Pulmonary Arterial Hypertension (PAH)


There are currently 5 clinical groups of pulmonary hypertension (PH), and these groups are defined based on the etiology, symptoms, and therapeutic approaches.1 Current therapeutic approaches that tackle PH are approved for patients with pulmonary arterial hypertension (PAH; Group 1) and chronic thromboembolic pulmonary hypertension (CTEPH; Group 4).2

Pulmonary arterial hypertension is a rare disorder characterized by elevated blood pressure in the pulmonary arteries.3 Patients with PAH experience progressive remodeling and degeneration of the pulmonary vessels, which results in an increase in pulmonary vascular resistance that leads to pulmonary vascular overload with right heart failure and death.4-6 CTEPH is a rare condition of PH in which the pulmonary vasculature is obstructed by pulmonary emboli. The primary treatment for patients with CTEPH is pulmonary endarterectomy (PEA); however, not all patients are eligible for this surgery, and the procedure does not result in a cure for many of these patients.4

Drug development in PH has focused on 3 different pathways: nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP), endothelin signaling, and prostacyclin signaling.2 The NO-sGC-cGMP pathway is involved in the regulation of vascular tone, causing vasodilation, vasoconstriction, inflammation, and/or cellular remodeling depending on its stimulation or on NO deficiency.7 sGC stimulators allow the blood vessels in the lungs to relax by promoting an increase in cGMP, independent of NO levels.7,8 This cGMP increase occurs by direct stimulation of the sGC enzyme and through promotion of sGC and NO interaction.8 Riociguat and vericiguat are two representatives of the sGC stimulator group.

Adempas (riociguat)

Adempas (riociguat is an sGC stimulator currently approved by US Food and Drug Administration (FDA) for the treatment of PAH and inoperable persistent/recurrent CTEPH. It is also approved for use after the surgical treatment of CTEPH. Riociguat is commercialized as Adempas® and is indicated for improving exercise capacity and delaying clinical worsening of disease.9

Riociguat directly stimulates sGC, even in conditions of NO deficiency, and stabilizes the NO-sGC complex, which increases cGMP bioavailability.4 Phase 1 to 3 clinical trials have been performed with riociguat.10-12 The phase 3 clinical trial, PATENT-1,13 was a randomized, double-blinded trial that assessed the efficacy of riociguat compared to that of a placebo in PAH.12 This study enrolled 443 participants with symptomatic PAH and was conducted over the course of 12 weeks. Results of the study showed that participants administered riociguat at 2.5 mg had an improved exercise capacity as evaluated by the 6-minute walk distance (6MWD), similar to participants who were receiving additional medications for the disease such as prostanoids.4 Many of the patients who completed the PATENT-1 study were enrolled in an open-label extension of the trial, PATENT-2.14 After 2 years of treatment, both the safety and tolerability of riociguat were determined following the observation of adverse events reported for the 307 participants of the study. An improvement in 6MWD was also registered, along with improvements in EuroQol Group 5-Dimension (EQ-5D) self-report questionnaire score and Borg dyspnea score.15 

The efficacy of riociguat in patients with CTEPH was assessed in a trial, CHEST-1,16 which was conducted over 16 weeks and included 261 participants with inoperable or persistent/recurrent PF after PEA.17 This randomized, double-blinded, multicenter trial reported an improved exercise capacity at the end of 16 weeks, which was more pronounced in participants with inoperable disease than in those who had previously undergone surgery. The most common adverse event was syncope, observed in 2% of the participants.17

Get full prescribing information for Adempas at MPR

Verquvo (vericiguat)

Verquvo (vericiguat) is an sGC stimulator developed with the aim of increasing the half-life observed in riociguat.18 Vericiguat is indicated to reduce the risks of cardiovascular death and heart failure (HF) following hospitalization for HF or the need for outpatient intravenous diuretics in adults with symptomatic chronic HF and a reduced ejection fraction (EF) of less than 45%. Heart failure is linked with a decrease in sGC enzymatic activity and NO deficiency. By direct sGC stimulation, vericiguat leads to an increase in cGMP and consequently to vessel relaxation and vasodilation.19

The safety and tolerability of vericiguat in HF has been assessed in different clinical trials.18 Approval by the FDA was granted in 2021 following the results of the VICTORIA phase 3 study,20 which compared the addition of this drug or a placebo to guideline-recommended medical therapy in patients with symptomatic chronic HF with an EF lower than 45%.21 The VICTORIA trial included 5050 patients and reported decreased incidences of death from cardiovascular causes and first hospitalization for HF.18 

