sign in sign up
<<
Home , Riociguat

Benza R, Raina A, Kanwar MK, Nathan SD, Mathai SC. J Rare Dis Res Treat. (2017) 2(6): Journal of 15-22 Rare Diseases Research www.rarediseasesjournal.com & Treatment

Mini-review Open Access

The soluble stimulator riociguat: Evidence in 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

Article Info ABSTRACT

Article Notes The soluble guanylate cyclase (sGC) stimulators riociguat and Received: August 11, 2017 elevate intracellular cyclic guanosine monophosphate (cGMP) levels via Accepted: November 02, 2017 stimulation of the –sGC–cGMP pathway resulting in vasodilatory, *Correspondence: anti-inflammatory, anti-proliferative, and anti-fibrotic effects. Riociguat is Prof. Raymond Benza approved for the treatment of pulmonary arterial hypertension (PAH) and Professor of Medicine, Program Director Advanced Heart inoperable or persistent/recurrent chronic thromboembolic pulmonary Failure, Transplant, Mechanical Circulatory Support and hypertension (CTEPH). Placebo-controlled phase 3 trials in both indications Pulmonary Hypertension Section, Allegheny Health Network, demonstrated significant improvements in exercise capacity, functional class, Pittsburgh, PA 15212, USA; Email: [email protected] and pulmonary hemodynamics, with sustained efficacy and good tolerability © 2017 Benza R. This article is distributed under the terms of in long-term open-label extension studies. Pilot or phase 2 studies of riociguat the Creative Commons Attribution 4.0 International License. in pulmonary hypertension associated with heart failure (HF) or chronic obstructive pulmonary disease showed improvements in some hemodynamic Keywords parameters, although riociguat is contraindicated in pulmonary hypertension Soluble guanylate cyclase associated with idiopathic interstitial pneumonias. Riociguat is undergoing Chronic thromboembolic pulmonary hypertension Pulmonary arterial hypertension trials in other conditions including diffuse cutaneous systemic sclerosis. Riociguat Vericiguat, a novel once-daily sGC stimulator, is well tolerated in patients with Vericiguat HF and is undergoing a phase 3 trial in HF with reduced ejection fraction. These Heart failure ongoing studies will clarify the roles of sGC stimulators in indications beyond PAH and CTEPH.

Abbreviations 6MWD: 6-minute walking distance; cGMP: cyclic guanosine monophosphate; CTEPH: chronic thromboembolic pulmonary hypertension; dcSSc: diffuse cutaneous systemic sclerosis; HF: heart failure; LVEF: left ventricular ejection fraction; mPAP: mean pulmonary artery pressure; NO: nitric oxide; NT-proBNP: N-terminal pro-brain natriuretic peptide; PAH: pulmonary arterial hypertension; PDE5: phosphodiesterase type 5; PEA: pulmonary endarterectomy; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; RP: Raynaud’s phenomenon; sGC: soluble guanylate cyclase; tid: three times daily; WHO: World Health Organization. Introduction Pulmonary hypertension (PH) is a broad term encompassing a

1. PH can lead to right ventricular dysfunction andvariety failure of disorders, and can eventually defined by be a fatalmean .pulmonary Globally, the artery prevalence pressure of (mPAP) ≥25 mmHg 2,3

Page 15 of 22 Benza R, Raina A, Kanwar MK, Nathan SD, Mathai SC. J Rare Dis Res Treat. (2017) Journal of Rare Diseases Research & Treatment 2(6): 15-22

