The soluble guanylate cyclase stimulator riociguat : Evidence in pulmonary hypertension and beyond

The soluble guanylate cyclase stimulator riociguat: Evidence in pulmonary hypertension and beyond Raymond Benza1*, Amresh Raina2, Manreet K. Kanwar3, Steven D. Nathan4, Stephen C. Mathai5 1Advanced Heart Failure, Transplant, Mechanical Circulatory Support and Pulmonary Hypertension Section, Allegheny Health Network, Pittsburgh, PA, USA 2Pulmonary Hypertension Program, Allegheny Health Network, Pittsburgh, PA, USA 3Chronic Thromboembolic Pulmonary Hypertension Program, Allegheny Health Network, Pittsburgh, PA, USA 4Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, Vienna, VA, USA 5Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care Medicine, Baltimore, MD, USA


Introduction
Pulmonary hypertension (PH) is a broad term encompassing a variety of disorders, defined by a mean pulmonary artery pressure (mPAP) ≥25 mmHg 1 .PH can lead to right ventricular dysfunction and failure and can eventually be fatal 2,3 .Globally, the prevalence of PH is estimated at approximately 1% of the population 4 .Based on etiology, PH is classified into five World Health Organization (WHO) groups 5 : Group 1: Pulmonary arterial hypertension (PAH), a category that contains several disorders/ subgroups, including idiopathic PAH, heritable PAH, and PAH associated with certain conditions such as connective tissue diseases (e.g.diffuse cutaneous systemic sclerosis (dcSSc)), congenital heart disease (CHD), and human immunodeficiency virus infection.The definition of PAH includes pulmonary vascular resistance (PVR) >3 Wood units (240 dyn•s•cm -5 ) and pulmonary capillary wedge pressure ≤15 mmHg 2 Group 2: Left-heart-related PH Group 3: Lung-/hypoxia-related PH Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH) Group 5: PH with unclear/multifactorial etiology.
PH in developing countries is often associated with CHD or infectious disease 4 .There has been a significant amount of recent research and drug development concentrated on PAH and CTEPH, which are both considered rare diseases and may share similar pathology 4,6,7 .
Riociguat (BAY-63-2521; Bayer AG, Wuppertal, Germany) is a soluble guanylate cyclase (sGC) stimulator approved for the treatment of PAH and inoperable or persistent/recurrent CTEPH.Currently, it is the only approved medical therapy for inoperable and persistent/ recurrent CTEPH 8 .sGC stimulators are a novel class of therapeutics with vasodilatory, anti-inflammatory, antiproliferative, and anti-fibrotic effects in various in vitro and in vivo models [9][10][11] .These diverse actions mean that sGC stimulators have the potential to treat many other diseases, including heart failure (HF), systemic sclerosis, and cystic fibrosis.This review discusses the clinical evidence for riociguat and another sGC stimulator, vericiguat (BAY 1021189; Bayer AG).Results are summarized in Table 1.

The NO-sGC-cGMP pathway
sGC is a key enzyme in the nitric oxide (NO) signaling pathway, which plays many roles in the control of the vascular system including regulation of vascular tone, inhibition of vascular smooth muscle cell proliferation, and protection against inflammation 9,10 .Impaired functioning of this system has been implicated in PH, coronary artery disease, peripheral vascular disease, and atherosclerosis 9,10 .NO from vascular endothelial cells binds with sGC, which catalyzes the synthesis of the secondary messenger cyclic guanosine monophosphate (cGMP), and the pharmacologic effects of sGC stimulators result from their action to enhance cGMP synthesis 12 .cGMP, once produced, has multiple effects, mostly mediated through activation of protein kinase G. Activation of this kinase ultimately leads to vasodilation via activation of myosin phosphatase that releases calcium from smooth muscle cells.In addition, the NO-sGC-cGMP pathway mediates many physiologic functions including regulation of cell proliferation, platelet aggregation, and fibrosis 13,14 .Depletion of NO leads to a variety of abnormalities including pulmonary vasoconstriction, vascular remodeling, and in situ thrombosis.Reduction in endogenous NO levels has been observed in several types of PH 9 .sGC stimulators have a dual mode of action; specifically, they enhance the sGC response to endogenous NO and also directly stimulate sGC independent of NO via a different binding site, leading to elevation of cGMP (Figure 1) 8,12 .This differs from phosphodiesterase type 5 (PDE5) inhibitors (another PAH-approved drug class), which prevent the breakdown of cGMP by occupying the catalytic site on PDE5.However, PDE5 inhibitors are dependent on cGMP synthesis and the presence of NO, a requirement that sGC stimulators circumvent 15 .Riociguat increases sGC activity by up to 112fold 16 .

