TABLE 1.
Completed and ongoing studies with drugs targeting airway diseases via anti-thymic stromal lymphopoietin (TSLP) and anti-interleukin (IL)-33/ST2 pathways
| Study/drug | Target population | Study design | Dose | Key inclusion criteria | Key results summary | Key results according to type 2 inflammation |
| Asthma | ||||||
| Anti-IL-33/ST2 | ||||||
| NCT02918019 [114] ZENYATTA study Astegolimab (anti-ST2) |
Severe asthma | n=502 (120 patients per arm) Primary end-point: annualised rate of asthma exacerbations at week 52 Stratified by screening blood eosinophil counts (<150, 150–<300, ≥300 cells·μL−1) |
1:1:1:1 70 mg every 4 weeks, 210 mg every 4 weeks, 490 mg every 4 weeks, placebo |
Age 18–75 years; ≥1 asthma exacerbation in prior 12 months; FEV1 40–80%; nonsmokers | 43% annualised asthma exacerbation rate reduction (p=0.0049) and FEV1 improvement of 0.128 L (nonsignificant) for 490 mg dose in comparison with placebo | Annualised rate of exacerbation reduction: 53.6% (p=0.0016) in patients with baseline blood eosinophils <300 cells·μL−1
versus 10.2% (p=0.7718) in patients with eosinophils ≥300 cells·μL−1 FEV1 improvement appeared to be higher in patients with baseline blood eosinophil counts <150 cells·μL−1 in the 490 mg group |
| NCT03387852 [112] Itepekimab (anti-IL-33) |
Moderate-to-severe asthma | n=296 (74 patients per arm) Primary end-point: loss of asthma control events from baseline to week 12 |
1:1:1:1 Itepekimab alone every 2 weeks, itepekimab+dupilumab every 2 weeks, dupilumab alone every 2 weeks, placebo |
Age 18–70; ≥1 asthma exacerbation in prior 12 months; FEV1 40–85%; nonsmokers | 22% of patients in the itepekimab group experienced an event indicating a loss of asthma control versus 27% in the combination group and 41% in the placebo group The corresponding odds ratio compared to placebo was 0.42 (95% CI 0.20–0.88; p=0.02) for itepekimab and 0.52 (95% CI 0.25–1.06; p=0.07) in the combination group |
In the itepekimab only group, for loss of asthma control events, patients with baseline blood eosinophils ≥300 cells·mm−3 had an odds ratio versus placebo of 0.39 (95% CI 0.14–1.05) compared to 0.46 (95% CI 0.15–1.41) in patients with baseline blood eosinophils <300 cells·mm−3 |
| NCT04570657 FRONTIER-3 study Tozorakimab (MEDI3506) (anti-IL-33) |
Moderate-to-severe uncontrolled asthma | n=228 (76 patients per arm) Primary end-point: change from baseline to week 16 in pre-BD FEV1 |
1:1:1 MEDI3506 dose 1, MEDI3506 dose 2, placebo |
Age 18–<65 years; ≥1 asthma exacerbation in prior 12 months, pre-BD FEV1 40–85%; nonsmokers | Study ongoing | |
| NCT03207243 Melrilimab (GSK3772847) (anti-ST2) |
Moderate-to-severe asthma | n=165 Primary end-point: percentage of participants with loss of asthma control over weeks 0–16 |
1:1 10 mg·kg−1 every 4 weeks i.v., placebo |
≥18 years of age, treatment with high dose ICS, ACQ-5 score 1.0–4.0, ≥1 asthma exacerbation within 12 months, nonsmokers | 67% of patients who received melrilimab intravenously every 4 weeks suffered loss of asthma control, compared to 81% of people on placebo Median rate ratio 0.82 (95% CI 0.66–0.99) |
|
| Anti-TSLP | ||||||
| NCT02054130 [109] PATHWAY study Tezepelumab (anti-TSLP) |
Severe asthma | n=550 (∼138 patients per arm) Primary end-point: annualised rate of asthma exacerbations at week 52 Randomisation stratified by blood eosinophil count of ≥250 or <250 cells·mL−1) |
1:1:1:1 70 mg every 4 weeks, 210 mg every 4 weeks, 280 mg every 2 weeks, placebo |
Age 18–75 years; ≥2 asthma exacerbations requiring glucocorticoids or ≥1 asthma exacerbation leading to hospitalisation in prior 12 months; FEV1 40–80%; nonsmokers or former smokers with smoking history ≤10 pack-years | 71% exacerbation rate reduction (p<0.001), FEV1 improvement of 0.13 L (p=0.009) for 210 mg dose in comparison with placebo | Annualised exacerbation reduction in the 210 mg every 4 weeks arm: 62% (p=0.021) in patients in high Th2 group versus 84% (p<0.001) in patients in low Th2 group# 65% (p=0.005) versus 79% (p<0.001) in patients with blood eosinophils <250 cells·mL−1 versus >250 cells·mL−1 |
