TABLE 1

Treatments with published evidence to suggest disease-modifying potential in asthma

Drug name	Drug class	Therapeutic target	Key evidence to suggest disease-modifying potential
Fluticasone propionate	ICS	NA	Ward et al. [41] 52-week randomised placebo-controlled trial in adults with asthma (n=35). 750 µg twice daily decreased reticular basement membrane thickness.
			Chetta et al. [42] 6-week randomised parallel-group trial in adults with mild-to-moderate asthma (n=30). 500 µg twice daily decreased reticular basement membrane thickness, number of vessels and vascular area.
			Hoshino et al. [43] 16-week study in adults with steroid-naïve asthma and healthy controls (n=62). 800 µg·day^–1 decreased airway wall area and thickness, as well as percentage of eosinophils and serum periostin.
Beclomethasone dipropionate	ICS	NA	Hoshino et al. [44] 6-month randomised placebo-controlled trial in adults with asthma (n=28). 800 µg·day^–1 decreased vascular area and number of vessels.
Omalizumab	Biologic	Anti-IgE	Nopp et al. [62] 3-year withdrawal follow-up study of omalizumab in adults with severe allergic asthma (n=18). 67% patients reported improved or unchanged asthma 3 years after discontinuation of omalizumab.
			Molimard et al. [63] Observational retrospective study in children and adults with severe allergic asthma (n=61). 44% reported no loss of asthma control after discontinuation of omalizumab (median follow-up: 9.3 months).
			Hoshino and Ohtawa [64] 16-week study in adults with severe allergic asthma (n=30). Add-on omalizumab treatment significantly reduced airway wall thickness versus conventional therapy.
			Riccio et al. [65] 3-year study in patients with severe allergic asthma (n=8). Omalizumab responders had a reduction in reticular basement membrane thickness and decreased levels of proteins specifically related to airway remodelling.
			Hayashi et al. [66] Randomised, crossover, placebo-controlled, single-centre study in adults with aspirin-exacerbated respiratory disease (n=16). Omalizumab led to a rapid reduction in median urinary LTE₄ and suppression of leukotrienes and other inflammatory mediators. Likely due to disarming of mast cells and potentially indicative of a modified response to aspirin.
Dupilumab	Biologic	Anti-IL-4R	Castro et al. [70] Phase III Liberty Asthma QUEST study in patients ≥12 years with uncontrolled asthma (n=1902). Dupilumab reduced serum IgE levels.
			Corren et al. [71] Post hoc analysis of patients from Liberty Asthma QUEST study classified by allergic status (allergic n=1083, non-allergic n=819). Dupilumab reduced serum IgE levels irrespective of allergic status.
			Wechsler et al. [73] Open-label, 96-week extension study in patients ≥12 years with moderate-to-severe or OCS-dependent severe asthma from previous phase II or III dupilumab trials (n=2282). By week 96, dupilumab reduced IgE levels by a median of 82% from parent study.
Mepolizumab	Biologic	Anti-IL-5	Flood-Page et al. [78] Study based on bronchial biopsies from adults with mild allergic asthma (n=24). After 8 weeks of treatment, mepolizumab administered intravenously reduced airway mucosal eosinophils, and reduced expression of markers of airway remodelling (ECM proteins tenascin, lumican and procollagen 3) compared with placebo.
Benralizumab	Biologic	Anti-IL-5	Chachi et al. [83] Computational model based on bronchial biopsies from adults with eosinophilic asthma (n=25). Benralizumab significantly reduced ASM mass and number of eosinophils versus placebo.
Tezepelumab	Biologic	Anti-TSLP	Sridhar et al. [89] Phase IIb PATHWAY trial in adults with uncontrolled asthma (n=550) [156]. Tezepelumab decreased serum levels of matrix remodelling proteins (MMP-10, periostin), and blood eosinophil and F_ENO levels over 52 weeks.
			Sverrild et al. [90] Phase II UPSTREAM trial in adults with asthma and AHR to mannitol (n=40). Proportion of patients without AHR to mannitol after 12 weeks was significantly greater in patients receiving tezepelumab (p=0.04). 12 weeks of tezepelumab did not significantly reduce AHR to mannitol versus placebo (p=0.06).
Montelukast	Small-molecule drug	CysLT antagonist	Debelleix et al. [99] Pre-clinical study in immature and adult mouse models of AHR. Montelukast decreased ASM mass in young developing mice, indicating the potential to reverse (or even prevent) airway remodelling.
Fevipiprant	Small-molecule drug	PGD₂ receptor 2 antagonist	Gonem et al. [101] Single-centre, randomised, placebo-controlled phase II trial in adults with moderate-to-severe asthma (n=61). After 12 weeks, fevipiprant significantly increased the proportion of intact epithelium and decreased functional residual capacity and expiratory CT lung volume.
			Saunders et al. [103] Computational model to capture airway remodelling based on bronchial biopsies from a phase II trial in adults with moderate-to-severe asthma [101]. 12 weeks of fevipiprant significantly decreased ASM mass versus placebo by decreasing airway eosinophilia and recruitment of myofibroblasts and fibrocytes to the ASM bundle.
Roflumilast^#	Small-molecule drug	PDE₄ inhibitor	Kim et al. [105] Pre-clinical study in a murine model of chronic asthma. Roflumilast significantly decreased parameters of airway remodelling (goblet cell hyperplasia and pulmonary fibrosis).
Dasatinib^#	Small-molecule drug	TKI	da Silva et al. [107] Pre-clinical study in a murine model of allergic asthma. Dasatinib attenuated alveolar collapse and contraction index and reduced inflammatory cell influx to the airway, indicating that dasatinib could therefore be used to reduce the remodelling process.

AHR: airway hyperresponsiveness; ASM: airway smooth muscle; COPD: chronic obstructive pulmonary disease; CT: computed tomography; CysLT: cysteinyl leukotriene; ECM: extracellular matrix; F_ENO: fractional exhaled nitric oxide; ICS: inhaled corticosteroid; IgE: immunoglobulin E; IL: interleukin; IL-4R: IL-4 receptor; LTE₄: leukotriene E₄; MMP: matrix metalloproteinase; NA: not applicable; OCS: oral corticosteroid; PDE₄: phosphodiesterase-4 inhibitor; PGD₂: prostaglandin D₂; TKI: tyrosine kinase inhibitor; TSLP: thymic stromal lymphopoietin. ^#: non-asthma indication.