Riociguat in PAH and CTEPH
Riociguat was investigated in PATENT-1, a 12-week, double-blind, placebo-controlled trial in 443 patients with symptomatic PAH (ClinicalTrials.gov:NCT00810693).Patients received either placebo or riociguat (individually optimized doses up to 2.5 mg three times daily (tid)).Riociguat significantly improved 6-minute walking distance (6MWD) (primary endpoint), PVR, N-terminal pro-brain natriuretic peptide (NT-proBNP), WHO functional class, and time to clinical worsening (secondary endpoints) compared with placebo in patients who were receiving no other treatment for the disease and those receiving endothelin-receptor antagonists (ERAs) or prostanoids 17 .In the open-label extension of this trial (PATENT-2; ClinicalTrials.gov:NCT00863681), the improvements in 6MWD, NT-proBNP, and WHO functional class with riociguat were maintained after 2 years, and riociguat was well tolerated as monotherapy or in combination with ERAs, prostanoids, or both 18 .In a subgroup of 35 patients in PATENT-1 with PAH associated with CHD, riociguat improved 6MWD, as well as NT-proBNP, WHO functional class, and PVR, compared with placebo 19 .The long-term outcome of patients in PATENT-1 and PATENT-2 with PH associated with connective tissue disease was similar to that seen in idiopathic PAH 20 .
CTEPH is characterized by obstruction of the pulmonary vasculature, usually as a consequence of unresolved pulmonary embolism 21 .Pulmonary endarterectomy (PEA) is a potentially curative surgery for CTEPH; however, not all patients are eligible and some have persistent and/or recurrent PH after surgery 22 .In addition, CTEPH frequently involves pulmonary small-vessel disease not amenable to PEA 21 .Riociguat was investigated in CHEST-1, a 16-week, double-blind, placebo-controlled trial in 261 patients with CTEPH who were ineligible for PEA or experienced persistent and/or recurrent PH after PEA (ClinicalTrials.gov: NCT00855465).Patients received placebo or riociguat (individual optimized doses up to 2.5 mg tid).Riociguat significantly improved 6MWD (primary endpoint), PVR, NT-proBNP, and WHO functional class compared with placebo 23 .In the open-label extension (CHEST-2; ClinicalTrials.gov: NCT00910429), the improvements in 6MWD, NT-proBNP, and WHO functional class were maintained after 2 years, and riociguat was well tolerated and exhibited a good safety profile 24 .
PDE5 inhibitors are widely used in the treatment of PAH but some patients do not attain treatment goals with these agents.A 24-week, open-label, uncontrolled trial (RESPITE; ClinicalTrials.gov:NCT02007629) has indicated that selected patients with PAH and an unsatisfactory response to PDE5 inhibitors may benefit from switching to riociguat 25 .

Riociguat in other forms of PH Group 2.1: PH associated with HF with reduced ejection fraction
PH resulting from HF with left ventricular systolic dysfunction is associated with high morbidity and mortality, and established therapies do not improve the associated PH 2 .LEPHT, a 16-week, double-blind, placebo-controlled, phase 2b trial in 201 patients with PH associated with HF and left ventricular ejection fraction (LVEF) ≤40%, randomized patients to placebo or riociguat (0.5, 1.0, or 2.0 mg tid (ClinicalTrials.gov:NCT01065454)).There was a non-significant (p=0.1)decrease in mPAP with riociguat 2 mg versus placebo (primary endpoint).PVR was significantly reduced and cardiac index significantly increased with riociguat, which was well tolerated 26 .

