy.

Design and setting

The REal-worlD Effectiveness and Safety of mepolizumab (REDES), a multicentre, observational cohort study, investigated the effectiveness and safety of mepolizumab in Spanish patients with SA-T2.

Participants

We conducted a post hoc analysis of data from REDES to examine relationships between patient characteristics and response to mepolizumab to identify predictive markers of response. Outcomes included annualised clinically significant exacerbations (primary), lung function (forced expiratory volume in 1 s), maintenance oral corticosteroid (OCS) dose and Asthma Control Test (ACT) score. Outcomes after 12 months’ treatment with mepolizumab were assessed and stratified by demographic and clinical characteristics. Analyses were descriptive; changes from baseline were summarised as mean (SD) and prespecified two-tailed unpaired t-tests were applied for comparisons (p<0.05).

Primary and secondary outcome measures

These were stratified by various demographic and clinical characteristics collected during the study.

Results

In total, 318 patients with SA-T2 were included in the analysis. Mepolizumab was effective in patients with a diverse range of demographic and clinical characteristics. Baseline blood eosinophil count ≥150 or ≥300 cells/µL or fraction of exhaled nitric oxide (FeNO) ≥25 or ≥50 ppb resulted in a 77%–88% reduction in exacerbations compared with 51%–55% in patients with lower baseline levels of these biomarkers (descriptive). Baseline factors of sex, body mass index, smoking status, atopic sensitisation and forced expiratory volume in 1 s had no appreciable effects on exacerbations, maintenance OCS use, lung function or asthma symptoms.

Conclusions

This post hoc analysis indicates mepolizumab is likely to provide clinical benefit in patients with SA-T2 across a broad range of patient characteristics. Patients with baseline blood eosinophils of ≥150 cells/µL and/or FeNO ≥25 ppb are likely to derive more benefit.

Trial registration number

213172.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• A key strength of this study is that patients with eosinophilic asthma who have a diverse range of demographic and clinical characteristics can be treated effectively with mepolizumab, particularly those with baseline blood eosinophils of ≥150 cells/µL and/or fraction of exhaled nitric oxide (FeNO) ≥25 ppb.

• Limitations of the current analysis include its post hoc nature and reliance on retrospectively collected real-world data from REal-worlD Effectiveness and Safety, as well as the very small numbers of patients in certain subgroups.

• The study is further limited by its observational nature and univariable comparisons, as well as the lack of CIs or p values, which may complicate interpretation of the results.

• Because certain baseline values were selected, regression to the mean is an additional source of bias, and since this analysis was performed retrospectively, we could not determine the impact of changes in treatments or whether treatment adherence was encouraged and potential treatable traits were addressed.

• In our analysis, 12-month changes in FeNO of ≥20 ppb were considered more conservative than recommendations from the American Thoracic Society³⁹ and blood eosinophil levels of <50 cells/µL were considered comparable to eosinophil depletion by the authors, as opposed to levels remaining between 50 and 100 cells/µL.

Introduction

Severe asthma with type 2 inflammation (SA-T2) is characterised by persistent airway inflammation and recurrent exacerbations, despite treatment with high-dose inhaled corticosteroids combined with other controllers and/or treatment with oral corticosteroids (OCS).¹ Escalation to a biologic agent is often required to prevent exacerbations and/or the chronic use of OCS.² Six biologics are currently available for the treatment of severe asthma.³ Besides other functions, IL-5 is a key factor in the growth, differentiation, recruitment, activation and survival of eosinophils.^4–8

Mepolizumab was the first approved anti–IL-5 monoclonal antibody for the treatment of SA-T2.⁹ During its phase 3 clinical development programme, mepolizumab was shown to reduce asthma exacerbations and maintenance OCS requirements, and improve lung function and quality of life, in a broad range of patients with SA-T2.^10–13 Real-world data also show that mepolizumab treatment is associated with improvements in clinically important outcomes in routine clinical practice, thereby complementing clinical trial data.^14–19 On-treatment remission (ie, sustained absence of asthma symptoms and attacks, reduction in exacerbations, optimisation and stabilisation of lung function and no use of OCS) may represent an achievable therapeutic goal for some patients,^{20 21} with 30% of patients achieving this with mepolizumab in a real-world study.²²