PH is estimated at approximately 1% of the population4. once produced, has multiple effects, mostly mediated Based o through activation of protein kinase G. Activation of this Organization (WHO) groups5: kinase ultimately leads to via activation of n etiology, PH is classified into five World Health phosphatase that releases from smooth Group 1: Pulmonary arterial hypertension muscle cells. In addition, the NO–sGC–cGMP pathway (PAH), a category that contains several disorders/ mediates many physiologic functions including regulation subgroups, including idiopathic PAH, heritable PAH, . and PAH associated with certain conditions such as Depletion of NO leads to a variety of abnormalities including13,14 connective tissue diseases (e.g. diffuse cutaneous pulmonaryof cell proliferation, vasoconstriction, platelet aggregation,vascular remodeling, and fibrosis and in systemic sclerosis (dcSSc)), congenital heart disease situ thrombosis. Reduction in endogenous NO levels has been observed in several types of PH9. sGC stimulators have (CHD), and human immunodeficiency virus infection.-5) The definition of PAH includes pulmonary vascular response to endogenous NO and also directly stimulate sGCa dual independent mode of action; of NO specifically, via a different they enhance binding the site,sGC resistance (PVR) >3 Wood units (240 dyn·s·cm2 and pulmonary capillary wedge pressure ≤15 mmHg leading to elevation of cGMP (Figure 1) . This differs from phosphodiesterase type 5 (PDE5) inhibitors8,12 (another Group 2: Left-heart-related PH PAH-approved drug class), which prevent the breakdown Group 4:3: Lung-/hypoxia-relatedChronic thromboembolic PH pulmonary hyperten- of cGMP by occupying the catalytic site on PDE5. However, sion (CTEPH) PDE5 inhibitors are dependent on cGMP synthesis and Group 5: PH with unclear/multifactorial etiology. the presence of NO, a requirement that sGC stimulators circumvent15 PH in developing countries is often associated with CHD fold16. or infectious disease4 . Riociguat increases sGC activity by up to 112- of recent research and drug development concentrated on Riociguat in PAH and CTEPH PAH and CTEPH, which. There are both has been considered a significant rare diseases amount and may share similar pathology4,6,7. Riociguat was investigated in PATENT-1, a 12-week, double-blind, placebo-controlled trial in 443 patients with Germany) is a soluble guanylate cyclase (sGC) stimulator Patients received either placebo or riociguat (individually symptomatic PAH (ClinicalTrials.gov: NCT00810693). approvedRiociguat for the (BAY-63-2521; treatment of BayerPAH and AG, inoperable Wuppertal, or persistent/recurrent CTEPH. Currently, it is the only optimized doses up to 2.5 mg three times daily (tid)). approved medical therapy for inoperable and persistent/ (6MWD) (primary endpoint), PVR, N-terminal pro-brain Riociguat significantly improved 6-minute walking distance recurrent CTEPH8. sGC stimulators are a novel class of 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 andtherapeutics in vivo models with 9-11 vasodilatory,. These diverse anti-inflammatory, actions mean that anti- sGC endothelin-receptor antagonists (ERAs) or prostanoids17. proliferative,stimulators have and the anti-fibrotic potential to effects treat many in various other diseases, in vitro including heart failure (HF), systemic sclerosis, and cystic inIn 6MWD, the open-label NT-proBNP, extension and WHO of thisfunctional trial (PATENT-2;class with riociguat and another sGC stimulator, vericiguat (BAY ClinicalTrials.gov: NCT00863681), the improvements fibrosis. This review discusses the clinical evidence for well tolerated as monotherapy or in combination with riociguat were maintained 18after 2 years, and riociguat was 1021189;The NO–sGC–cGMP Bayer AG). Results pathway are summarized in Table 1. ERAs, prostanoids, or both in PATENT-1 with PAH associated with CHD, riociguat sGC is a key in the nitric oxide (NO) signaling improved 6MWD, as well as. InNT-proBNP, a subgroup WHO of 35 functional patients pathway, which plays many roles in the control of the class, and PVR, compared with placebo19. The long-term vascular system including regulation of vascular tone, inhibition of vascular smooth muscle cell proliferation, associated with connective tissue disease was similar to . Impaired thatoutcome seen ofin idiopathicpatients in PAH PATENT-1. and PATENT-2 with PH functioning of this system has been implicated9,10 in PH, 20 coronaryand protection artery disease, against peripheral inflammation vascular disease, CTEPH is characterized by obstruction of the pulmonary and atherosclerosis . NO from vascular endothelial vasculature, usually as a consequence of unresolved cells binds with sGC,9,10 which catalyzes the synthesis of the pulmonary embolism . Pulmonary endarterectomy (PEA) secondary messenger cyclic guanosine monophosphate is a potentially curative21 surgery for CTEPH; however, not (cGMP), and the pharmacologic effects of sGC stimulators all patients are eligible and some have persistent and/or result from their action to enhance cGMP synthesis . cGMP, recurrent PH after surgery . In addition, CTEPH frequently 12 22

Page 16 of 22 Benza R, Raina A, Kanwar MK, Nathan SD, Mathai SC. J Rare Dis Res Treat. (2017) Journal of Rare Diseases Research & Treatment 2(6): 15-22

