Riociguat: a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension

Figures & data

Figure 1 Generation of NO.

Notes: Reprinted with permission from the American Thoracic Society. Copyright © 2016 American Thoracic Society. Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188(6):639–646.¹⁰ The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
Abbreviations: ADMA, asymmetric dimethylarginine; ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; DDAH, dimethylarginine dimethylaminohydrolase; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; O₂⁻, superoxide anion.

Figure 2 The NO–sGC–cGMP pathway.

Notes: Reprinted with permission from Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263–2273.¹¹ http://circ.ahajournals.org/. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer. Please contact [email protected] for further information.¹¹

Abbreviations: ADMA, asymmetric dimethylarginine; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; GMP, guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; PDE, phosphodiesterase; PKG, cGMP-dependent protein kinase; sGC, soluble guanylate cyclase.

Figure 3 The dual mode of action of riociguat.

Notes: Reprinted from Chest, 151(2), Ghofrani HA, Humbert M, Langleben D, et al, Riociguat: mode of action and clinical development in pulmonary hypertension, 468–480, Copyright (2017), with permission from Elsevier.²⁶
Abbreviations: cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; sGC, soluble guanylate cyclase.

Table 1 PK parameters of riociguat in plasma following single-dose administration of 2.5 mg and 1 mg riociguat

Parameter	Riociguat 1 mg (n=5)			Riociguat 2.5 mg (n=10)
	Geometric mean	CV%	Range	Geometric mean	CV%	Range
AUC, μg·h/L	602.3	14.9	456.5–749.6	1,411	39.2	597.5–3,121
Cmax, μg/L	59.43	5.9	53.49–65.05	119.4	16.1	74.69–172.4
tmax, h	0.75a		0.500–1.500	0.500a		0.250–1.500
t1/2, h	9.953	8.6	8.737–12.14	11.65	38.6	4.680–28.58
Vz/F, L/kg	0.354	73	0.307–0.393	0.378	20.7	0.005–0.609
CL/F, L/h	1.660	14.9	1.334–2.191	1.771	39.2	0.801–4.184

Notes: Subjects valid for PK and pharmacodynamic analysis. This material has not been reviewed prior to release; therefore the European Respiratory Society may not be responsible for any errors, omissions or inaccuracies, or for any consequences arising there from, in the content. Reproduced with permission of the European Respiratory Society ©. European Respiratory Journal. 2009;33(4):785–792. DOI: 10.1183/09031936.00039808.³⁶

a Median.

Abbreviations: AUC, area under the plasma concentration–time curve; C_max, maximum plasma concentration; CL/F, apparent total clearance of the drug from plasma; CV, coefficient of variation; PK, pharmacokinetic; t_max, time to reach C_max; t_1/2, terminal half-life; Vz/F, apparent volume of distribution during the terminal phase.

Table 2 Changes in selected parameters in the CHEST-1 study

Parameter	Riociguat		Placebo		Placebo-corrected LS mean difference	P-value, riociguat vs placebo
	Baseline	Mean change from baseline	Baseline	Mean change from baseline
PVR, dyn·s·cm^−5	791	−226	779	+23	−246	<0.001
mPAP, mmHg	45	−4	44	+0.8	−4	<0.001
CO, L/min	4	+0.8	4	−0.03	+0.9	<0.001
NT-proBNP, ng/L	1,508	−291	1,706	+76	−444	<0.001
WHO FCa
I/II/III/IV (%)	2/32/62/5	–	0/29/69/2	–	–
Improved/unchanged/worsened (%)	–	33/62/5	–	15/78/7	–	0.003
Borg dyspnea score	4	−0.8	4	+0.2	–	0.004

Notes: Baseline values are mean values. From N Engl J Med, Ghofrani HA, D’Armini AM, Grimminger F, et al; CHEST-1 Study Group, Riociguat for the treatment of chronic thromboembolic pulmonary hypertension, 369(4):319–329.⁷ Copyright © (2013) Massachusetts Medical Society. Reprinted with permission from the Massachusetts Medical Society.

a WHO FC data show percentages of patients in class I/II/III/IV and baseline, and percentages improved/unchanged/worsened at the end of Week 16.