A new phase 3 trial, VICTOR (NCT05093933), is currently recruiting to study vericiguat in patients with chronic HF and an EF of up to 40%.22

Get full prescribing information for Vercuvo at MPR

References

1. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. doi:10.1183/13993003.01913-2018

2. Sommer N, Ghofrani HA, Pak O, et al. Current and future treatments of pulmonary arterial hypertension. Br J Pharmacol. 2021;178(1):6-30. doi:10.1111/bph.15016

3. Pulmonary arterial hypertension. National Organization for Rare Disorders (NORD). Accessed May 19, 2022. 

4. Boutou AK, Pitsiou G. Treatment of pulmonary hypertension with riociguat: a review of current evidence and future perspectives. Expert Opin Pharmacother. 2020;21(10):1145-1155. doi:10.1080/14656566.2020.1727446

5. Hassoun PM. Pulmonary arterial hypertension. N Engl J Med. 2021;385(25):2361-2376. doi:10.1056/NEJMra2000348

6. Gladwin MT, Levine AR. Pulmonary hypertension. MSD Manual Professional Version. Updated September 2020. Accessed March 19, 2022.

7. Misselwitz F. The clinical development of sGC modulators, riociguat and vericiguat. BMC Pharmacol Toxicol. 2015;16(Suppl 1):A2. doi:10.1186/2050-6511-16-S1-A2

8. Parikh V, Bhardwaj A, Nair A. Pharmacotherapy for pulmonary arterial hypertension. J Thorac Dis. 2019;11(Suppl 14):S1767-S1781. doi:10.21037/jtd.2019.09.14

9. Adempas. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2021. Accessed May 19, 2022.

10. Frey R, Mück W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G. Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. J Clin Pharmacol. 2008;48(8):926-934. doi:10.1177/0091270008319793

11. Grimminger F, Weimann G, Frey R, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009;33(4):785-792. doi:10.1183/09031936.00039808

12. Ghofrani HA, Galiè N, Grimminger F, et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340. doi:10.1056/NEJMoa1209655

13. A study to evaluate efficacy and safety of oral BAY63-2521 in patients with pulmonary arterial hypertension (PAH) (PATENT-1). ClinicalTrials.gov. December 18, 2008. Updated November 28, 2016. Accessed May 19, 2022.

14. BAY63-2521:long-term extension study in patients with pulmonary arterial hypertension (PATENT-2). ClinicalTrials.gov. March 18, 2009. Updated October 22, 2020. Accessed May 19, 2022.

15. Ghofrani HA, Grimminger F, Grünig E, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016;4(5):361-371. doi:10.1016/S2213-2600(16)30019-4

16. A study to evaluate efficacy and safety of oral BAY63-2521 in patients with CTEPH. (CHEST-1). ClinicalTrials.gov. March 4, 2009. Updated November 28, 2016. Accessed May 19, 2022.

17. Ghofrani HA, D’Armini AM, Grimminger F, et al; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-329. doi:10.1056/NEJMoa1209657

18. Xia J, Hui N, Tian L, et al. Development of vericiguat: the first soluble guanylate cyclase (sGC) stimulator launched for heart failure with reduced ejection fraction (HFrEF). Biomed Pharmacother. 2022;149:112894. doi:10.1016/j.biopha.2022.112894

19. Verquvo. Prescribing information. Merck & Co, Inc; 2022. Accessed May 19, 2022.

20. A study of vericiguat in participants with heart failure with reduced ejection fraction (HFrEF) (MK-1242-001) (VICTORIA). ClinicalTrials.gov. August 10, 2016. Updated November 15, 2021. Accessed May 19, 2022.

21. Armstrong PW, Roessig L, Patel MJ, et al. A multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator: the VICTORIA trial. JACC Heart Fail. 2018;6(2):96-104. doi:10.1016/j.jchf.2017.08.013

22. A study of vericiguat (MK-1242) in participants with chronic heart failure with reduced ejection fraction (HFrEF) (MK-1242-035) (VICTOR). ClinicalTrials.gov. October 26, 2021. Updated May 13, 2022. Accessed May 19, 2022.

Reviewed by Harshi Dhingra, MD, on 5/29/2022.