Rationale and Study Design of the RESPITE Trial: Riociguat Clinical Effects Studied in Pulmonary Arterial Hypertension (PAH) Patients With Insufficient Treatment Response to PDE-5 Inhibitors (PDE-5i)

October 2015, Vol 148, No. 4_MeetingAbstracts

Pulmonary Vascular Disease | October 2015

Rationale and Study Design of the RESPITE Trial: Riociguat Clinical Effects Studied in Pulmonary Arterial Hypertension (PAH) Patients With Insufficient Treatment Response to PDE-5 Inhibitors (PDE-5i Marius Hoeper; Raymond Benza; James Klinger; Gérald Simonneau; David Langleben; Robert Naeije; Paul Corris Clinic for Respiratory Medicine, Hannover Medical School, Hannover, Germany; Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, PA; Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital, Providence, RI; Assistance Publique-HÔpitaux de Paris, Service de Pneumologie, CHU-Le Kremlin Bicetre, Centre Hospitalier Universitaire, Paris, France; Center for Pulmonary Vascular Disease, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada; Department of Cardiology, Erasme University Hospital, Brussels, Belgium; Department of Thoracic Medicine, Freeman Hospital, Newcastle Under Tyne, United Kingdom Chest. 2015;148(4_MeetingAbstracts):923A. doi:10.1378/chest.2272572

Abstract SESSION TITLE: Hot Topics in PAH SESSION TYPE: Original Investigation Slide PRESENTED ON: Wednesday, October 28, 2015 at 04:30 PM - 05:30 PM PURPOSE: A significant proportion of PAH patients fail to reach or maintain treatment goals with PDE-5i. Nitric oxide-dependent activation of soluble guanylate-cyclase (sGC) may be failing and lead to insufficient endogenous cyclic guanosine monophosphate (cGMP) levels. The RESPITE study will investigate whether it is safe, feasible and beneficial to replace PDE-5i with riociguat, a direct sGC stimulator restoring endogenous cGMP production, in PAH patients demonstrating insufficient response to PDE-5 inhibition. METHODS: The study is a prospective, international, multicenter, open-label, single-arm, phase IIIb trial in PAH patients who demonstrate an insufficient clinical response to PDE-5i therapy determined by the following: WHO FC III, 6-minute walk distance (6MWD) of 165-440 m, and cardiac index (CI) <3.0 L/min/m2 despite stable doses of sildenafil (maximum dose 80 mg tid) or tadalafil (maximum dose 40 mg once daily), with or without background ERA therapy. RESULTS: Patients will be followed for 24 weeks and all endpoints are exploratory and include adverse events, invasive hemodynamic measurements, echocardiogram, 6MWD, Borg CR 10 scale, WHO FC, the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score, N-terminal pro-brain natriuretic peptide (NT-proBNP) and European Quality of life-Group -5D Questionnaire. Additional explorative analysis of pre-specified responder outcomes will be performed: proportion of

patients with CI≥2.5/3.0 l/min/m2, proportion of patients with NT-proBNP<1500 ng/L, proportion of patients without clinical worsening who improve in WHO FC and achieve treatment levels of CI≥2.5/3.0 l/min/m2 or NT-proBNP<1500 ng/L.

CONCLUSIONS: The RESPITE study will explore a novel therapeutic transitioning strategy where PAH patients in WHO FC III with an insufficient response to PDE-5i will be transitioned to riociguat. CLINICAL IMPLICATIONS: A significant proportion of patients with PAH who are prescribed PDE-5i monotherapy fail to reach their therapeutic goals after 3-6 months of therapy. The RESPITE study is the first explorative pilot study to investigate the “replace” strategy (sGC stimulation with riociguat replaces PDE-5 inhibition) in PAH patients and whether riociguat can achieve clinically relevant improvements in these patients. DISCLOSURE: Marius Hoeper: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: GSK , Consultant fee, speaker bureau, advisory committee, etc.: Pfizer James Klinger: Grant monies (from industry related sources): Research support from Actelion, Grant monies (from industry related sources): Research support from Bayer, Grant monies (from industry related sources): Research support from Gilead Sciences, Grant monies (from industry related sources): Research support from Lung Biotechnology, Grant monies (from industry related sources): Research support from NIH-NHLBI, Grant monies (from industry related sources): Research support from Pfizer, Grant monies (from industry related sources): Research support from United Therapeutics , Consultant fee, speaker bureau, advisory committee, etc.: Travel expenses for Consultations from Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Travel expenses for Consultations from United Therapeutics Gérald Simonneau: Grant monies (from industry related sources): Grant support from Actelion, Grant monies (from industry related sources): Grant support from Bayer, Grant monies (from industry related sources): Grant support from GSK, Grant monies (from industry related sources): Grant support from Novartis, Grant monies (from industry related sources): Grant support from Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Personal fees from Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Personal fees from Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Personal fees from GSK, Consultant fee, speaker bureau, advisory committee, etc.: Personal fees from Novartis, Consultant fee, speaker bureau, advisory committee, etc.: Personal fees from Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Non-financial support from Pfizer David Langleben: Grant monies (from industry related sources): Grant support from Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Personal fees and non-financial support from Bayer Robert Naeije: Consultant fee, speaker bureau, advisory committee, etc.: Speakers fees from Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Speakers fees from Glaxo, Consultant fee, speaker bureau, advisory committee, etc.: Advisory board member fees from Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Advisory board member fees from LungRX, Consultant fee, speaker bureau, advisory committee, etc.: Advisory board member fees from Actelon Paul Corris: Grant monies (from industry related sources): Grant support from Bayer (University Research Fund), Consultant fee, speaker bureau, advisory committee, etc.: Fees for advisory boards and talks from Bayer, Actelion and GSK. The following authors have nothing to disclose: Raymond Benza No Product/Research Disclosure Information