Group 2.2: PH associated with HF with preserved ejection fraction
Up to half of patients with HF have preserved LVEF, with most patients developing PH for which there is no proven therapy 2,27 .Reduced cGMP has been observed in these patients 28 , therefore targeting the NO-sGC-cGMP pathway is logical.DILATE-1, a single-dose, double-blind, placebocontrolled, parallel-group, phase 2a trial in 39 patients with PH associated with HF and LVEF >50%, randomized patients to placebo or riociguat (0.5, 1.0, or 2.0 mg) 29 (ClinicalTrials.gov:NCT01172756).The decrease in mPAP from baseline to 6 hours (primary endpoint) did not differ significantly with riociguat 2 mg versus placebo but other hemodynamic endpoints were improved (Table 1) and riociguat was well tolerated 29 .

Group 3.1: PH associated with chronic obstructive pulmonary disease
The prognosis of severe chronic obstructive pulmonary disease (COPD) associated with PH is poor 30 .In a singledose pilot study (ClinicalTrials.gov:NCT00640315) in 22 patients with PH associated with COPD, riociguat (1.0 or 2.5 mg) was associated with significant improvements in mPAP and PVR, and was well tolerated 31 .

Group 3.2: PH associated with interstitial lung disease
Two trials have assessed the effect of riociguat in patients with PH associated with interstitial lung disease (ILD).In an open-label, uncontrolled, pilot study (ClinicalTrials.gov:NCT00694850) in 22 patients, riociguat (1.0−2.5 mg tid) was generally well tolerated, with increases in mean cardiac output and decreases in PVR 32 .However, a phase 2, 26-week, placebo-controlled, double-blind randomized controlled trial in 147 patients with PH associated with idiopathic interstitial pneumonias (PH-IIP)-a distinct subset of ILD-(RISE-IIP; ClinicalTrials.gov:NCT02138825) was halted early (after a mean treatment duration 121±66 days) due to an excess of deaths and serious adverse events with riociguat compared with placebo as well as a lack of efficacy 33 .Riociguat is therefore contraindicated in PH-IIP 34,35 .

Diffuse cutaneous systemic sclerosis
DcSSc is a rare but incapacitating and life-threatening form of systemic sclerosis characterized by progressive fibrosis of the skin and internal organs resulting from deposition of extracellular matrix [36][37][38] .DcSSc is characterized by early-onset organ involvement and a mortality of almost 50% at 10 years 39 .Leading causes of death in patients with systemic sclerosis include pulmonary fibrosis and PAH 40 .

Studies
in several animal models have demonstrated that riociguat has anti-fibrotic effects 41,42 , and a subgroup analysis of PATENT-1 and -2 reported that riociguat was well tolerated and associated with long-term improvements in 6MWD and other endpoints in patients with PAH associated with connective tissue disease 20 .These observations may suggest a potential benefit for riociguat in dcSSc.Moreover, dcSSc is characterized by small-vessel vasculopathy, caused in part by upregulation of endothelin and reduced NO levels, leading to decreased levels of cGMP 38 .Elevation of cGMP by riociguat could therefore be beneficial in this condition.RISE-SSc is an ongoing, 52-week, double-blind, placebo-controlled, phase 2 trial investigating the efficacy and safety of riociguat in patients with dcSSc 42a .The recruitment target is approximately 130 patients (ClinicalTrials.gov:NCT02283762).

Raynaud's phenomenon
Raynaud's phenomenon (RP) is a cold-or stresstriggered digital ischemia caused by vasoconstriction in the digital blood vessels sometimes associated with systemic sclerosis 43 .Medical therapy for RP is unsatisfactory, with many patients not responding 44 .The efficacy and tolerability of riociguat in RP were investigated in DIGIT, a single-dose (2 mg), double-blind, placebo-controlled, cross-over trial in 20 patients (ClinicalTrials.gov:NCT01926847).Two hours after administration, riociguat increased mean digital blood flow versus baseline by 41% at room temperature and by 15% after cold water exposure, and 12 (60%) patients responded to treatment (response defined as an increase of ≥10% in digital blood flow at room temperature or after cold water exposure) 45 .

