Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study

Vallerie V McLaughlin, Pavel Jansa, Jens E Nielsen-Kudsk, Michael Halank, Gérald Simonneau, Ekkehard Grünig, Silvia Ulrich, Stephan Rosenkranz, Miguel A Gómez Sánchez, Tomás Pulido, Joanna Pepke-Zaba, Joan Albert Barberá, Marius M Hoeper, Jean-Luc Vachiéry, Irene Lang, Francine Carvalho, Christian Meier, Katharina Mueller, Sylvia Nikkho, Andrea M D'Armini, Vallerie V McLaughlin, Pavel Jansa, Jens E Nielsen-Kudsk, Michael Halank, Gérald Simonneau, Ekkehard Grünig, Silvia Ulrich, Stephan Rosenkranz, Miguel A Gómez Sánchez, Tomás Pulido, Joanna Pepke-Zaba, Joan Albert Barberá, Marius M Hoeper, Jean-Luc Vachiéry, Irene Lang, Francine Carvalho, Christian Meier, Katharina Mueller, Sylvia Nikkho, Andrea M D'Armini

Abstract

Background: Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH.

Methods: We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n = 84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints.

Results: In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, mean ± standard deviation 6MWD had increased by 33 ± 42 m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups.

Conclusions: Riociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed.

Trial registration: ClinicalTrials.org NCT01784562 . Registered February 4, 2013.

Keywords: Chronic thromboembolic pulmonary hypertension; Early access study; Riociguat.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by the ethics committees of all participating centers and all patients gave their written informed consent. Please see Additional file 1 for details about each ethical committee.

Consent for publication

Not applicable.

Competing interests

VVM received grants, personal fees, and non-financial support from Actelion, Bayer, Gilead, United Therapeutics, and Ikaria, and grants from Novartis. PJ received personal fees from AOG, and acted as an investigator for Actelion and Bayer. JENK has nothing to disclose. MH received personal fees for lectures and/or consultations from Actelion, Bayer, Gilead, GSK, MSD, Novartis, and OMT. GS received grants, personal fees, and non-financial support from Bayer, Actelion, GSK, Lilly, Pfizer, and Novartis. EG received grants and personal fees from Bayer, grants from Actelion, GSK, Lilly, and Pfizer, non-financial support from Alexion, and personal fees from Miltenyi, Novartis, and United Therapeutics. SU received personal fees from Bayer and Actelion, and grants from the Swiss National Science Foundation, the Zürich Lung League, and United Therapeutics. SR received grants and personal fees from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics, and personal fees from Gilead and GSK. MAGS received personal fees from Actelion, Bayer, GSK, and Ferrer Pharma. TP has nothing to disclose. JPZ received grants, personal fees, and non-financial support from Actelion and Bayer, and personal fees from GSK, and has served on advisory boards for Actelion, Bayer AG, and GSK. JAB received grants and personal fees from Actelion, Bayer, and GSK, and grants from Pfizer. MMH received grants, personal fees, and non-financial support from Bayer AG, and personal fees from Actelion. JLV received grants and personal fees from Actelion, and personal fees from Bayer, GSK, Lilly, and Merck. IL has relationships with drug companies including AOPOrphan Pharmaceuticals, Actelion, Bayer-Schering, Astra-Zeneca, Servier, Cordis, Medtronic, GSK, Novartis, Pfizer, and United Therapeutics. In addition to being an investigator in trials involving these companies, relationships include consultancy service, research grants, and membership of scientific advisory boards. FC is an employee of Bayer AG. CM is an employee of Bayer AG. KM is an employee of Bayer AG. SN is an employee of Bayer AG. AMD received personal fees from Actelion, Bayer AG, and MSD.

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Figures

Fig. 1
Fig. 1
Patient disposition. *Patients who discontinued treatment prematurely were to enter the safety follow-up phase

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