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Riociguat for Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension: a Phase II Study

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Riociguat for Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension: a Phase II Study Eur Respir J 2010; 36: 792–799 DOI: 10.1183/09031936.00182909 CopyrightßERS 2010 Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study H.A. Ghofrani*,++, M.M. Hoeper#,++, M. Halank", F.J. Meyer+, G. Staehler1, J. Behre, R. Ewert**, G. Weimann## and F. Grimminger*, on behalf of the study investigators"" ABSTRACT: We assessed the therapeutic potential of riociguat, a novel soluble guanylate AFFILIATIONS cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; *Dept of Internal Medicine, University Hospital Giessen and n542) or pulmonary arterial hypertension (PAH; n533) in World Health Organization (WHO) Marburg, Giessen, functional class II/III. #Dept of Respiratory Medicine, In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral Hannover Medical School, Hannover, " riociguat 1.0–2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary Medical Clinic 1/Pneumology, University Hospital Carl Gustav end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Carus, Dresden, Riociguat was generally well tolerated. Asymptomatic hypotension (SBP ,90 mmHg) occurred +Dept of Internal Medicine III, in 11 patients, but blood pressure normalised without dose alteration in nine and after dose Medical University Clinic, reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from Heidelberg, 1Medical Clinic I, Loewenstein Clinic , , baseline (390 m); p 0.0001) and PAH (57.0 m from baseline (337 m); p 0.0001); patients in gGmbH, Loewenstein, functional class II or III and bosentan pre-treated patients showed similar improvements. eDept of Internal Medicine I, Pulmonary vascular resistance was significantly reduced by 215 dyn?s?cm-5 from baseline Grosshadern Clinic, Ludwig (709 dyn?s?cm-5;p,0.0001). 42 (56%) patients were considered to have experienced drug-related Maximilian University of Munich, Munich, adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the **Centre for Internal Medicine B, most frequent AEs. Study discontinuation because of AEs was 4%. Ernst-Moritz-Arndt-University of These preliminary data show that riociguat has a favourable safety profile and improves Greifswald Clinic, Greifswald and ## exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised Clinical Pharmacology, Bayer Schering Pharma AG, Wuppertal, controlled trials are underway. Germany. ""A full list of the study investigators KEYWORDS: Chronic thromboembolic pulmonary hypertension, clinical study, phase II, and their affiliations can be found in pulmonary arterial hypertension, riociguat, soluble guanylyl cyclase the Acknowledgements section. ++These authors contributed equally to the study. ulmonary hypertension encompasses a dis- chronic thromboembolic pulmonary hypertension CORRESPONDENCE parate collection of disease subtypes. Pul- (CTEPH), most likely because of the use of H.A. Ghofrani, Dept of Internal Medicine, Medical Clinic II/V, monary arterial hypertension (PAH) is the pulmonary endarterectomy in specialised centres. P University Hospital Giessen and best characterised of these [1], but its aetiology is CTEPH is characterised by the presence of Marburg GmbH, Klinikstrasse 36, still incompletely understood. Several mediators thrombi in the pulmonary artery. Pulmonary 35392 Giessen, Germany are involved in the pathogenesis of PAH; bioavail- endarterectomy is the treatment of choice for E-mail: ardeschir.ghofrani@ abilityofendogenousvasodilatorssuchasnitric proximal (major vessel) CTEPH, and improves innere.med.uni-giessen.de oxide and prostacyclin is reduced, and production symptoms and survival rates [6], but a substantial of vasoconstrictors such as endothelin-I is increased number of patients with CTEPH are not candi- Received: [2]. The introduction of phosphodiesterase-5 in- dates for pulmonary endarterectomy (those with Nov 17 2009 Accepted after revision: hibitors, prostacyclins, and endothelin-receptor distal CTEPH or severe concomitant illness), or antagonists to target these signalling pathways April 21 2010 suffer persistent or recurrent pulmonary hyper- First published online: has improved the survival of patients with PAH [3] tension after pulmonary endarterectomy [7, 8]. June 07 2010 and, although their long-term prognosis remains Pathophysiological similarities between CTEPH extremely poor, large-scale registries report that the and PAH suggest that therapies targeting aberrant 1-yr survival rate is ,90% [4] and about half now signalling in PAH may also be beneficial in survive 5 yrs from initial diagnosis [5]. CTEPH. However, although uncontrolled studies European