*3.5. Anti-IL-33 mAbs*

Upon cellular damage or allergen exposure, interleukin (IL)-33 is released as an alarmin by airway epithelial cells, airway smooth muscle (ASM) cells (ASMCs), and endothelium to trigger innate and adaptive immune responses [68]. In patients affected by severe asthma refractory to steroids, IL-33 activates type 2 innate lymphoid cells (ILC2s), which may promote persistent airway eosinophilia [69]. Targeted inhibition of IL-33 receptor (IL-33R) signalling may prevent downstream production of type 2 cytokines and chemokines [70].

Two RCTs [32,33,40,41] investigated the anti-IL-33 mAbs itepekimab (SAR440340/ REGN3500) and etokimab (ANB020), and two other RCTs [23,24] assessed the efficacy of the anti-IL-33R mAb melrilimab (GSK3772847/CNTO7160).

A Phase II RCT [32,33] investigated the efficacy of subcutaneous itepekimab 300 mg administered alone or in combination with dupilumab 300 mg to patients with moderate to severe asthma, who progressively reduced and discontinued background therapy of inhaled corticosteroid/long-acting β2 adrenoceptor agonist (ICS/LABA) over 12 weeks. Itepekimab significantly (*p* < 0.05) improved trough FEV1 compared to PCB (MD 140 mL (95%CI 10–270)) and it was as effective as dupilumab, but no improvement was seen upon treatment with the combination therapy. Itepekimab did not increase post-bronchodilator FEV1 vs. PCB, but when combined with dupilmab, the improvement was significant (*p* < 0.05) (MD 130 mL (95%CI 10–250)) and comparable to that of dupilumab administered alone [32,33].

The percentage of patients with an event indicating a loss of asthma control was lower in the itepekimab (22.0%) and combination therapy (27.0%) groups vs. PCB (41.0%). The corresponding odds ratio (OR) for the comparison of itepekimab vs. PCB was significant (*p* < 0.05) (OR 0.42 (95%CI 0.20–0.88)) and similar to the OR for dupilumab vs. PCB; no difference was detected in the ORs for the comparison between combination therapy and PCB, itepekimab monotherapy, and dupilumab monotherapy. Itepekimab alone and combined with dupilumab significantly (*p* < 0.05) improved ACQ5 score vs. PCB (MD −0.42 units (95%CI −0.73–−0.12) and MD −0.32 units (95%CI −0.63–−0.01), respectively), and the effect was similar to that observed with dupilumab [32,33].

The BEC significantly (*p* < 0.05) decreased upon treatment with itepekimab administered alone or combined with dupilumab vs. PCB, and the effect was significantly (*p* < 0.05) different from that induced by dupilumab monotherapy, which, as expected [32], transiently induced blood eosinophilia. The FENO level was significantly (*p* < 0.05) lowered in the itepekimab group, although the magnitude of reduction was lower than that observed in the combination therapy and dupilumab groups. Patients treated with itepekimab administered alone or combined with dupilumab showed a significant (*p* < 0.05) improvement in their AQLQ score vs. PCB (MD 0.45 units (95% CI 0.14–0.77) and MD 0.43 units (95% CI 0.11–0.75), respectively), with an effect comparable to that of dupilumab [32,33].

In a Phase II RCT [40,41], a single dose of etokimab administered at 300 mg/100 mL via intravenous infusion did not improve FEV1 compared to PCB in severe eosinophilic asthma; no data are available for symptoms control.

The reduction in peripheral BEC following etokimab treatment was similar to that observed with PCB, and no difference was detected in FENO levels. The number of asthma exacerbations experienced by patients treated with etokimab was no different from those treated with PCB [40,41].

A Phase II RCT [23] reported that intravenously administering melrilimab 10 mg/kg to patients with moderate to severe asthma and allergic fungal airway disease for 12 weeks did not improve their FEV1 and ACQ5 score compared to PCB. No differences between melrilimab and PCB were observed with respect to the change from baseline in BEC, FENO level, and AQLQ score [23].

Another Phase II RCT [24] showed that melrilimab 10 mg/kg administered for 16 weeks to moderately severe asthmatic patients who gradually reduced and discontinued background therapy with fluticasone propionate/salmeterol (FP/SAL) 500/50 μg, did not improve trough FEV1 and morning and evening PEF vs. PCB. The reduction in ACQ5 score was similar with both melrilimab and PCB, but the percentage of patients who experienced loss of asthma control was lower in the group treated with melrilimab (67.0%) than with PCB (81.0%). No differences between the two treatment groups were

observed in the percentage of night-time awakenings due to asthma symptoms requiring rescue medication use and in the daytime asthma symptom score [24].

The effect induced on BEC and FENO level was similar in the melrilimab and PCB groups. The percentage of patients with an asthma exacerbation requiring OCS and/or hospitalisation was higher with melrilimab (13.0%) than with PCB (7.0%). No differences between the two groups were observed in terms of daily use of rescue medications and SGRQ total score [24].