To help clinicians decide whether to instigate therapy with mepolizumab or another biologic agent, it is important to identify characteristics that help predict which patients will have the best response to treatment.^{21 23 24} Baseline blood eosinophil count (≥150 cells/µL) at screening is a proven biomarker for the selection of patients likely to benefit from mepolizumab.^{25 26} Also, there is evidence that patients with comorbid nasal polyposis may respond particularly well to mepolizumab.^{27 28} However, additional predictors of treatment response are required to help target mepolizumab therapy in routine clinical practice.^{26 29}

The REal-worlD Effectiveness and Safety of mepolizumab (REDES) study was an observational study that assessed the effectiveness and safety of mepolizumab in patients with severe eosinophilic asthma/SA-T2.¹⁵ Here, we conducted a post hoc analysis of REDES study data in order to evaluate the effect of various patient characteristics on response to mepolizumab.

Methods

Study design and patients

REDES was a retrospective, multicentre, observational cohort study in adults with SA-T2 treated with mepolizumab at 24 asthma units in Spain between December 2019 and July 2020 (full details of study design and methodology have been published previously).¹⁵

This post hoc analysis of data from REDES examined relationships between patient characteristics and response to mepolizumab, to identify biomarkers predictive of response. Informed consent was obtained from all individual participants included in the study.

Patient and public involvement

Patients and/or the public were not involved in the design, conduct, reporting or dissemination of this study.

Analysis

Outcomes

The primary outcome of REDES was the annual rate of clinically significant asthma exacerbations in the 12 months after mepolizumab initiation, as compared with the 12 months before receiving mepolizumab.¹⁵ Clinically significant asthma exacerbations were defined as those requiring either OCS for ≥3 days, doubling of OCS maintenance dose, a visit to the emergency department or hospitalisation due to asthma. Secondary outcomes relevant to the present analysis included prebronchodilator and postbronchodilator forced expiratory volume in 1 s (FEV₁), average OCS daily maintenance dose and symptom control based on Asthma Control Test (ACT) scores^{30 31} at baseline and 12 months after mepolizumab initiation.

In the current post hoc analysis, primary and secondary outcomes were assessed in patients stratified by various demographic and clinical characteristics collected during the study. Demographic characteristics included patient sex, body mass index (BMI; <18.5 (underweight), 18.5–25 (normal weight), >25–30 (overweight), >30–35 (obese), >35 kg/m² (severely obese)) and age (≥65 vs <65 years). Clinical characteristics included baseline fraction of exhaled nitric oxide (FeNO; <25, 25–50, ≥50 ppb), comparisons of baseline FeNO (<25 vs ≥25 ppb; <50 vs ≥50 ppb) and baseline blood eosinophil count (<150 vs ≥150 eosinophils/μL; <300 vs ≥300 eosinophils/µL). Outcomes were also stratified by change in FeNO from baseline at 12 months (decrease of ≥20 ppb, no change (±<20 ppb), increase of ≥20 ppb) and blood eosinophil count at 12 months (<50 vs 50–100, <100 vs ≥100, <150 vs ≥150 eosinophils/μL). Additional biomarkers evaluated were atopic sensitisation (immunoglobulin E positivity or skin prick test positivity to food or airborne allergens); baseline FEV₁ (percentage of predicted value; <50%, 50%–70%, >70%); comorbid bronchiectasis; presence of psychological comorbidities (ie, anxiety and depression); early versus late onset (asthma diagnosis at <35 vs ≥35 years) and early versus late intervention (asthma duration <20 vs ≥20 years). Due to the lack of consensus regarding the definition of early/late intervention and early/late asthma onset, the study median for both variables was used.

