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

Figures & data

Figure 1 Model of GR transactivation and transrepression of genes, when induced by classical GCs and SEGRAs. SEGRAs have been designed to improve the therapeutic index compared to classical GCs, by preferentially inducing transrepression with negligible transactivating activity.

Abbreviations: GC, glucocorticoid; GR, glucocorticoid receptor; GRE, glucocorticoid response element; SEGRA, selective glucocorticoid receptor agonist; TF, transcription factor; TFRE, transcription factor responsive element.

Figure 2 PRISMA flow diagram for the identification of the studies included in the systematic review concerning the impact of experimental GR agonists for the treatment of asthma.

Abbreviations: GC, glucocorticoid; GR, glucocorticoid receptor; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1 Characteristics of the Clinical Studies Included in the Systematic Review

Study and Year	ClinicalTrials.gov Identifier and/or Company ID	Study Characteristics	Treatment Duration (Days)	Number of Analyzed Patients	Drugs, Doses, and Regimen of Administration	Comparator	Route of Administration	Inhaler Device	Patient Characteristics	Age (Years)	Male (%)	Current Smokers (%)	Smoking History (Pack-Years)	BMI (kg/m^2)	Pre-Bronchodilator FEV1 Predicted (%)	Investigated Outcomes	Jadad Score
Brown et al, 2019^Citation43,Citation44	NCT02479412	Phase IIa, multicenter, randomized, double-blind, 3-period, placebo-controlled, incomplete-block, crossover	15	54	AZD7594 58 μg (q.d.), 250 μg (q.d.), 800 μg (q.d.)	Placebo (q.d.)	Oral inhalation	DPI	Mild to moderate asthmatic (pre-bronchodilator FEV1 ≥40% and ≤90% of predicted, FENO ≥25 ppb)	50.8	82.9	0.0	NA	27.3	≥40.0 and ≤90.0	Lung function, symptom control, PK, PD, and safety	5
Prothon et al, 2019^Citation45,Citation46	NCT02645253	Phase I, single-center, randomized, single-blind, placebo-controlled, sequential-group	20	27	AZD7594 200 μg (q.d.), 400 μg (q.d.), 1600 μg (q.d.)	Placebo (q.d.)	Oral inhalation	DPI	Healthy Japanese subjects (NA)	34.0	100.0	NA	NA	23.1	NA	PK, PD, and safety	3
Melin et al, 2017^Citation47,Citation48	NCT01310322, Study A	Phase I, single-center, partly randomized, open-label, 4-way, crossover	1	13	AZD5423 250 μg, 420 μg, 450 μg, 1200 μg (single dose)	NA	AZD5423 420 μg, 450 μg: oral inhalation, AZD5423 250 μg: IV, AZD5423 1200 μg: PO	Jet nebulizer, hand-held vibrating mesh nebulizer	Healthy subjects (NA) and mild allergic asthmatic (pre-bronchodilator FEV1 ≥70%)	18.0–42.0	100.0	0.0	NA	20.5–28.4	≥70.0	PK and safety	1
Melin et al, 2017^Citation48,Citation49	NCT01635985, Study B	Phase I, single-center, partly randomized, open-label, 6-way, crossover	1	18	AZD5423 250 μg, 332 μg, 405 μg, 456 μg, 523 μg, 1200 μg (single dose)	NA	AZD5423 332 μg, 405 μg, 456 μg, 523 μg: oral inhalation, AZD5423 250 μg: IV, AZD5423 1200 μg: PO	Jet nebulizer, hand-held vibrating mesh nebulizer, approved DPI, new DPI	Healthy subjects (NA)	21.0–40.0	100.0	0.0	NA	19.2–30.0	NA	PK and safety	1
Chen et al, 2017^Citation51,Citation52	NCT02648438	Phase I, single-center, partiy randomized, open-label, 4-period, parallel	1	30	AZD7594 150 μg, 400 μg, 1200 μg	NA	AZD7594 400 μg: oral inhalation, AZD7594 150 μg: IV, AZD7594 1200 μg: PO	Mono-dose DPI, MDI	Healthy subjects (NA)	32.9	100.0	0.0	NA	18.0–30.0	NA	PK and safety	1