| NCT03347279 [117] NAVIGATOR study Tezepelumab (anti-TSLP) |
Severe asthma | n=1061 (∼530 patients per arm) Primary end-point: annualised rate of asthma exacerbations at week 52 |
1:1 210 mg every 4 weeks, placebo |
Age 12–80 years; ≥2 asthma exacerbations in prior 12 months; FEV1 <80% (<90% for patients 12–17 years old) | 66% exacerbation rate reduction (p<0.001), FEV1 improvement of 0.13 L (p<0.001) for 210 mg dose in comparison with placebo | Annualised exacerbation rate reduction: 41% (p<0.001) in patients with blood eosinophils <300 cells·μL−1, versus 70% for patients with blood eosinophils ≥300 cells·μL−1 |
| NCT03688074 [116] CASCADE study Tezepelumab (anti-TSLP) |
Moderate-to-severe asthma | n=55 patients per arm Primary end-point: reduction in number of airway submucosal inflammatory cells (eosinophils, neutrophils, T-cells and mast cells) at 28 weeks Stratified by screening blood eosinophil counts (<150, 150–<300 cells·μL−1) |
1:1 210 mg every 4 weeks, placebo |
Age 18–75 years; FEV1 >50%, nonsmokers or former smokers with smoking history ≤10 pack-years | Airway submucosal eosinophils reduction in tezepelumab versus placebo group (ratio of geometric least-squares means 0.15 (nominal p<0.0010) No differences between treatment groups in the other cell types evaluated | Reduction in airway submucosal eosinophils was similar across all groups according to baseline blood eosinophils |
| NCT03406078 [123] SOURCE study Tezepelumab (anti-TSLP) |
Severe uncontrolled, OCS-dependent asthma | n=150 Primary end-point: percent reduction from baseline in the daily OCS dose while not losing asthma control at week 48 |
1:1 210 mg every 4 weeks, placebo |
Age 18–80 years; FEV1 >50%, nonsmokers or former smokers with smoking history ≤10 pack-years, medium- or high-dose ICS and LABA, OCS for at least 6 months, pre-BD FEV1 <80% predicted normal | The (cumulative) odds of achieving a category of greater percentage reduction in maintenance OCS dose at week 48 was numerically higher with tezepelumab than placebo (OR 1.28, 95% CI 0.69–2.35; p=0.43) | In patients with a baseline blood eosinophil count ≥150 and ≥300 cells·µL−1, the (cumulative) odds of achieving a category of greater percentage reduction in maintenance OCS dose at week 48 were 2.58 (95% CI 1.16–5.75) and 3.49 (95% CI 1.16–10.49) times higher with tezepelumab than placebo, respectively No effects of tezepelumab versus placebo on OCS dose reduction were observed in patients with low baseline blood eosinophil counts (<300 and <150 cells·µL−1) |
| NCT04410523 CSJ117 (inhaled anti-TSLP) |
Severe asthma | n=625 Primary end-point: change from baseline in pre-BD FEV1 |
0.5 mg, 1 mg, 2 mg, 4 mg, 8 mg and placebo | Age ≥18 and ≤75 years, treatment with medium/high dose ICS plus LABA with up to two additional controllers, pre-BD FEV1 of ≥40% and ≤85% of the predicted normal, ACQ-5 score of ≥1.5 | Data expected 2022 | |
| COPD | ||||||
| Anti-IL-33/ST2 | ||||||
| NCT03546907 [13] Itepekimab (anti-IL-33) |
Moderate-to-severe COPD | n=170 patients per arm Primary end-point: annualised rate reduction of moderate-to-severe COPD exacerbations during 24–52-week treatment period |
1:1 300 mg every 2 weeks, placebo |
Age 40–75 years, current and former smokers, chronic bronchitis, FEV1 30–80%; ≥2 moderate or ≥1 severe COPD exacerbations in prior 12 months | 19% exacerbation rate reduction (p=0.13) Pre-BD FEV1 improvement of 0.06 L (p=0.024) in comparison with placebo |
Annualised exacerbation rate reduction: 22% (p=0.28) in patients with eosinophils ≥250 cells·μL−1 versus 16% (p=0.32) in patients with eosinophils <250 cells·μL−1 42% (p=0.0061) in former smokers versus −9% (p=0.65) in current smokers |
| NCT03615040 [15] COPD ST2OP Astegolimab (anti-ST2) |
Moderate to very severe COPD | n=40 patients per arm Primary end-point: annualised rate reduction of moderate-to-severe COPD exacerbations during 48-week treatment period |
1:1 490 mg every 4 weeks, placebo | Age 40–75 years, current and former smokers, FEV1 30–80%; ≥2 moderate or severe exacerbations in prior 12 months | 22% annualised exacerbation rate reduction (p=0.195) Post-BD improvement in FEV1 of 40.0 mL (p=0.094) for astegolimab versus placebo group at 48 weeks Improvement in SQGRQ-c of −3.3 points (p=0.039) for astegolimab versus placebo group at 48 weeks |
