Novel Pulmonary Hypertension Drug Proves Safe and Effective in Phase III Trial

Newswise — ATS 2014, SAN DIEGO ─ After a year of being treated with a novel drug, patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) and those with persistent or recurrent pulmonary hypertension after an operation for the disease showed sustained improvement in a multicenter, international trial presented at the 2014 American Thoracic Society International Conference.

The drug, riociguat, is a guanylate cyclase stimulator that works independently and in concert with endogenous nitric oxide to induce vasodilation. A long-term extension study, CHEST-2 enrolled patients from CHEST-1, which followed these patients for 16 weeks and achieved its primary endpoint: improved six-minute walking distance (6MWD).

“The pivotal study, CHEST-1, showed significant improvements in exercise capacity and hemodynamics in patients treated with riociguat,” said principal investigator Marius Hoeper, MD, of the Hannover Medical School (Germany). “However, the study was relatively short, and CHEST-2 adds important information on the long-term tolerability and efficacy of riociguat in patients with CTEPH.”

CTEPH is a relatively rare disease; about 5000 people in the U.S. are diagnosed with the disease each year. It occurs when blood clots from previous episodes of acute pulmonary embolism do not resolve, causing persistent obstruction of the pulmonary vasculature, which may ultimately lead to pulmonary hypertension.

A surgical procedure called pulmonary endarterectomy (PEA) is the treatment of choice for operable patients with CTEPH. However, not all patients are candidates for PEA, a long and complex operation, and 20 to 30% of those who undergo the surgery are not cured. Thus, there is an urgent medical need to develop effective drugs for patients with inoperable CTEPH or persistent pulmonary hypertension after PEA.

Both groups of patients were part of the CHEST studies. In CHEST-2, 172 patients (73%) had inoperable CTEPH and 65 (27%) had persistent/recurrent PH after PEA. Unlike in CHEST-1, which had a placebo arm, in the extension trial all patients received riociguat.

The primary endpoint of CHEST-2 was safety and tolerability, which riociguat met. The drug was well tolerated by the majority of patients: 4% of inoperable patients and 2% of persistent/recurrent patients withdrew due to adverse events.

The researchers presenting at ATS 2014 also reported data related to the secondary endpoints: change in 6MWD and World Health Organization Functional Class, a means of classifying disease severity in patients with pulmonary hypertension (PHJ).Compared to the baseline established with CHEST-1, after one year of CHEST-2, 6MWD improved by 54±62 m in the inoperable subgroup and 44±64 m in the persistent/recurrent subgroup.

Similarly, when compared to the CHEST-1 baseline, at the first year mark of CHEST-2, the percentage of inoperable patients who improved in WHO FC was 46%. Those stabilized represented 50%. And those whose function worsened was 5%. The comparable percentages for the persistent/recurrent patients were 47, 49, and 0.

Based on the data from CHEST-1 and CHEST-2, Hoeper noted, riociguat was recently approved in the U.S., Canada, Europe and Japan for patients with inoperable or recurrent CTEPH, closing an important therapeutic gap for these patients.

CHEST-1 and CHEST-2 were funded by Bayer.

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* Please note that numbers in this release may differ slightly from those in the abstract. Many of these investigations are ongoing; the release represents the most up-to-date data available at press time.

Abstract 52139Effects Of Riociguat In Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Vs Persistent/Recurrent Pulmonary Hypertension (PH) After Pulmonary Endarterectomy (PEA): 1-Year Results From The CHEST-2 StudyType: Scientific AbstractCategory: 18.10 - Pulmonary Hypertension: Clinical – Treatment and Outcomes (PC)Authors: M. Hoeper1, N.H. Kim2, E. Mayer3, T. Pulido4, M.R. Wilkins5, G. Simonneau6, A. Torbicki7, C. Wang8, N. Davie9, A. Fritsch9, H.-A. Ghofrani10; 1Hannover Medical School - Hannover/DE, 2Division of Pulmonary and Critical Care Medicine, UCSD School of Medicine - San Diego, CA/US, 3Kerckhoff Heart and Lung Center - Bad Nauheim/DE, 4Cardiopulmonary Department, Ignacio Chávez National Heart Institute - Mexico City/MX, 5National Institute for Health Research/Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London - London/UK, 6Univ. Paris-Sud; INSERM U999; AP-HP, Hôpital Bicêtre, Service de Pneumologie - Le Kremlin-Bicêtre/FR, 7Department of Pulmonary Circulation and Thromboembolic Diseases, Center of Postgraduate Medical Education, ECZ-Otwock - Otwock/PL, 8Beijing Institute of Respiratory Medicine, Beijing Chao Yang Hospital, Department of Respiratory Medicine, Capital Medical University, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders - Beijing/CN, 9Global Clinical Development, Bayer HealthCare Pharmaceuticals - Wuppertal/DE, 10University of Giessen and Marburg Lung Center (UGMLC), member of the German Center of Lung Research (DZL); and Department of Medicine, Imperial College London - Giessen/DE

Abstract BodyRationaleIn the 16-week Phase III CHEST-1 study, riociguat, a novel guanylate cyclase stimulator, improved 6-minute walking distance (6MWD) and a range of secondary endpoints in patients with inoperable or persistent/recurrent CTEPH. Here we compare 1-year data from the long-term extension study, CHEST-2, for both patient subgroups.MethodsPatients with inoperable CTEPH or persistent/recurrent PH after PEA (aged 18–80 years; 6MWD 150–450 m; pulmonary vascular resistance (PVR) <300 dyn∙s∙cm–5; mean pulmonary arterial pressure ≥25 mmHg) were eligible for CHEST-2 after completing CHEST-1 without ongoing riociguat-related serious adverse events (AEs). On entering CHEST-2, former placebo patients received riociguat individually adjusted to a target dose of 2.5 mg tid, while former riociguat patients underwent sham dose adjustment. The primary endpoint of CHEST-2 was safety and tolerability. This abstract will focus on secondary endpoints, including change in 6MWD and World Health Organization Functional Class (WHO FC).ResultsOf 261 patients enrolled in CHEST-1, 237 (91%) entered CHEST-2. Of these, 172 (73%) had inoperable CTEPH and 65 (27%) had persistent/recurrent PH after PEA. At the March 2013 data cut-off, 155 (90%) patients in the inoperable subgroup were ongoing and 134 (78%) had received ≥1 year of treatment; in the persistent/recurrent subgroup, 56 (86%) patients were ongoing and 45 (69%) had received ≥1 year of treatment. Mean treatment duration was 582 days in the overall population and in both subgroups. Riociguat was well tolerated by the majority of patients; 4% of inoperable patients and 2% of persistent/recurrent patients withdrew due to AEs. At 1 year of CHEST-2, mean±SD 6MWD had increased by 54±62 m in the inoperable subgroup and 44±64 m in the persistent/recurrent subgroup vs CHEST-1 baseline. WHO FC had improved/stabilized/worsened vs CHEST-1 baseline in 46/50/5% of inoperable patients and 47/49/0% of persistent/recurrent patients at 1 year of CHEST-2. Based on Kaplan–Meier plots, the survival rate at 1 year of CHEST-2 was 97% for inoperable patients and 96% for persistent/recurrent patients; the rate of freedom from clinical worsening was 89% in the inoperable subgroup and 88% in the persistent/recurrent subgroup.ConclusionsRiociguat has a good safety profile and appears to lead to sustained improvements in 6MWD and WHO FC in both patients with inoperable CTEPH and persistent/recurrent PH after PEA for up to 1 year.