Werkström et al, 2016^Citation50	NA, Study A	Single-dose Phase I, single-center, randomized, double-blind, placebo-controlled, escalated-dose	1	59	AZD5423 8.4–2400 μg	Placebo	Oral inhalation	Jet nebulizer	Healthy subjects (NA)	26.0	100.0	NA	NA	24.0	NA	PK, PD, and safety	2
Werkström et al, 2016^Citation50	NA, Study B	Multiple-ascending dose Phase I, randomized, double-blind, placebo-controlled, parallel	14	27	AZD5423 125 μg (q.d.), 375 μg (q.d.), 499 μg (q.d.)	Placebo	Oral inhalation	Jet nebulizer	Healthy subjects (NA)	28.0	100.0	NA	NA	25.0	NA	PK, PD, and safety	2
Werkström et al, 2016^Citation50	NA, Study C	Single- and multiple-ascending dose Phase I, single-center, randomized, double-blind, placebo-controlled, parallel	14	30	AZD5423 50 μg (single-dose), 100 μg (q.d.), 300 μg (q.d.)	Placebo	Oral inhalation	Hand-held vibrating mesh nebulizer	Healthy Japanese subjects (NA)	29.6	100.0	NA	NA	22.2	NA	PK, PD, and safety	2
Leaker et al, 2015^Citation53	NCT00483899, Part B	Phase II, multicenter, randomized, double-blind, placebo-controlled, 3-way, crossover	21	21	GW870086X 1 mg (q.d.), 3 mg (q.d.)	Placebo	Oral inhalation	DPI	Mild asthmatic (pre-bronchodilator FEV1 ≥60% of predicted, FENO ≥25 ppb)	28.0	100.0	NA	NA	24.0	87.0	Lung function, PK, PD, and safety	3
Gauvreau et al, 2015^Citation54,Citation55	NCT01225549	Phase II, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled, 4-way, crossover	7	20	AZD5423 75 μg (q.d.), 300 μg (q.d.), and BUD 200 μg (b.i.d.)	Placebo	Oral inhalation	AZD5423: vibrating mesh nebulizer I-neb^®, BUD: DPI (Turbuhaler^®)	Mild atopic asthmatic (pre-bronchodilator FEV1 ≥70% of predicted, NA)	29.6	55.0	0.0	NA	NA	92.1	Lung function, PD, and safety	4
Bareille et al, 2013^Citation56,Citation57	NCT00945932	Phase II, multicenter, randomized, double-blind, placebo-controlled, 2-way crossover	28	36	GW870086X 1 mg (q.d.)	Placebo	Oral inhalation	DPI (Diskhaler^®)	Mild to moderate asthmatic (pre-bronchodilator FEV1 ≥40% and ≤85% of predicted)	49.0	56.0	0.0	≤10.0	26.0	73.7	Lung function, and safety	4
Allen et al, 2013^Citation58,Citation59	NCT01160003, SIG113209	Dose-ascending, Phase I, single-center, randomized, double-blind, placebo-controlled, 3-way crossover	14	12	GW870086X 5 mg (q.d.), 8.75 mg (q.d.)	Placebo	Oral inhalation	Nebulizer (NA)	Healthy subjects (NA)	54.0	100.0	0.0	>5.0	24.5	NA	PK, PD, and safety	3
Bareille et al, 2013^Citation60,Citation63	NCT01245426, SIG114749	Phase II, multicenter, randomized, double-blind, placebo-controlled, parallel	27	135	GW870086X 2 mg (q.d.), 4 mg (q.d.), 3 mg (q.d. added at interim)	Placebo	Oral inhalation	NA	Persistent asthmatic (pre-bronchodilator FEV1 ≥60% and <85% of predicted)	43.5	80.7	0.0	≤10.0	25.4	NA	Lung function, and safety	5
Bareille et al, 2013^Citation61,Citation64	NCT00857857, SIG110762	Phase IIa, multicenter, randomized, double-blind, placebo- and active-controlled, incomplete block, 3-way crossover	13	24	GW870086X 0.25 mg (q.d.), 1 mg (q.d.), 3 mg (q.d.), and FP 0.25 mg (b.i.d.)	Placebo	Oral inhalation	DPI	Mild asthmatic (pre-bronchodilator FEV1 >65% of predicted)	39.4	100.0	0.0	≤10.0	NA	>65.0	Lung function, PD, and safety	5
Boulet et al, 2009^Citation62	NA	Dose-ascending, Phase I, multicenter, randomized, double-blind, escalated-dose	21	26	TPI 1020 600 μg (b.i.d. for 2 weeks), 1200 μg (b.i.d. for 1 week), BUD 400 μg (b.i.d. for 2 weeks), 800 μg (b.i.d. for 1 week)	NA	Oral inhalation	DPI	Mild asthmatic (pre-bronchodilator FEV1 ≥75% of predicted)	34.4	51.9	100.0	10.8	NA	85.3	PK, PD, and safety	3