Table 1. Summary of clinical trials of sGC stimulators in PAH, CTEPH, other forms of PH, dcSSc, and HF. Study, population Study design Primary outcome Other outcomes 12-wk, DB, RCT. Riociguat 6MWD at Week 12: –6±86 m with WHO FC, PVR, NT-proBNP, and clinical PATENT-117 (NCT00810693) maximum dose 1.5 (exploratory) PBO, +30±66 m with riociguat: worsening significantly improved vs PAH (n=443) or 2.5 mg tid p<0.001 PBO PATENT-218 Improvements in NT-proBNP and (NCT00863681) OL extension of PATENT-1 6MWD +47 m vs baseline at 2 yr WHO FC maintained PAH (n=396) 16-wk, DB, RCT 6MWD at Week 16: –6±84 m with CHEST-123 (NCT00855465) WHO FC, PVR, and NT-proBNP Riociguat maximum dose PBO, +39±79 m with riociguat: CTEPH (n=261) significantly improved vs PBO 2.5 mg tid p<0.001 CHEST-224 (NCT00910429) OL extension of CHEST-1 Improvements in NT-proBNP and 6MWD +50 m vs baseline at 2 yr CTEPH (n=237) WHO FC maintained 24-wk, OL, multicenter, 6MWD +31 m vs baseline at WHO FC and NT-proBNP significantly RESPITE (NCT02007629) uncontrolled Week 24: p=0.001 improved vs baseline PAH (n=61)25 Patients with inadequate (All endpoints were exploratory) (All endpoints were exploratory) response to PDE5i LEPHT26 (NCT01065454) 16-wk, DB, RCT mPAP PBO-corrected mean difference Significantly improved cardiac index PH-sLVD (n=201) Riociguat 0.5, 1.0, or 2.0 mg tid –2.7 mmHg: p=0.10 (p=0.0018) and PVR (p=0.03) Riociguat 2.0 mg significantly 16-wk, DB, RCT mPAP: –6.3±4.2 mmHg with PBO, DILATE-129 (NCT01172756) increased SV (p=0.04) and decreased Riociguat single dose 0.5, 1.0, or –5.1±4.7 mmHg with riociguat PH-diastolic HF (n=39) SBP (p=0.03) and RV end-diastolic 2.0 mg 2.0 mg: p=0.60 area (p=0.04) Ghofrani et al 201531 Non-randomized, non-blinded, mPAP: –4.8±4.17 mmHg with 2.5 mg PVR: –123.8±73.53 dyn·s·cm-5 with (NCT00640315) non-controlled pilot vs baseline: p=0.002 2.5 mg vs baseline: p=0.0002 PH-COPD (n=22) Riociguat single dose 1.0 or 2.5 mg Hoeper et al 201332 Non-randomized, non-blinded, Safety and tolerability: generally well Increased mean cardiac output and (NCT00694850) non-controlled pilot. Riociguat tolerated decreased PVR PH-ILD (n=22) target dose 2.5 mg tid RISE-IIP33 (NCT02138825) 26-wk, DB, RCT Trial terminated PH-IIP (n=147) RISE-SSc 42a (NCT02283762) 52-wk, DB, RCT Trial ongoing dcSSc Digital blood flow (room DIGIT45 (NCT01926847) Single dose, DB, RCT Digital blood flow (cold): +15% with temperature): +41% with riociguat at RP (n=20) Riociguat 2.0 mg riociguat at 2 hours 2 hours Rio-CF (NCT02170025) DB, RCT Trial terminated CF (Phe508del mutation) SOCRATES-REDUCED50 12-wk, DB, RCT Ratio of geometric mean NT-proBNP Dose-dependent effect of vericiguat (NCT01951625) Vericiguat 1.25, 2.5, 5.0, or vs PBO 0.885; p=0.15 on NT-proBNP (p<0.02) HF reduced LVEF (n=456) 10.0 mg 12-wk, DB, RCT Difference in log NT-proBNP vs PBO SOCRATES-PRESERVED52,53 Vericiguat 1.25 or 2.5 mg fixed 0.14; p=0.20 Quality of life improvement at highest (NCT01951638) HF dose or titrated to 5.0 or Difference in LAV vs PBO 1.6 mL; dose preserved LVEF (n=447) 10.0 mg p=0.37 Abbreviations: 6MWD: 6-minute walking distance; CF: cystic fibrosis; COPD: chronic obstructive pulmonary disease; CTEPH: chronic thromboembolic pulmonary hypertension; DB: double-blind; dcSSc: diffuse cutaneous systemic sclerosis; HF: heart failure; IIP: idiopathic interstitial pneumonias; ILD: interstitial lung disease; LAV: left atrial volume; LVEF: left ventricular ejection fraction; mPAP: mean pulmonary artery pressure; NT-proBNP: N-terminal pro-brain natriuretic peptide; OL: open-label; PAH: pulmonary arterial hypertension; PBO: placebo; PDE5i: phosphodiesterase type 5 inhibitor; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; RCT: randomized controlled trial; RP: Raynaud's phenomenon; RV: right ventricular; SBP: systolic blood pressure; sGC: soluble guanylate cyclase; sLVD: systolic left ventricular dysfunction; SV: stroke volume; tid: three times daily; wk: week; WHO FC: World Health Organization functional class; yr: years Outcome values are means ± standard deviation unless otherwise stated. involves pulmonary small-vessel disease not amenable to PEA . Riociguat was investigated in CHEST-1, a 16-week, 21 gov: NCT00855465). Patients received placebo or riociguat with CTEPH who were ineligible for PEA or experienced proBNP,(individual and optimizedWHO functional doses class up tocompared 2.5 mg with tid). placebo Riociguat. persistentdouble-blind, and/or placebo-controlled recurrent PH after trial PEA in (ClinicalTrials. 261 patients significantly improved 6MWD (primary endpoint), PVR, NT-23

In the open-label extension (CHEST-2; ClinicalTrials.