Abbreviations: CO, cardiac output; FC, functional class; LS, least squares; mPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal pro-brain natriuretic peptide; PVR, pulmonary vascular resistance; WHO, World Health Organization.

Figure 4 Mean change in 6MWD in the CHEST-1 study.

Notes: Last visit – last observed value (not including follow-up) for patients who completed the study or withdrew, except imputed worst value (0) in case of death or clinical worsening without a termination visit or a measurement at that termination visit. From N Engl J Med, Ghofrani HA, D’Armini AM, Grimminger F, et al; CHEST-1 Study Group, Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. 369(4):319–329.⁷ Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from the Massachusetts Medical Society.
Abbreviations: 6MWD, 6-minute walking distance; CI, confidence interval.

Table 3 Changes in selected parameters in the PATENT-1 study

Parameter	Riociguat		Placebo		Placebo-corrected LS mean difference	P-value, riociguat vs placebo
	Baseline	Mean change from baseline	Baseline	Mean change from baseline
PVR, dyn·s·cm^−5					−226	<0.001
mPAP, mmHg	47	−4	49	−0.5	−4	<0.001
CO, L/min	4	+1	4	−0.01	+0.9	<0.001
NT-proBNP, ng/L	1,027	−198	1,228	+232	−432	<0.001
WHO FCa
I/II/III/IV (%)	2/43/55/0.4	–	3/48/46/2	–	–
Improved/unchanged/worsened (%)	–	21/76/4	–	14/71/14	–	0.003
Borg dyspnea score	4	−0.4	3.9	+0.1	–	0.002

Notes: Baseline values are mean values. From N Engl J Med, Ghofrani HA, Galiè N, Grimminger F, et al, Riociguat for the treatment of pulmonary arterial hypertension, 369(4):330–340.⁴⁵ Copyright © (2013) Massachusetts Medical Society. Reprinted with permission from the Massachusetts Medical Society.

a WHO FC data show percentages of patients in class I/II/III/IV and baseline, and percentages improved/unchanged/worsened at the end of Week 12.

Abbreviations: CO, cardiac output; FC, functional class; LS, least squares; mPAP, mean pulmonary artery pressure; NT-proBNP, N-terminal pro-brain natriuretic peptide; PVR, pulmonary vascular resistance; WHO, World Health Organization.

Figure 5 Change from baseline in 6MWD in PATENT-1 and PATENT-2.

Notes: Note that “12 weeks” in PATENT-2 represents 24 weeks of treatment: treatment was continuous from PATENT-1 to PATENT-2. Reproduced with permission of the European Respiratory Society ©: European Respiratory Journal. 2015;45(5):1303–1313. DOI: 10.1183/09031936.00090614.⁴⁷
Abbreviation: 6MWD, 6-minute walking distance.

Table 4 Incidences of most common AEs with riociguat therapy in the CHEST-2⁵¹ and PATENT-2⁵⁷ studies

AE, n (%)	CHEST-2 (n=237)	PATENT-2 (n=396)
Any AE	233 (98)	388 (98)
AEs in ≥15% of patients in either study
Nasopharyngitis	67 (28)	118 (30)
Peripheral edema	55 (23)	98 (25)
Dizziness	52 (22)	101 (26)
Diarrhea	43 (18)	84 (21)
Cough	37 (16)	88 (22)
Headache	35 (15)a	82 (21)
Dyspnea	35 (15)a	64 (16)
Upper respiratory tract infection	33 (14)a	64 (16)
Nausea	30 (13)a	76 (19)
Dyspepsia	26 (11)a	54 (14)a
Vomiting	20 (8)a	67 (17)
AEs of special interest in >5% of patients in either study
Syncope	23 (10)	38 (10)
Hypotensionb	18 (8)	51 (13)
Other AEs of interest
Hemoptysis/pulmonary hemorrhage	13 (5)	30 (8)
Drug-related AEs	114 (48)	232 (59)
Serious AEs	129 (54)	238 (60)
Syncope	23 (10)	38 (10)
Hemoptysis/pulmonary hemorrhage	4 (2)	13 (3)
Discontinuation due to AE	14 (6)	45 (11)

Notes:

a Bayer AG, data on file.

b Judged by the investigator based on patient symptoms.

Abbreviation: AE, adverse event.

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