Abbreviations: b.i.d., twice daily; BMI, body mass index; BUD, budesonide; DPI, dry powder inhaler; F_ENO, fraction exhaled of nitric oxide; FEV_1, forced expiratory volume in 1 second; FP, fluticasone propionate; IV, intravenous administration; MDI, metered-dose inhaler; NA, not available; PD, pharmacodynamics; pMDI, pressurized metered-dose inhaler; PO, oral administration; PK, pharmacokinetics; ppb, parts per billion; q.d., once daily.

Figure 3 Weighted plot for the assessment of the overall risk of bias via the Cochrane RoB 2 tool (n=15 RCTs).

Abbreviation: RCT, randomized controlled trial.

Figure 4 Traffic light plot for assessing the specific risk of bias of each RCT via the Cochrane RoB 2 tool. D1: bias arising from the randomization process; D2: bias due to deviations from intended intervention; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result. Red circle indicates high risk of bias, yellow circle indicates some concerns on the risk of bias, green circle represents low risk of bias, and blue circle refers to lack of information due to limited data results available on Clinicaltrials.gov database.

Abbreviations: RCT, randomized controlled trial; RoB, Risk of Bias.

Table 2 Main PK Characteristics of Investigational GR Agonists for the Treatment of Asthma

Medication	Dose	Route of Administration and Inhaler Device	Cmax (pg/mL)	tmax (h)	t1/2 (h)	AUC (nmol*h/L)	AUC0–t (nmol*h/L)	AUC0–24 (nmol*h/L)	AUC0–∞ (nmol*h/L)	CL/F (L/h)	Vd (L)
GW870086X	1 mg (repeat dose)	Via inhalation, DPI	198.0	0.08	NA	NA	NA	2.4	NA	NA	NA
	3 mg (repeat dose)	Via inhalation, DPI	440.0	2.5	18.6	NA	NA	NA	NA	NA	NA
	3 mg (single and repeat dose)	Via inhalation, DPI	207.0	4.5	NA	NA	NA	6.9	NA	NA	NA
	5 mg	Via inhalation, jet nebulizer	1212.0	0.4	25.0	NA	NA	10.7	NA	NA	NA
	6 mg (repeat dose)	Via inhalation, DPI	NA	0.8–3.5	22.7	47.71	NA	NA	NA	NA	NA
	8.75 mg	Via inhalation, jet nebulizer	2073.0	0.3	29.6	NA	NA	24.2	NA	NA	NA
	12 mg (single and repeat dose)	Via inhalation, DPI	NA	0.8–3.5	22.7	47.71	NA	NA	NA	NA	NA
	15 mg (single and repeat dose)		NA	0.8–3.5	22.7	47.71	NA	NA	NA	NA	NA
AZD5423	100 μg	Via inhalation, hand-held vibrating mesh nebulizer	2417.7	0.1	62.5*	NA	NA	4.3**	NA	67.5	NA
	125 μg	Via inhalation, jet nebulizer	1803.6	0.08	51.3*	NA	NA	4.3**	NA	91.6	NA
	250 μg	IV	5166.9	0.4	25.0	10.9	10.4	NA	NA	47.2	1700.0*
			6531.8	0.4	30.7	13.5	12.8	NA	NA	NA	NA
	300 μg	Via inhalation, hand-held vibrating mesh nebulizer	5410.7	0.08	65.0*	NA	NA	10.1**	NA	85.1	NA