Page 17 of 22 Benza R, Raina A, Kanwar MK, Nathan SD, Mathai SC. J Rare Dis Res Treat. (2017) Journal of Rare Diseases Research & Treatment 2(6): 15-22

Figure 1: Mechanism of action of riociguat8,12. (a) Riociguat directly stimulates sGC in an NO-independent manner. (b) Riociguat sensitizes sGC to endogenous NO by stabilizing binding of the molecules. cGMP: cyclic guanosine monophosphate; GTP: ; NO: nitric oxide; sGC: soluble guanylate cyclase. Original figure based on cited references.

mortality, and established therapies do not improve NT-proBNP, and WHO functional class were maintained the associated PH . LEPHT, a 16-week, double-blind, gov: NCT00910429), the improvements in 6MWD, 2 . associated with HF and left ventricular ejection fraction after 2 years, and riociguat24 was well tolerated and exhibited placebo-controlled, phase 2b trial in 201 patients with PH a goodPDE5 safety inhibitors profile are widely used in the treatment of PAH but some patients do not attain treatment goals with these (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 selectedagents. A patients 24-week, with open-label, PAH and uncontrolled an unsatisfactory trial (RESPITE; response increasedriociguat 2with mg riociguat, versus placebo which was (primary well tolerated endpoint).. PVR ClinicalTrials.gov: NCT02007629) has indicated that. was significantly reduced and cardiac index significantly26 25 Group 2.2: PH associated with HF with preserved Riociguatto PDE5 inhibitors in other may forms benefit of from PH switching to riociguat ejection fraction Group 2.1: PH associated with HF with reduced Up to half of patients with HF have preserved LVEF, with ejection fraction most patients developing PH for which there is no proven PH resulting from HF with left ventricular systolic therapy . Reduced cGMP has been observed in these dysfunction is associated with high morbidity and patients2,27, therefore targeting the NO–sGC–cGMP pathway 28

