Experimental Glucocorticoid Receptor Agonists for the Treatment of Asthma: A Systematic Review

Abstract

Inhaled corticosteroids (ICSs) are considered the cornerstone of asthma treatment. Despite the solid evidence documenting the efficacy and safety of ICSs at the level of the airways, their use can be affected by pulmonary and systemic adverse events (AEs) when administered chronically and/or at high doses. Thus, there is a pharmacological and medical need for new glucocorticoid (GC) receptor (GR) ligands with a more favorable therapeutic index, in order to overcome the shortcomings of currently available ICSs. The therapeutic profile of GCs can be improved by enhancing genomic mechanisms mediated by transrepression, which is assumed to be responsible for several anti-inflammatory and immunomodulatory actions, rather than transactivation, which causes most of the GC-associated AEs. It was assumed that an independent modulation of the molecular mechanisms underlying transactivation and transrepression could translate into the dissociation of beneficial effects from AEs. Therefore, current research is looking for GCs that are able to elicit prevalently transrepression with negligible transactivating activity. These compounds are known as selective glucocorticoid receptor agonists (SEGRAs). In this review, experimental GR agonists currently in pre-clinical and clinical development for the treatment of asthma have been systematically assessed. Several compounds are currently under pre-clinical development, but only three novel experimental GR agonists (GW870086X, AZD5423, AZD7594) seem to have some potential therapeutic relevance and have entered clinical trials for the treatment of asthma. Since data from pre-clinical studies have not always been confirmed in clinical investigations, well-designed randomized controlled trials are needed in asthmatic patients to confirm the potentially positive benefit/risk ratio of each specific SEGRA and to optimize the development strategy of these agents in respiratory medicine.

Keywords:

• asthma
• glucocorticoid agonists
• SEGRA
• efficacy
• safety

Abbreviations

AE, adverse event; AHR, airway hyperresponsiveness; ASM, airway smooth muscle; BALf, bronchoalveolar lavage fluid; BUD, budesonide; CCL2, C-C motif ligand 2; CCL5, C-C motif ligand 5 (also known as RANTES); C_max, maximum drug concentration; CXCL8, C-X-C motif ligand 8 (also known as IL-8); CXCL10, C-X-C motif ligand 10; DEX, dexamethasone; DPI, dry powder inhaler; DUSP1, dual-specificity phosphatase-1 (also known as mitogen-activated protein kinase phosphatase-1 [MKP1]); EAR, early asthmatic response; E_max, maximal response of efficacy; F_ENO, fraction exhaled of nitric oxide; FEV₁, forced expiratory volume in 1 second; FF, fluticasone furoate; FP, fluticasone propionate; GC, glucocorticoid; GM-CSF, granulocyte–macrophage colony-stimulating factor; GR, glucocorticoid receptor; GRE, glucocorticoid response element; ICS, inhaled corticosteroid; IFN-γ, interferon gamma; IL, interleukin; IRF-1, interferon regulatory factor-1; IV, intravenous administration; LABA, long-acting β₂-adrenoceptor agonist; LAR, late asthmatic response; LPS, lipopolysaccharide; MD, mean difference; MMTV, mouse mammary tumor virus; MOM, mometasone; NF-κB, nuclear factor-kappa B; NO, nitric oxide; PD, pharmacodynamics; PEF, peak expiratory flow; PICO, patient problem, intervention, comparison, and outcome; PK, pharmacokinetics; pMDI, pressurized metered-dose inhaler; PO, per os; PR, progesterone receptor; PRISMA-P, preferred reporting items for systematic reviews and meta-analyses protocols; RANTES, regulated on T-cell activation, normal T-cell expressed and secreted; RCT, randomized controlled trial; RGS2, regulator of G protein signaling 2; RoB2, Risk of Bias 2; SAE, serious adverse event; SAL, salbutamol; SEGRA, selective glucocorticoid receptor agonist; SEGRM, selective glucocorticoid receptor modulator; t_1/2, half-life; t_max, time to reach C_max; TNF-α, tumor necrosis factor-alpha; TSC22D3, TSC22 domain family member 3 (also known as glucocorticoid-induced leucine zipper).

Disclosure

PR reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, personal fees from AstraZeneca, grants and personal fees from Chiesi Farmaceutici, grants and personal fees from Almirall, grants from Zambon, personal fees from Biofutura, personal fees from GlaxoSmithKline, personal fees from Menarini, and personal fees from Mundipharma. MC has participated as a faculty member and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi Farmaceutici, GlaxoSmithKline, Menarini Group, Lallemand, Mundipharma, Novartis, Pfizer, Verona Pharma, and Zambon; is or has been a consultant to ABC Farmaceutici, AstraZeneca, Chiesi Farmaceutici, Edmond Pharma, Lallemand, Novartis, Ockham Biotech, Verona Pharma, and Zambon, and his department was funded by Almirall.

LC reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, nonfinancial support from AstraZeneca, grants from Chiesi Farmaceutici, grants from Almirall, personal fees from ABC Farmaceutici, personal fees from Edmond Pharma, grants and personal fees from Zambon, personal fees from Verona Pharma, and personal fees from Ockham Biotech. The authors report no other conflicts of interest in this work.