	332 μg	Via inhalation, DPI	1798.7	0.2	25.5	8.5	8.0	NA	NA	NA	NA
	375 μg	Via inhalation, jet nebulizer	8091.6	0.1	95.1*	NA	NA	15.6**	NA	75.8	NA
	405 μg	Via inhalation, hand-held vibrating mesh nebulizer	1150.4	0.3	17.9	6.2	5.9	NA	NA	NA	NA
	420 μg		1603.7	0.2	21.4	4.5	4.3	NA	NA	NA	NA
	450 μg	Via inhalation, jet nebulizer	3850.8	0.2	11.5	9.0	8.9	NA	NA	NA	NA
	456 μg	Via inhalation, DPI	1438.0	0.2	21.5	8.1	7.7	NA	NA	NA	NA
	499 μg	Via inhalation, jet nebulizer	7019.2	0.1	58.2*	NA	NA	17.9**	NA	88.1	NA
	523 μg		1969.3	0.3	26.6	10.9	10.4	NA	NA	NA	NA
	1200 μg	PO	409.9	0.8	4.00	1.6	1.7	NA	NA	NA	NA
			293.9	1.5	13.0	2.9	2.5	NA	NA	NA	NA
TPI 1020	600 μg	Via inhalation, DPI	95.2	3.0	NA	342.6	NA	NA	NA	NA	NA
AZD7594	58 μg	Via inhalation, DPI	36.4	0.25	NA	NA	0.467	0.467	NA	NA	NA
	150 μg	IV	6598.0	NA	1.8–9.2	NA	3.34	NA	6.19	NA	NA
	200 μg (single dose)	Via inhalation, DPI	56.1	0.25	39.9*	NA	1.314	2.426	NA	NA	NA
	250 μg	Via inhalation, DPI	92.0	0.25	NA	NA	1.728	1.725	NA	NA	NA
	400 μg (single dose)	Via inhalation, DPI	76.9	0.52	NA	NA	2.736	4.409	NA	NA	NA
	400 μg (repeat dose)	Via inhalation, DPI	NA	NA	NA	NA	NA	2.426	NA	NA	NA
	400 μg (single dose)	Via inhalation, DPI	112.6	NA	NA	NA	2.524	NA	NA	NA	NA
		Via inhalation, DPI	68.9	NA	NA	NA	2.648	NA	NA	NA	NA
		Via inhalation, pMDI	13.9	NA	NA	NA	0.04293	NA	NA	NA	NA
	800 μg	Via inhalation, DPI	169.7	0.25	NA	NA	4.897	4.894	NA	NA	NA
	1200 μg	PO	19.3	NA	NA	NA	0.110	NA	NA	NA	NA
	1600 μg (single dose)	Via inhalation, DPI	430.8	0.50	43.6*	NA	13.96	NA	32.63	144.5	NA
	1600 μg (repeat dose)	Via inhalation, DPI	NA	NA	NA	NA	NA	20.830	NA	NA	NA

Notes: *PK parameter associated with the terminal slope of a semi-logarithmic concentration–time curve; **PK parameter evaluated at steady state.

Abbreviations: AUC, area under the curve; AUC_0–t, area under the plasma concentration–time curve up to the last measurable concentration; AUC_0–24, area under the plasma concentration–time curve extrapolated from 0 to 24 hours; AUC_0–∞, area under the plasma concentration–time curve extrapolated to infinity; C_max, peak plasma concentration; CL/F, apparent total body clearance; DPI, dry powder inhaler; GR, glucocorticoid receptor; IV, intravenous; NA, not available; PK, pharmacokinetics; pMDI, pressurized metered-dose inhaler; PO, oral administration; t_max, time to peak concentration; t_1/2, half-life; V_d, volume of distribution.

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