Page 18 of 22 Benza R, Raina A, Kanwar MK, Nathan SD, Mathai SC. J Rare Dis Res Treat. (2017) Journal of Rare Diseases Research & Treatment 2(6): 15-22 is logical. DILATE-1, a single-dose, double-blind, placebo- 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 controlled, parallel-group, phase 2a trial in 39 patients of cGMP . Elevation of cGMP by riociguat could therefore be with PH associated with HF and LVEF >50%, randomized29 38 frompatients baseline to placebo to 6 hours or riociguat(primary endpoint) (0.5, 1.0, did or 2.0not mg)differ (ClinicalTrials.gov: NCT01172756). The decrease in mPAP beneficial in this condition. RISE-SSc is an ongoing, 52-week,. hemodynamic endpoints were improved (Table 1) and double-blind, placebo-controlled, phase 2 trial investigating42a riociguatsignificantly was with well riociguat tolerated 2 .mg versus placebo but other the efficacy and safety of riociguat in patients with dcSSc 29 The recruitment target is approximately 130 patients Group 3.1: PH associated with chronic obstructive (ClinicalTrials.gov:Raynaud’s phenomenon NCT02283762). pulmonary disease Raynaud’s phenomenon (RP) is a cold- or stress- The prognosis of severe chronic obstructive pulmonary triggered digital ischemia caused by vasoconstriction in the disease (COPD) associated with PH is poor . In a single- digital blood vessels sometimes associated with systemic 30 sclerosis . Medical therapy for RP is unsatisfactory, with many patients43 not responding44 dose pilot study (ClinicalTrials.gov: NCT00640315) in 22 of riociguat in RP were investigated in DIGIT, a single-dose mPAPpatients and with PVR, PH and associated was well toleratedwith COPD,. riociguat (1.0 or . The efficacy and tolerability 2.5 mg) was associated with significant31 improvements in Group 3.2: PH associated with interstitial lung after(2 mg), administration, double-blind, placebo-controlled, riociguat increased cross-over mean trialdigital in disease 20 patients (ClinicalTrials.gov: NCT01926847). Two hours Two trials have assessed the effect of riociguat in patients blood flow versus baseline by 41% at room temperature with PH associated with interstitial lung disease (ILD). In and by 15% after cold water exposure, and 12 (60%) an open-label, uncontrolled, pilot study (ClinicalTrials.gov: orpatients after cold responded water exposure) to treatment45. (response defined as an increase of ≥10% in digital blood flow at room temperature was generally well tolerated, with increases in mean cardiac Cystic fibrosis outputNCT00694850) and decreases in 22 in patients, PVR riociguat (1.0−2.5 mg tid) placebo-controlled, double-blind32 randomized controlled P trial in 147 patients with PH. However, associated a phase with 2, idiopathic 26-week, interstitial pneumonias (PH-IIP)—a distinct subset of regulatorhe508del (CFTR) is aand specific the most mutation common of the cause gene of for cystic the protein cystic46. Preclinical fibrosis transmembrane data have suggested conductance that riociguat may improve CFTR channel function. The Rio-CF days)ILD—(RISE-IIP; due to an excess ClinicalTrials.gov: of deaths and serious NCT02138825) adverse events was fibrosis (CF) withhalted riociguat early (after compared a mean with treatment placebo as duration well as a 121±66 lack of . Riociguat is therefore contraindicated in PH- phase 2 trial assessed safety, tolerability, and early signs IIP . 33 of efficacy of riociguat in patients with CF homozygous for efficacy34, 35 hasPhe508del been terminated. with mild-to-moderate Based on multiple disease factors, (ClinicalTrials. the design Riociguat in non-PH disorders gov: NCT02170025). After completion of part 1, the study Diffuse cutaneous systemic sclerosis of part 2 is no longer appropriate. There were no safety DcSSc is a rare but incapacitating and life-threatening concernsVericiguat identified. in HF form of systemic sclerosis characterized by progressive In patients with HF, endothelial dysfunction and reactive oxygen species reduce NO levels and , deposition of extracellular matrix . DcSSc is characterized fibrosis of the skin and internal36-38 organs resulting from by early-onset organ involvement and a mortality of almost in cGMP synthesis. cGMP is essential for normal cardiac and . Leading causes of death in patients with vascularresulting function.in insufficient In HF, stimulation reduced NO–sGC–cGMP of sGC and a reduction signaling 39 . results in vasoconstriction, vascular stiffness, adverse 50% at 10 years 40 remodeling, and decreased renal and coronary blood systemicStudies sclerosis in includeseveral pulmonary animal fibrosis models and PAHhave 47-49. Restoration of effects NO–sGC–cGMP signaling is a promising approach for the demonstratedreported41,42 that riociguat that was riociguat well tolerated has and anti-fibrotic associated treatmentflow with increasedof HF and organone that impairment is not directly addressed by with long-term, and improvements a subgroup analysis in 6MWD of and PATENT-1 other endpoints and -2 current standard of care (angiotensin-converting enzyme in patients with PAH associated with connective tissue inhibitors, angiotensin receptor blockers, mineralocorticoid