Sample size calculation

The sample size was determined based on the change in the number of exacerbations (primary objective).¹⁵ Data from an open-label 1-year extension study—COSMOS (MEA115661)—was used to calculate the minimum sample size to measure the real-life change in asthma exacerbations. Since patients on the placebo during the MENSA study (MEA115588) had demonstrated a 42% reduction in asthma exacerbation during COSMOS and used a sample size of 350 (after assuming 10% missing data), we calculated that our study would need to include 320 patients. Considering a one-sided test and alpha=0.05, a sample of 320 patients had ~100% power to detect a change in exacerbations as outlined above.¹⁵

Statistical analysis

Measures of treatment response at baseline, 12 months and changes from baseline at 12 months were summarised using means and SDs. Prespecified two-tailed, unpaired t-tests were performed for selected analyses (eg, between patient subgroups), with statistical significance defined as p<0.05. All other stratified analyses were descriptive in nature, and no additional formal hypothesis testing was prespecified. Analyses were conducted on available data; no imputation was performed, and variable-specific denominators are presented in tables. Given the exploratory post hoc nature of the analysis and small subgroup sizes, formal distributional assumptions were not routinely tested and results from parametric summaries and tests should be interpreted cautiously.

Results

Study population

In total, 318 patients with SA-T2 were included in REDES, all of whom were included in this post hoc analysis. The baseline characteristics of this patient cohort are described in the primary REDES study publication.¹⁵ Briefly, mean age was 56.6 years, 69.2% were female, mean BMI was 28.6 kg/m² and 89% Caucasian and 9% Hispanic (table 1).

Table 1.

Demographic and clinical characteristics among various population subgroups

	Mean age, years	Female sex, %	NERD, %	Anxiety, %	Depression, %	Comorbid nasal polyps, %	Comorbid bronchiectasis, %	Atopic sensitisation, %
All patients (n=318)	56.6	69.2	13.2	19.5	17.3	46.2	18.6	41.5
Subgroups by patient characteristics
Sex
Male (n=98)	55.2	0	14	9	10	58	15	39
Female (n=220)	57.2	100	13	24	20	41	20	42
Age, years
≥65 (n=85)	70.8	76	15	19	26	38	28	31
<65 (n=233)	51.3	67	12	20	14	49	15	45
FEV1, % of predicted
<50% (n=51)	57.9	63	4	24	18	39	0	36
50%–70% (n=79)	56.5	73	10	16	11	46	18	43
>70% (n=124)	55.8	69	19	22	19	49	17	45
Blood EO counts*, cells/µL
<50 (n=75)	57.8	71	13	29	19	40	17	49
50–100 (n=107)	57.5	59	15	18	16	54	16	41
Anxiety
Yes (n=59)	56.1	86	12	100	47	36	27	48
No (n=256)	56.6	65	14	0	10	48	17	39
Depression
Yes (n=55)	61.0	82	15	53	100	35	18	41
No (n=262)	55.7	67	13	12	0	49	19	41
Atopic sensitisation
Yes (n=131)	53.2	71	13	24	17	39	14	100
No (n=185)	58.9	68	14	16	17	51	22	0
Bronchiectasis
Yes (n=59)	61.8	75	17	27	17	56	100	31
No (n=259)	55.4	68	12	18	17	44	0	44
Nasal polyps
Yes (n=147)	56.3	61	22	16	13	100	22	35
No (n=171)	56.7	76	5	23	21	0	15	47
Age at asthma onset
Early (<35 years; n=143)	50.4	69	17	22	12	52	19	43
Late (≥35 years; n=158)	62.2	71	11	18	21	42	18	39
Asthma duration at intervention
Early (<20 years; n=158)	55.9	68	11	18	18	43	15	44
Late (≥20 years; n=143)	57.4	71	16	21	15	52	22	37
Subgroups by change in FeNO from baseline at 12 months
≥20 ppb increase (n=23)	54.9	78	4	17	30	48	9	48
No change (±<20 ppb; n=73)	55.7	74	21	22	15	52	30	48
≥20 ppb decrease (n=43)	54.7	65	5	23	14	58	16	40

*Blood EO counts 12 months after treatment with mepolizumab.