Annualised exacerbation rate reduction: 37% reduction in patients with baseline blood eosinophils <300 per μL versus 37% increase in patients with blood eosinophils >300 cells·μL−1 (p=0.072) |
| NCT04701983 NCT04751487 AERIFY-1 and AERIFY-2 studies Itepekimab (anti-IL-33) |
Moderate-to-severe COPD | n=310 patients per arm Annualised rate reduction of moderate-to-severe COPD exacerbations in former smokers during 52-week treatment period |
1:1:1 300 mg every 2 weeks, every 4 weeks, placebo |
Age 40–85 years, former smokers¶, chronic bronchitis, ≥2 moderate or ≥1 severe COPD exacerbation in prior 12 months | Study ongoing | |
| NCT05037929 ALIENTO study Astegolimab (anti-ST2) |
Moderate to very severe COPD | n=310 patients per arm Annualised rate reduction of moderate-to-severe COPD exacerbations during 52-week treatment period |
1:1:1 476 mg every 2 weeks, 476 mg every 4 weeks, placebo | Age 40–90 years, current and former smokers, FEV1 20–80%; ≥2 moderate or severe exacerbations in 12-month period within prior 24 months | Study ongoing | |
| NCT04631016 FRONTIER-4 Tozorakimab (MEDI3506) (anti-IL-33) |
Moderate-to-severe COPD | n=114 (57 patients per arm) Primary end-point: change from baseline to week 12 in pre-BD FEV1 |
1:1 Tozorakimab, placebo |
Age 40–75; current or former smokers with COPD, chronic bronchitis, ≥1 moderate or severe COPD exacerbation in the previous 12 months, dual or triple therapy | Study ongoing | |
| NCT05166889 OBERON study Tozorakimab (MEDI3506) (anti-IL-33) |
Moderate to very severe COPD | n=1272 (424 patients per arm) Primary end-point: annualised rate of moderate-to-severe COPD exacerbations in participants who are former smokers+ |
1:1:1 Tozorakimab dose 1, tozorakimab dose 2, placebo |
Age ≥40, current and former smokers, FEV1 ≥20%, ≥2 moderate COPD exacerbations or ≥1 severe COPD exacerbation in the prior 12 months | Study ongoing | |
| NCT05158387 TITANIA study Tozorakimab (MEDI3506) (anti-IL-33) |
Moderate to very severe COPD | n=1272 (424 patients per arm) Primary end-point: annualised rate of moderate-to-severe COPD exacerbations in participants who are former smokers§ |
1:1:1 Tozorakimab dose 1, tozorakimab dose 2, placebo |
Age ≥40, current and former smokers, FEV1 ≥20%, ≥2 moderate COPD exacerbations or ≥1 severe COPD exacerbation in the prior 12 months | Study ongoing | |
| Anti-TSLP | ||||||
| NCT04039113 Tezepelumab (anti-TSLP) |
Moderate to very severe COPD | n=338 Primary end-point: moderate or severe COPD exacerbation rate ratio (tezepelumab versus placebo) |
1:1 Every 4 weeks or placebo |
Age 40–80 years, current and former smokers, FEV1 20–80%; ≥2 moderate or severe exacerbations in 12 months, CAT score ≥15, on triple therapy (ICS/LABA/LAMA) | Data expected 2023 | |
| NCT04882124 CSJ117 (inhaled anti-TSLP) |
COPD | n=300 Primary end-point: change from baseline in E-RS symptom score at 12 weeks |
1:1:1 4 mg, 8 mg and placebo inhaled once daily |
Age ≥40 years, former or current smokers with COPD on triple therapy (ICS/LABA/LAMA) | Data expected 2023 | |
ACQ: asthma control questionnaire; BD: bronchodilator; CAT: COPD Assessment Test; COPD: chronic obstructive pulmonary disease; E-RS: Evaluating Respiratory Symptoms–COPD; FEV1: forced expiratory volume in 1 s; ICS: inhaled corticosteroids; LABA: long-acting beta-agonists; LAMA: long-acting muscarinic antagonist; OCS: oral corticosteroids; SQGRQ-c: St George Respiratory Questionnaire-COPD; Th2: T-helper 2. #: Th2 status defined as: high=immunoglobulin E (IgE) >100 IU·mL−1 and eosinophil count ≥140 cells·μL−1; low IgE <100 IU·mL−1 or eosinophil count <140 cells·μL−1. ¶: AERIFY-2 contains an additional two arms (itepekimab every 2 weeks, placebo) with current smokers. +: Primary end-point will be assessed first in primary population (former smokers) and then assessed in the overall population. §: Primary end-point will be assessed first in primary population (former smokers) and then assessed in the overall population.