disease receptor antagonists, or beta-blockers). Vericiguat, a novel 20 . These observations may suggest a potential benefit Page 19 of 22 Benza R, Raina A, Kanwar MK, Nathan SD, Mathai SC. J Rare Dis Res Treat. (2017) Journal of Rare Diseases Research & Treatment 2(6): 15-22 sGC stimulator with optimized pharmacokinetic properties Vericiguat is well tolerated in patients with HF , and allowing once-daily dosing, has been investigated in 50,52,53 patients with HF. SOCRATES-REDUCED (ClinicalTrials.gov: fraction is in progress51. Ongoing and future trials will clarifya phase the 3 clinical trial of roles this agentof sGC in stimulators. HF with reduced ejection worseningNCT01951625) chronic was HF and a 12-week, reduced LVEF double-blind, ( <45%) .placebo- Patients Acknowledgements controlled, dose-finding, phase 2 trial in 456 patients50 with Editorial support for this review was provided by Adelphi Communications Ltd, Bollington, UK supported by were randomized to placebo or vericiguat once daily (1.25, Bayer AG. levels,2.5, 5.0, comparedor 10.0 mg). with Vericiguat placebo. was wellHowever, tolerated secondary but had analysisno significant suggested effect a ondose–response the primary endpoint,relationship NT-proBNP whereby Conflicts of interest higher vericiguat doses were associated with greater Raymond Benza reports grant support from reductions in NT-proBNP level . Based on these results, a Belleraphon, Actelion, Eiger, and Bayer AG. 50 Amresh Raina reports speaker fees from Bayer AG. with LVEF <45% is recruiting (VICTORIA). The study is designedlarge phase to 3test clinical whether outcome vericiguat trial of is vericiguat superior into patientsplacebo Manreet K. Kanwar is on a Speakers’ Bureau and (each on top of standard of care) in increasing the time to Advisory Board for Bayer AG. Steven D. Nathan has received consulting fees and Inova or HF hospitalization. This trial is expected to be completed Fairfax Hospital has received research funding from Bayer first occurrence of the composite of cardiovascular51. death AG for work pertaining to a clinical trial of riociguat. in 2020 (ClinicalTrials.gov: NCT02861534) Stephen C. Mathai reports: in 447SOCRATES-PRESERVED patients with symptomatic (ClinicalTrials.gov: worsening NCT01951638)chronic HF and was a 12-week, double-blind, placebo-controlled phase 2b trial and United Therapeutics . Vericiguat • Consultancies in the past 2 years: Actelion, Bayer AG, LVEF ≥45%. Patients were randomized to placebo52 or vericiguat once daily (1.25, 2.5, 2.5−5.0, or 2.5−10.0 mg) from placebo for change in NT-proBNP from baseline or left • Grants: NIH/NHLBI and Scleroderma Foundation was well tolerated, but there was no significant difference at the highest dose vericiguat was associated with quality • Associations: Pulmonary Hypertension Association References ofatrial life volumeimprovements at 12 from weeks baseline (primary. A endpoints). larger proportion However, of Scientific Leadership Council. 52 1. 62 meaningful improvements in the Kansas City Cardiomyopathy Hoeper MM, Bogaard HJ, Condliffe R, et al.. Definitions and diagnosis Questionnairepatients treated Clinical with vericiguat,Summary Score 10 mg, (KCCQ-CSS) achieved clinicallyand the of pulmonary hypertension. J Am Coll Cardiol. 2013; (25 Suppl): D42-D50. 5-dimension EuroQol Questionnaire (EQ-5D) score, and a dose- for the diagnosis and treatment of pulmonary hypertension: The dependent relationship was observed . 2. JointGaliè, Task N. Humbert Force for M, the Vachiery Diagnosis JL, et and al. 2015Treatment ESC/ERS of Pulmonary Guidelines 52,53 Hypertension of the European Society of Cardiology (ESC) and the Summary European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. and tolerability in two separate PH indications, namely 46 PAHRiociguat and inoperable was the firstor persistent/recurrent drug to demonstrate CTEPH efficacy17, 2015;Schermuly (4): RT, p. Ghofrani 903-975. HA, Wilkins MR, et al. Mechanisms of disease: . This raised the possibility that sGC stimulators 8 18,23,24 3. 455. pulmonary arterial hypertension. Nat Rev Cardiol. 2011; (8): p. 443- PH associated with HF with reduced or preserved left 4. Hoeper MM, Humbert M, Souza R, et al. A global view of pulmonary ventricularmay have efficacy systolic in function other forms or ofCOPD PH. Initial, although trials in 4 26,29,31 with mixed results in terms of achieving their primary 5. hypertension.Simonneau, G, Lancet Gatzoulis Respir MA, Med. Adatia 2016; I,(4): et p. al.306-322. Updated clinical endpoints, did give signals which warrant further well- 62 designed investigations in this area. In a subgroup of classification of pulmonary hypertension. J Am Coll Cardiol. 2013; patients with PH-IIP, riociguat may be harmful and its use 6. McGoon(25 Suppl.): MD, Benza p. D34-D41. RL, Escribano-Subias P, et al. Pulmonary arterial in this disease subset is contraindicated. 62 hypertension: epidemiology and registries. J Am Coll Cardiol. 2013; The involvement of the NO–sGC–cGMP pathway in many 7. Lang(25 I. Suppl):Chronic p. thromboembolic D51-D59. pulmonary hypertension: a distinct diseases suggests that sGC stimulators could have diverse 24