EO, eosinophil; FeNO, fraction of exhaled nitric oxide; FEV₁, forced expiratory volume in 1 s; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease.

Analysis of baseline characteristics in patient subgroups revealed that mean age was greater in patients with versus without bronchiectasis (61.8 vs 55.4 years, p<0.001), with versus without depression (61.0 vs 55.7 years, p=0.004), and without versus with atopic sensitisation (58.9 vs 53.2 years;table 1, p<0.001). The proportion of patients with comorbid gastro-oesophageal reflux disease (GERD) increased as baseline FEV₁ increased, from 12% in patients with FEV₁<50% to 25% in patients with FEV₁>70% (p=0.05). No significant differences in the reduction of exacerbations or lung function were found in patients with GERD versus those without (74% vs 78%, respectively). We also found that patients with GERD had slightly better baseline FEV1 (75%) versus without GERD (68%) (p=0.04); the improvement was similar in both groups (p=0.42).

FeNO and blood eosinophil counts

Mepolizumab showed a clinically significant response across all subgroups, although elevated baseline type 2 (T2) biomarkers (FeNO≥25 or ≥50 ppb and/or blood eosinophil count ≥150 or ≥300 cells/µL) predicted an even higher response, as measured by change in exacerbations, lung function, OCS use and ACT score (table 2, descriptive results).

Table 2.

Response to mepolizumab in patients stratified by baseline FeNO (25 and 50 ppb thresholds) and eosinophil count (150 and 300 cells/µL thresholds)

