CHICAGO – Patients with chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension maintained benefits with riociguat at 1 year in two long-term extension studies.
Riociguat (Adempas) is the first drug approved for chronic thromboembolic pulmonary hypertension (CTEPH) and the first to show sustained benefits in 6-minute walk distance and functional class in this setting, Dr. Gérald Simonneau said in a late-breaking session at the annual meeting of the American College of Chest Physicians.
The oral soluble guanylate cyclase stimulator was approved in the United States in October 2013 to treat CTEPH and pulmonary arterial hypertension (PAH) based on the phase III CHEST-1 and PATENT-1 studies.
CHEST-1 randomized 261 patients with inoperable CTEPH or persistent pulmonary hypertension after endarterectomy to placebo or riociguat up to 2.5 mg three times daily for 16 weeks.
In all, 237 patients entered CHEST-2, and were either maintained on their optimum riociguat dose, up to 2.5 mg three times daily, or switched to riociguat titrated up to 2.5 mg three times daily. Only 8% of patients required additional PAH drugs at 1 year.
Patients maintained on riociguat gained only 15 m on the 6-minute walk test at 1 year, but added 66 m overall from baseline, said Dr. Simonneau, head of pneumology and intensive care medicine at Hôpital Kremlin Bicêtre, University of Paris-Sud, Le Kremlin-Bicêtre, France.
Patients switching from placebo to riociguat gained 37 m in the walk test at 1 year, but only 45 m from baseline.
WHO functional class improved in about 15% of patients in the riociguat maintenance arm and about 30% of those switched from placebo, he reported.
Freedom from clinical worsening at years 1 and 2 were 88% and 80%, with estimated overall survival rates of 97% and 94%.
During a discussion of the results, Dr. Simonneau observed that the 2-year overall survival rate for CTEPH patients is approximately 92% for patients treated surgically, but only about 70% for those receiving traditional medical therapy.
Adverse events
One fatal pulmonary hemorrhage occurred during CHEST-2, but it was not considered related to the study drug, said Dr. Simonneau, who noted that riociguat's label includes a warning about the risk of pulmonary bleeding events.
Two fatal pulmonary hemorrhages occurred in PATENT-2, and one was related to riociguat, Dr. Lewis Rubin reported during the same session. A third serious pulmonary hemorrhage occurred that was considered related to riociguat, but it resolved.
Hemoptysis was another serious adverse event (SAE) of "interest and concern" in both pulmonary arterial hypertension and CTEPH patients, said Dr. Rubin of the University of California, San Diego. Two patients (1%) had serious hemoptysis in PATENT-1, with seven additional events occurring in the extension phase (2%). All but one case resolved, five were moderate, and no cases were considered related to the study drug, although this could not be entirely excluded.
"The outcome of pulmonary bleeding-related SAEs was, in general, resolved in most cases, and there does not appear to be an association between dose of riociguat used and the occurrence of hemoptysis," said Dr. Rubin. However, "we need some further clarification on the mechanism responsible," he added.
Six serious hemoptysis events occurred in the two CHEST studies (three each), and one patient required bronchial artery embolization. All patients were receiving anticoagulants and none of these events was considered related to the study drug, Dr. Simonneau said.
Overall, 100 (42%) patients in CHEST-2 had a serious AE, and 12 were considered related to riociguat. SAEs were reported in 204 patients (52%) in PATENT-2, with 7% considered study drug related. Syncope was the most common adverse event (2%).
PATENT study
PATENT-1 randomized 443 patients with PAH to placebo or riociguat titrated to 1.5 mg or 2.5 mg three times daily. In all, 98% of patients (434) entered PATENT-2 and received riociguat titrated up to 2.5 mg three times daily. Notably, 54% of patients were on additional PAH medications at 1 year (97% of those pretreated with riociguat and 11% of controls).
Six-minute walk distances increased from a mean of 400 m at the close of PATENT-1 to 417 m in patients initially given the maximum dose of riociguat, for a gain of 17 m; from 406 to 417 m in those initially capped at riociguat 1.5 mg; and from 390 to 426 m in the former placebo group, Dr. Rubin said.
WHO functional class improved by approximately 10% in all three arms.
Freedom from clinical worsening at 1 and 2 years was 88% and 77%, with overall survival estimated at 97% and 93%, he said.