Cystic fibrosis
Phe508del is a specific mutation of the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR) and the most common cause of cystic fibrosis (CF) 46 .Preclinical data have suggested that riociguat may improve CFTR channel function.The Rio-CF phase 2 trial assessed safety, tolerability, and early signs of efficacy of riociguat in patients with CF homozygous for Phe508del with mild-to-moderate disease (ClinicalTrials.gov: NCT02170025).After completion of part 1, the study has been terminated.Based on multiple factors, the design of part 2 is no longer appropriate.There were no safety concerns identified.

Vericiguat in HF
In patients with HF, endothelial dysfunction and reactive oxygen species reduce NO levels and bioavailability, resulting in insufficient stimulation of sGC and a reduction in cGMP synthesis.cGMP is essential for normal cardiac and vascular function.In HF, reduced NO-sGC-cGMP signaling results in vasoconstriction, vascular stiffness, adverse remodeling, and decreased renal and coronary blood flow with increased organ impairment [47][48][49] .Restoration of NO-sGC-cGMP signaling is a promising approach for the treatment of HF and one that is not directly addressed by current standard of care (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or beta-blockers).Vericiguat, a novel sGC stimulator with optimized pharmacokinetic properties allowing once-daily dosing, has been investigated in patients with HF.SOCRATES-REDUCED (ClinicalTrials.gov:NCT01951625) was a 12-week, double-blind, placebocontrolled, dose-finding, phase 2 trial in 456 patients with worsening chronic HF and reduced LVEF ( <45%) 50 .Patients were randomized to placebo or vericiguat once daily (1.25, 2.5, 5.0, or 10.0 mg).Vericiguat was well tolerated but had no significant effect on the primary endpoint, NT-proBNP levels, compared with placebo.However, secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level 50 .Based on these results, a large phase 3 clinical outcome trial of vericiguat in patients with LVEF <45% is recruiting (VICTORIA).The study is designed to test whether vericiguat is superior to placebo (each on top of standard of care) in increasing the time to first occurrence of the composite of cardiovascular death or HF hospitalization.This trial is expected to be completed in 2020 (ClinicalTrials.gov:NCT02861534) 51 .
SOCRATES-PRESERVED (ClinicalTrials.gov:NCT01951638) was a 12-week, double-blind, placebo-controlled phase 2b trial in 447 patients with symptomatic worsening chronic HF and LVEF ≥45%.Patients were randomized to placebo or vericiguat once daily (1.25, 2.5, 2.5−5.0, or 2.5−10.0mg) 52 .Vericiguat was well tolerated, but there was no significant difference from placebo for change in NT-proBNP from baseline or left atrial volume at 12 weeks (primary endpoints).However, at the highest dose vericiguat was associated with quality of life improvements from baseline 52 .A larger proportion of patients treated with vericiguat, 10 mg, achieved clinically meaningful improvements in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and the 5-dimension EuroQol Questionnaire (EQ-5D) score, and a dosedependent relationship was observed 52,53 .

Summary
Riociguat was the first drug to demonstrate efficacy and tolerability in two separate PH indications, namely PAH and inoperable or persistent/recurrent CTEPH 17,18,23,24 .This raised the possibility that sGC stimulators may have efficacy in other forms of PH.Initial trials in PH associated with HF with reduced or preserved left ventricular systolic function or COPD 26,29,31 , although with mixed results in terms of achieving their primary endpoints, did give signals which warrant further welldesigned investigations in this area.In a subgroup of patients with PH-IIP, riociguat may be harmful and its use in this disease subset is contraindicated.
The involvement of the NO-sGC-cGMP pathway in many diseases suggests that sGC stimulators could have diverse benefits.For riociguat this supposition is supported by its established indications (PAH and CTEPH) 17,18,23,24 and early results in RP 45 , and it is under investigation in dcSSc.
Vericiguat is well tolerated in patients with HF 50,52,53 , and a phase 3 trial of this agent in HF with reduced ejection fraction is in progress 51 .Ongoing and future trials will clarify the clinical roles of sGC stimulators.

Table 1 .
Summary of clinical trials of sGC stimulators in PAH, CTEPH, other forms of PH, dcSSc, and HF.