Treatment response	Baseline FeNO 25 ppb and 150 EOs/µL thresholds
	FeNO <25 ppb,		FeNO ≥25 ppb,		FeNO <25 ppb,		FeNO ≥25 ppb,
	<150 EOs/µL		<150 EOs/µL		≥150 EOs/µL		≥150 EOs/µL
	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)
Exacerbations in the previous 12 months
Baseline	8	4.9 (4.0)	11	3.8 (2.9)	51	3.9 (3.4)	152	4.4 (3.6)
12 months	8	2.4 (1.4)	11	0.6 (0.9)	51	0.9 (1.0)	152	0.8 (1.3)
Prebronchodilator FEV1, L
Baseline	6	1.7 (0.9)	8	2.1 (0.8)	43	1.7 (0.6)	132	1.9 (0.8)
12 months	3	2.0 (0.5)	7	2.3 (0.8)	34	1.9 (0.6)	109	2.2 (0.8)
Postbronchodilator FEV1, L
Baseline	5	1.8 (0.7)	8	1.8 (0.8)	37	1.9 (0.5)	99	2.1 (0.8)
12 months	5	1.6 (0.5)	7	2.2 (1.0)	26	1.9 (0.5)	65	2.3 (0.8)
Prednisolone dose in the last month, mg/day
Baseline	3	16.4 (12.1)	5	8.6 (7.1)	18	8.3 (6.8)	47	11.7 (10.0)
12 months	3	3.2 (2.8)	5	5.0 (4.7)	17	2.4 (3.4)	41	3.7 (6.9)
ACT score
Baseline	6	17.5 (6.8)	8	13.1 (5.2)	46	13.8 (5.4)	147	14.4 (5.0)
12 months	4	18.3 (6.1)	7	20.9 (3.2)	44	20.3 (4.1)	131	21.2 (3.9)
Treatment response	Baseline FeNO 25 ppb and 300 EOs/µL thresholds
	FeNO <25 ppb,		FeNO ≥25 ppb,		FeNO <25 ppb,		FeNO ≥25 ppb,
	<300 EOs/µL		<300 EOs/µL		≥300 EOs/µL		≥300 EOs/µL
	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)
Exacerbations in the previous 12 months
Baseline	17	3.7 (3.1)	19	4.4 (3.1)	42	4.1 (3.5)	144	4.3 (3.6)
12 months	17	1.7 (1.3)	19	0.9 (1.3)	42	0.8 (1.0)	144	0.8 (1.3)
Prebronchodilator FEV1, L
Baseline	12	1.8 (0.8)	16	2.0 (0.8)	37	1.7 (0.6)	124	1.9 (0.8)
12 months	7	2.1 (0.6)	14	2.1 (1.0)	30	1.8 (0.5)	102	2.2 (0.7)
Postbronchodilator FEV1, L
Baseline	14	1.8 (0.6)	11	2.1 (0.9)	28	1.9 (0.5)	96	2.1 (0.8)
12 months	10	1.7 (0.4)	10	2.3 (1.0)	21	1.9 (0.5)	62	2.2 (0.7)
Prednisolone dose in the last month, mg/day
Baseline	7	10.2 (8.7)	12	6.9 (5.8)	16	9.3 (7.1)	57	10.9 (9.4)
12 months	8	2.5 (2.5)	12	5.2 (8.3)	16	2.7 (4.2)	51	2.8 (5.0)
ACT score
Baseline	14	16.4 (4.9)	15	13.1 (5.2)	38	13.4 (5.6)	140	14.5 (5.0)
12 months	12	19.3 (4.5)	14	19.4 (5.7)	36	20.4 (4.1)	124	21.4 (3.5)
Treatment response	Baseline FeNO 50 ppb and 300 EOs/µL thresholds
	FeNO <50 ppb,		FeNO ≥50 ppb,		FeNO <50 ppb,		FeNO ≥50 ppb,
	<300 EOs/µL		<300 EOs/µL		≥300 EOs/µL		≥300 EOs/µL
	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)	n	Mean (SD)
Exacerbations in the previous 12 months
Baseline	24	3.6 (3.5)	12	4.9 (2.5)	99	4.2 (3.6)	87	4.5 (3.6)
12 months	24	1.6 (1.5)	12	0.6 (0.8)	99	0.8 (1.1)	87	0.9 (1.3)
Prebronchodilator FEV1, L
Baseline	17	1.9 (0.8)	11	2.0 (0.9)	88	1.8 (0.8)	73	2.0 (0.7)
12 months	10	2.1 (0.8)	11	2.1 (1.0)	74	1.9 (0.7)	58	2.4 (0.7)
Postbronchodilator FEV1, L
Baseline	19	1.9 (0.7)	6	2.2 (1.0)	69	2.0 (0.7)	55	2.2 (0.8)
12 months	14	1.9 (0.8)	6	2.4 (0.9)	46	1.9 (0.5)	37	2.5 (0.8)
Prednisolone dose in the last month, mg/day
Baseline	9	9.4 (8.5)	6	8.5 (7.7)	29	9.7 (7.5)	29	12.9 (11.2)
12 months	9	3.0 (3.0)	6	8.3 (11.4)	26	2.8 (5.2)	25	3.1 (5.4)
ACT score
Baseline	19	15.7 (5.4)	10	12.9 (5.2)	92	14.6 (5.5)	86	13.8 (4.7)
12 months	16	18.9 (5.5)	10	20.1 (5.1)	85	21.4 (3.5)	75	21.0 (3.9)

ACT, Asthma Control Test; EOs, eosinophils; FeNO, fraction of exhaled nitric oxide; FEV₁, forced expiratory volume in 1 s.

Compared with the 12 months before initiation of mepolizumab, the number of exacerbations in the 12 months after the start of treatment was reduced by approximately 51%–55% in patients with lower T2 biomarkers (FeNO<25 ppb and <150 eosinophils/µL, FeNO<50 ppb and <300 eosinophils/µL or FeNO<25 ppb and <300 eosinophils/µL), and by approximately 77%–88% in patients with one or more elevated T2 biomarkers (figure 1). Additionally, ACT score increased across all groups regardless of FeNO and eosinophil values (table 2). Mepolizumab also showed a clinically significant response across all subgroups stratified by baseline FeNO values of <25, 25–50 or ≥50 ppb (online supplemental table S1).