8. diseaseGhofrani entity. HA, Humbert Eur Respir M, LanglebenRev. 2015; D, et(136): al. Riociguat: p. 246-252. mode of action its established indications (PAH and CTEPH) and benefits. For riociguat45 this supposition is supported17,18,23,24 by 151 early results in RP , and it is under investigation in dcSSc. and clinical development in pulmonary hypertension. Chest. 2017; (2): p. 468-480.

Page 20 of 22 Benza R, Raina A, Kanwar MK, Nathan SD, Mathai SC. J Rare Dis Res Treat. (2017) Journal of Rare Diseases Research & Treatment 2(6): 15-22

9. Stasch JP, Evgenov OV. Soluble guanylate cyclase stimulators in 218 59 death in heart failure: a community study. J Am Coll Cardiol. 2012; pulmonary hypertension. Handb Exp Pharmacol. 2013; : p. 279- van(3): Heerebeek p. 222-231. L, Hamdani N, Falcão-Pires I, et al. Low myocardial 313.Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an protein kinase G activity in heart failure with preserved ejection emerging therapeutic target in cardiopulmonary disease. Circulation. 28. 126 10. 123 fraction.Bonderman Circulation. D, Pretsch 2012; I, Steringer-Mascherbauer(7): p. 830-839. R, et al. Acute 11. 2011;Dees C, Beyer(20): C, Distlerp. 2263-2273. A, et al. Stimulators of soluble guanylate cyclase hemodynamic effects of riociguat in patients with pulmonary 29. hypertension associated with diastolic heart failure (DILATE-1): a 74 randomized, double-blind, placebo-controlled, single-dose study. (sGC) inhibit experimental skin fibrosis of different aetiologies. Ann 146 RheumKim NH. Dis. Riociguat: 2015; an(8): upcoming p. 1621-1625. therapy in chronic thromboembolic 19(115): p. 68-71. Chest.Cuttica 2014; MJ, Kalhan (5): R, p. Shlobin 1274-1285. OA, et al. Categorization and impact 12. of pulmonary hypertension in patients with advanced COPD. Respir pulmonary hypertension? Eur Respir Rev. 2010; 30. 104 endothelial dysfunction in pulmonary arterial hypertension. Am J 13. Klinger JR, Abman SH, Gladwin188 MT. Nitric oxide deficiency and Med.Ghofrani 2010; HA, Staehler(12): p. G, 1877-1882. Grünig E, et al. Acute effects of riociguat in borderline or manifest pulmonary hypertension associated with chronic 14. Respir Crit Care Med. 2013; (6): p. 639-646. 31. 5 stimulators and activators: a review of the preclinical evidence. Respir Sandner P, Stasch122(Suppl J. Anti-fibrotic 1): p. S1-S9. effects of soluble guanylate cyclase obstructiveHoeper MM, pulmonary Halank M, disease. Wilkens Pulm H, et Circ. al. Riociguat 2015; (2): for p. interstitial 296-304. lung

15. Med.Humbert 2017; M, Ghofrani HA. The molecular targets of approved 32. 41 disease and pulmonary hypertension: a pilot trial. Eur Respir J. 2013; 71 Nathan(4): p. S, 853-860. Behr J, Collard H, et al. Riociguat for the treatment of treatments for pulmonary arterial hypertension. Thorax. 2016; pulmonary hypertension associated with idiopathic interstitial 16. Schermuly(1): p. 73-83. RT, Stasch JP, Pullamsetti SS, et al. Expression and function 33. pneumonia. European Respiratory Society International Congress – of soluble guanylate cyclase in pulmonary arterial hypertension. Eur 32(4): p. 881-891. Milan,Bayer Italy,AG. Adempas9–13 September (riociguat 2017. tablets): OA1985. EU summary of product 17. RespirGhofrani J. 2008;HA, Galiè N, Grimminger F, et al. Riociguat for the treatment 369 34. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_ characteristics. 2017 [cited 2017 6th October]; Available from: of pulmonary arterial hypertension. N Engl J Med. 2013; (4): 330- 18. Ghofrani HA, Grimminger F, Grünig E, et al. Predictors of long-term 340. Product_Information/human/002737/WC500165034.pdf.Bayer AG. Highlights of prescribing information: ADEMPAS (riociguat) outcomes in patients treated with riociguat for pulmonary arterial 35. labeling.bayerhealthcare.com/html/products/pi/Adempas_PI.pdf. 4 tablets, for oral use [cited 2017 6th October ]; Available from: http:// hypertension: data from the PATENT-2 open-label, randomised, long- Herrick AL, Pan X, Peytrignet S, et al. Treatment outcome in early diffuse 19. termRosenkranz extension S, Ghofrani trial. Lancet HA, BeghettiRespir Med. M, et 2016; al. Riociguat (5): p. for361-371. pulmonary cutaneous systemic sclerosis: the European Scleroderma Observational arterial hypertension associated with congenital heart disease. Heart. 36. 76 101 Study (ESOS). Ann Rheum Dis. 2017; (6), p. 1207-1218. 390 2015;Humbert M,(22): Coghlan p. 1792-1799. JG, Ghofrani HA, et al. Riociguat for the treatment p. 1685-1699. of pulmonary arterial hypertension associated with connective tissue 37. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017; (10103): 20. Pattanaik D, Brown M, Postlethwaite BC, et al. Pathogenesis of 76 6 disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017; 38. Rubio-Rivas M, Royo C, Simeón CP, et al. Mortality and survival in Simonneau(2): p. 422-426. G, Torbicki A, Dorfmüller P, et al. The pathophysiology of systemic sclerosis. Front Immunol. 2015; :272. chronic thromboembolic pulmonary hypertension. Eur Respir Rev. systemic sclerosis: systematic review and meta-analysis. Semin 21. 26 39. 44 Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death 2017;Pepke-Zaba (143). J, Ghofrani pii: 160112. HA, Hoeper doi: 10.1183/16000617.0112-2016 M. Medical management of chronic Arthritis Rheum. 2014; (2): p. 208-219. in systemic sclerosis: a study from the EULAR Scleroderma Trials and 22. 26 40. 69 thromboembolic pulmonary hypertension. Eur Respir Rev. 2017; 1815. Ghofrani(143). pii:HA, 160107. D’Armini doi: AM, 10.1183/16000617.0107-2016. Grimminger F, et al. Riociguat for the Research (EUSTAR) database. Ann Rheum Dis. 2010; (10): p. 1809- treatment of chronic thromboembolic pulmonary hypertension. N 41. Sharkovska Y, Kalk P, Lawrenz B, et al. Nitric oxide-independent 23. 369 stimulation of soluble guanylate cyclase reduces organ damage in