Respiratory Journal Similar survival trends have been seen in patients of several PAH therapies in patients with CTEPH Print ISSN 0903-1936 with another subtype of pulmonary hypertension, have shown improvement from baseline in Online ISSN 1399-3003 792 VOLUME 36 NUMBER 4 EUROPEAN RESPIRATORY JOURNAL H.A. GHOFRANI ET AL. PULMONARY VASCULAR DISEASE haemodynamics and exercise capacity, randomised placebo- Patients with CTEPH were eligible for inclusion if they had controlled trials have yielded inconclusive results [9, 10]. technically inoperable (i.e. distal) CTEPH, were deemed inoperable owing to concomitant diseases or had refused an Further progress in the management of CTEPH and PAH is operation. In addition, their diagnosis was established by at likely to be driven by the availability of drugs with a novel least two of the following: perfusion–ventilation scan, spiral mode of action. One new class of drug currently in develop- computed tomography, magnetic resonance angiography or ment directly targets the nitric oxide receptor, soluble invasive pulmonary angiography (contrast medium injected guanylate cyclase (sGC). Such sGC stimulators show a dual into pulmonary arteries via catheter). Patients with severe mode of action: they increase the sensitivity of sGC to systemic arterial hypertension (SBP .200 mmHg or diastolic endogenous bioavailable nitric oxide, and mimic those effects blood pressure .120 mmHg), systemic SBP ,100 mmHg, when nitric oxide is absent or scarce [11, 12]. Riociguat (BAY acute or chronic left heart failure, significant renal insuffi- 63-2521) is the first member of this class to enter clinical ciency (creatinine .2mg?dL-1 (177 mM) or proteinuria development. Orally administered riociguat has been shown to .1g?day-1) or hepatic insufficiency (bilirubin .2.5 mg?dL-1 have beneficial effects on pulmonary haemodynamics, right m heart hypertrophy, and remodelling of the pulmonary vascu- (43 M)) were excluded. Patients taking endothelin-receptor lature in rat and mouse models of pulmonary hypertension antagonists were allowed to continue this treatment, but those [11]. A phase I study of 58 healthy, white male volunteers (18– taking phosphodiesterase-5 inhibitors or prostacyclin deri- 45 yrs of age) showed that single oral doses (0.25–5 mg) of vates were excluded. Diuretics, oral anticoagulants, digitalis, riociguat were readily absorbed and well tolerated [13]. calcium channel blockers and oxygen supplementation were Adverse events (AEs) were reported by 50% of the subjects, permitted. all of which were mild or moderate. No serious or life- Local institutional review boards and independent ethics threatening events were reported and all but one case was committees approved the study protocol, and written resolved by study completion. A subsequent proof-of-concept informed consent was obtained from all patients. study was carried out in 19 patients with CTEPH or PAH. A pilot dose titration study determined the dose of riociguat that Procedures gave the maximum clinical effect without compromising safety and tolerability. Patients then received a single, oral dose (1 or The primary end-points of the study were the safety, tolerability and feasibility of individual titration of riociguat 2.5 mg) following an overnight fasting period (o8 h). Pharmacodynamic parameters were evaluated at baseline, according to peripheral SBP. Patients received an immediate- and during and after a 10-min nitric oxide inhalation period. release tablet of riociguat (Bayer Schering Pharma AG, Riociguat was administered when the haemodynamic para- Wuppertal, Germany) t.i.d. for 12 weeks, titrated in 0.5-mg meters returned to baseline. Results from the proof-of-concept increments at 2-week intervals from a starting dose of 1 mg to study showed that riociguat had a favourable safety profile, a maximum of 2.5 mg t.i.d. Trough SBP was measured 1 h and significantly improved pulmonary haemodynamic para- before administration of the morning dose of riociguat. As meters and cardiac index in patients with pulmonary specified by the protocol, BP measurements were taken hypertension, in a dose-dependent manner, and to a greater using a noninvasive method after a resting period of 20 min. extent than nitric oxide. Mean pulmonary arterial pressure The methods used to take BP measurements were at the (P¯ pa) was reduced by f40% [14]. Results of the proof-of- discretion of the physician and were not standardised concept study indicated that, as is the case for a number of (consistent between the study centres). The dose of riociguat currently available PAH therapies, individualised dose titra- was increased if trough peripheral SBP was .100 mmHg, tion may be the most appropriate way to utilise the potential maintained
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