Figure 1.

Approximate percentage reduction in the mean number of exacerbations in the 12 months after initiation of mepolizumab versus the previous 12 months in patients stratified by baseline FeNO and eosinophil count: (A) FeNO 25 ppb and 150 EOs/µL thresholds; (B) FeNO 25 ppb and 300 EOs/µL thresholds; (C) FeNO 50 ppb and 150 EOs/µL thresholds. EOs, eosinophils; FeNO, fraction of exhaled nitric oxide.

When patients were stratified by change in FeNO from baseline to 12 months, response to mepolizumab was generally comparable across subgroups (online supplemental table S2).

Compared with the 12 months before initiation of mepolizumab, the number of exacerbations in the 12 months after the start of treatment was reduced by approximately 85%–89% (p<0.001) across patients with a ≥20 ppb decrease in FeNO, a ≥20 ppb increase in FeNO, and no change in FeNO at 12 months (online supplemental figure S1). Interestingly, patients with a ≥20 ppb reduction in FeNO at 12 months had numerically greater baseline FeNO than the other two subgroups (mean, 102.9 vs 41.4–45.1 ppb), and had numerically greater baseline FEV₁ (mean, 2.1 vs 1.7–1.9 L), descriptive results.

In patients with a blood eosinophil count of 50–100 cells/µL at 12 months after the introduction of mepolizumab, response to treatment was similar to that in patients with a 12-month eosinophil count of <50 cells/µL (online supplemental table S3). Compared with the 12 months before initiation of mepolizumab, the number of exacerbations in the 12 months after the start of treatment was reduced by approximately 76%–81% (p<0.001) across these two subgroups (online supplemental figure S2), and ACT score improved by a mean of 6.9–7.0 points from baseline at 12 months (p<0.001). There was a similar reduction in the number of exacerbations and improvement in ACT score at 12 months in patients with a 12-month eosinophil count of <100 cells/µL vs ≥100 cells/µL, and in those with <150 cells/µL vs ≥150 cells/µL (online supplemental table S3), descriptive results.

Other patient characteristics

Additional analyses showed that baseline factors of sex, BMI, smoking status, atopic sensitisation, and FEV₁ had no appreciable impact on 12-month reductions in the number of exacerbations, use of maintenance OCS, or improvements in lung function or ACT score associated with mepolizumab treatment (online supplemental tables S4-S8). Compared with the 12 months before initiation of mepolizumab, the number of exacerbations in the 12 months after the start of treatment was reduced by approximately 81% among men and 87% in women (figure 2; online supplemental table S4). The number of exacerbations in normal weight, overweight, obese and severely obese patients was similarly reduced by 71%–80% after 12 months of mepolizumab treatment (online supplemental table S5). The number of exacerbations in non-smokers, ex-smokers and smokers was reduced by approximately 78%, 76% and 73% at 12 months, respectively (online supplemental table S6). The number of exacerbations after 12 months of mepolizumab treatment was reduced by approximately 78% in patients without atopic sensitisation and by 77% in patients with atopic sensitisation (figure 2; online supplemental table S7). As expected, maintenance OCS use (as indicated by mean dose) was highest in patients with the worst baseline lung function (FEV₁<50%) versus patients with FEV₁≥50%; although patients with baseline FEV₁<50% demonstrated the greatest improvement in lung function at 12 months, other responses to mepolizumab were similar regardless of baseline FEV₁ (online supplemental table S8).

Figure 2.

Absolute (red) and relative (blue) reductions in exacerbations in the 12 months after initiation of mepolizumab versus the previous 12 months, stratified according to baseline characteristics. EOs, eosinophils; FeNO, fraction of exhaled nitric oxide; FEV₁, forced expiratory volume in 1 s.