EnglSimonneau J Med. 2013;G, D’Armini (4): AM, p. 319-329.Ghofrani HA, et al. Predictors of long- 28(8): p. 1666-1675. term outcomes in patients treated with riociguat for chronic experimental low-renin and high-renin models. J Hypertens. 2010; 24. Geschka S, Kretschmer A, Sharkovska Y, et al. Soluble guanylate open-label, randomised, long-term extension trial. Lancet Respir Med. 42. thromboembolic4 pulmonary hypertension: data from the CHEST-2 6 cyclase stimulation prevents fibrotic tissue remodeling and improves 2016;Hoeper (5):MM, p. Simonneau 372-380. G, Corris PA, et al. RESPITE: switching to survival in salt-sensitive Dahl rats. PLoS One. 2011; (7): p. e21853. riociguat in PAH patients with inadequate response to PDE5i. Eur 122(Suppl.):S14-S17. 42a. Distler O, Pope J, Denton C, et al. RISE-SSc: riociguat in diffuse 25. 50 cuntaneousFardoun MM, systemic Nassif sclerosis.J, Issa K, Respiret al. Raynaud’s Med 2017; phenomenon: a brief 7 Respir J. 2017; (3): pii 1602425. doi: 10.1183/13993003.02425- Bonderman D, Ghio S, Felix SB, et al. Riociguat for patients with 43. 2016. 44. reviewEnnis H, of Hughes the underlying M, Anderson mechanisms. ME, et al. Front Calcium Pharmacol. channel 2016; blockers : 438. for pulmonary hypertension due to systolic left ventricular dysfunction: 26. a phase IIb double-blind, randomized, placebo-controlled, dose- 2 128 primary Raynaud’s phenomenon. Cochrane Database Syst Rev. 2016; 45. Huntgeburth: p. CD002069. M, Kießling, Weimann G, et al. The sGC-stimulator ranging hemodynamic study. Circulation. 2013; (5): p. 502-511. riociguat for the treatment of Raynaud’s phenomenon: a single-dose, 27. Bursi F, McNallan SM, Redfield MM, et al. Pulmonary pressures and

Page 21 of 22 Benza R, Raina A, Kanwar MK, Nathan SD, Mathai SC. J Rare Dis Res Treat. (2017) Journal of Rare Diseases Research & Treatment 2(6): 15-22

double-blind, randomized, placebo-controlled, cross-over study with worsening chronic heart failure and reduced ejection fraction: 16(Suppl 1): p. A58. 314

46. (DIGIT). BMC Pharmacol Toxicol. 2015; the SOCRATES-REDUCED randomized trial. JAMA. 2015; (21): p. analysis of CFTR mutations--correlation with incidence data and 51. 2251-2262.Armstrong PW, Roessig L, Patel MJ, et al. A multicenter, randomized, Bobadilla JL, Macek M Jr, Fine JP, et al. Cystic19 fibrosis: a worldwide the oral soluble guanylate cyclase stimulator: the VICTORIA trial. 47. applicationGheorghiade to M, screening. Marti CN, Hum Sabbah Mutat. HN, 2002; et al. Soluble (6): p.guanylate 575-606. cyclase: double-blind, placebo-controlled trial of the efficacy and safety of

18 JACC Heart Fail. 2017. pii: S2213-1779(17)30562-0. doi: 10.1016/ a potential therapeutic target for heart failure. Heart Fail Rev. 2013; Pieske B, Maggioni AP, Lam CSP, et al. Vericiguat in patients with 48. Breitenstein(2): p. 123-134. S, Roessig L, Sandner P, et al. Novel sGC stimulators jchf.2017.08.013. [Epub ahead of print.] and sGC activators for the treatment of heart failure. Handb Exp worsening chronic heart failure and preserved ejection fraction: 52. 243 results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur 49. Pharmacol.Marti CN, Gheorghiade2017; : p. M,225-247. Kalogeropoulos AP, et al. Endothelial 38 dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol. 60(16): p. 1455-1469. HeartFilippatos J. 2017; G, Maggioni (15): p.AP, 1119-1127. Lam CSP, et al. Patient-reported outcomes in the Soluble guanylate Cyclase stimulatoR in heArT failure patients 2012;Gheorghiade M, Greene SJ, Butler J, et al. Effect of vericiguat, a soluble 53. with PRESERVED ejection fraction (SOCRATES-PRESERVED) study. guanylate cyclase stimulator, on natriuretic peptide levels in patients 19 50. Eur J Heart Fail. 2017; (6): p. 782-791.

Page 22 of 22