Patients with increases in FeNO of ≥20 ppb and those with baseline FEV₁ 50%–70% had greater absolute reductions in exacerbations (>4 exacerbations/year) after mepolizumab treatment. The greatest relative reductions in exacerbations were observed in patients with comorbid nasal polyps and those with baseline FEV₁ 50%–70% (figure 2). Patients with the poorest lung function at baseline (FEV₁<50% or 50%–70%) had the greatest absolute and relative improvements in lung function with mepolizumab, and those with the best lung function pretreatment (FEV₁>70%) had the least improvement post-treatment (online supplemental figure S3). Patients with the lowest baseline FEV₁ were receiving the greatest maintenance doses of OCS at baseline. Reductions in maintenance OCS were consistent across all patient subgroups, with the greatest relative reduction in OCS dose observed in patients with reduced FeNO after mepolizumab (figure 3).

Figure 3.

Maintenance oral corticosteroid dose before and 12 months after initiation of mepolizumab, stratified according to baseline characteristics. EOs, eosinophils; FeNO, fraction of exhaled nitric oxide; FEV₁, forced expiration volume in 1 s.

The improvement in exacerbations at 12 months was numerically greater among patients with comorbid nasal polyps than in those without (figure 2). More details regarding the effects of nasal polyps in patients in REDES are reported elsewhere.²⁸

Discussion

In line with the findings of other real-world studies,^{14 16–19} previously reported results of the REDES study showed that mepolizumab significantly reduced the occurrence of severe exacerbations, maintenance OCS use and blood eosinophil count; and significantly improved lung function and ACT scores in patients with SA-T2.¹⁵ The current post hoc analysis of data from REDES suggests that mepolizumab therapy may be effective for patients with SA-T2 with a broad range of demographic and comorbid clinical characteristics. In addition, this analysis identified baseline FeNO and blood eosinophil count as key patient characteristics that may be used to predict treatment response. Our analyses found that mepolizumab was effective across baseline FeNO and blood eosinophil subgroups, although some subgroups with lower T2 biomarkers were very small (ie, groups with blood eosinophil counts of <150 eosinophils/μL or FeNO <25 ppb), and as such, our results need to be confirmed in larger patient populations. Overall, response rates were numerically greater in patients with high levels of T2 disease expression at baseline (ie, blood eosinophil count ≥150 or ≥300 eosinophils/µL and/or FeNO ≥25 or ≥50 ppb) versus those with lower levels of T2 disease expression at baseline. These results are consistent with previous reports that ‘super-responders’ to mepolizumab typically have higher baseline blood eosinophil counts and FeNO levels than other patients.²⁴

When we assessed the response to mepolizumab in patients stratified by change in FeNO at 12 months, results were comparable between patients with a ≥20 ppb reduction in FeNO, a ≥20 ppb increase in FeNO, and no change in FeNO from baseline; also between patients with baseline FeNO values of <25, 25–50, or ≥50 ppb. These results suggest that baseline FeNO levels alone are not prognostic of the therapeutic effect of mepolizumab. Indeed, anti-IL-5 therapy is not typically associated with changes in FeNO.¹³ Nevertheless, our study identified a subset of patients (n=43) with reduced FeNO after 12 months of mepolizumab treatment. These patients displayed a high mean FeNO level at baseline (102.9 ppb), which is similar to results of a real-world study that reported significant 1-year reductions in FeNO following mepolizumab or benralizumab therapy in patients with severe asthma and median baseline FeNO of 96 ppb.³² These results may be explained by an excess IL-13 production by eosinophils in these patients, or by a cross-link between immune pathways yet unknown. We did not expect to find that the subgroup of patients with a reduction in FeNO from baseline at 12 months also had a higher mean FEV₁ at baseline. Nor was it expected that patients who had a baseline FEV₁ of 50%–70% and who experienced an increase in FeNO (of ≥20 ppb from baseline) had among the greatest absolute reduction in exacerbations after mepolizumab treatment.

We also found that patients with a blood eosinophil count of <50 cells/µL after 12 months of mepolizumab treatment had similar response to those with a 12-month eosinophil count of 50–100 cells/µL. This was also the case for patients with a 12-month eosinophil count of <100 vs ≥100 cells/µL, and for those with <150 vs ≥150 cells/µL. Indeed, previous studies indicated that mepolizumab may not completely deplete eosinophils^{33 34}; however, our results support the notion that complete depletion of blood eosinophils is not required to achieve a good response.

Blood eosinophilia is correlated with sputum eosinophilia.^{35 36} As shown in a study by Schleich et al, FeNO levels were also correlated with sputum eosinophil count, but since both FeNO and blood eosinophil counts were independent predictors of sputum eosinophilia, the authors concluded that FeNO and blood eosinophil counts appear to be biomarkers related to different mechanisms promoting the eosinophilic asthma phenotype.³⁵ Our post hoc analysis results support that baseline blood eosinophil count may be a better predictor of response than baseline FeNO.

Responses to mepolizumab were observed irrespective of sex, baseline BMI, smoking status, atopic sensitisation, lung function and comorbid nasal polyps, demonstrating the effectiveness of mepolizumab across a diverse patient population. Our results are generally in keeping with several other studies that reported no effect of sex, nasal polyps, allergen sensitivity, lung function, BMI and smoking history on response to mepolizumab in patients with severe asthma.14 16 19 29 While others have reported that some characteristics (eg, the presence of nasal polyps, higher baseline lung function, lower baseline BMI and never having smoked) may predict an increased rate of response or better response to mepolizumab,^{24 37 38} mepolizumab has shown to be beneficial for patients spanning a broad range of demographic and clinical characteristics. Indeed, analysis of characteristics associated with complete remission after mepolizumab treatment demonstrated that patients achieving clinical remission were less likely to have depression, atopic sensitisation or GERD at baseline, and more likely to have non-steroidal anti-inflammatory drug-exacerbated respiratory disease or nasal polyps than those not achieving clinical remission.²² Further studies are needed to examine whether earlier-stage versus late-stage treatment of SA-T2 may predict response to mepolizumab, and whether earlier intervention may optimise patient outcomes and promote clinical remission in patients with SA-T2.

Limitations of the current analysis include its post hoc nature and reliance on retrospectively collected real-world data from REDES, as well as very small numbers of patients in certain subgroups (particularly those with lower baseline T2 biomarkers). As an observational, exploratory analysis, residual confounding cannot be excluded and most comparisons were univariable and descriptive; multivariable modelling was not prespecified and would be unstable in several strata. Centre-level effects across the 24 participating units were not evaluated. Several variables had missing data at baseline or 12 months and no imputation was performed. Because baseline biomarker thresholds were selected and outcomes were assessed over time, regression to the mean is a potential source of bias. In addition, detailed information on changes in concomitant treatments and adherence during follow-up was not available, which may influence observed responses. The multicentre real-world design supports the representativeness of the REDES cohort for patients with severe asthma treated with mepolizumab in specialised clinical practice, although generalisability beyond referral centres may be limited.

In conclusion, our post hoc analysis of the REDES study showed that in patients with SA-T2, treatment with mepolizumab is likely to provide clinical benefit across patients with a broad range of characteristics (eg, regardless of sex, baseline BMI, smoking status, comorbid nasal polyps, atopic sensitisation or lung function). Further, our analysis indicates that mepolizumab may be associated with better response rates in patients with high levels of T2 disease expression at baseline (ie, blood eosinophil count ≥150 cells/µL or ≥300 cells/µL and/or FeNO ≥25 ppb or ≥50 ppb). More studies are needed to better identify the patients most likely to achieve clinical remission with mepolizumab.

Data availability statement

Data are available on reasonable request. Please refer to GSK weblink to access the company’s data sharing policies and, as applicable, seek anonymised subject level data (https://www.gsk-studyregister.com/en/).

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

The REDES study was performed in line with the principles of the Declaration of Helsinki and order SAS/3470/2009. Approval was granted by the Ethics Committee of Hospital La Princesa, Madrid, on 25 September 2019, code GLA-MEP-2019-01. Informed consent was obtained from all individual participants included in the study.