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Riociguat fails to improve outcomes in idiopathic interstitial pneumonia-associated pulmonary hypertension: RISE-IIP

Among patients with idiopathic interstitial pneumonia-associated pulmonary hypertension, treatment with riociguat was linked to an increase in adverse events with no significant evidence of benefit, according to the RISE-IIP trial.

In fact, the international, multicenter, double-blind, randomized, placebo-controlled phase 2b trial was terminated early due to a higher incidence of deaths, serious adverse events and adverse event-related drug discontinuations in patients treated with riociguat (Adempas, Bayer) vs. placebo, researchers wrote in The Lancet Respiratory Medicine.

During the main study, most patients in the riociguat (65 of 73 patients) and placebo (64 of 74 patients) groups experienced an adverse event. The most common adverse events included peripheral edema (22% in the riociguat group vs. 9% in the placebo) and diarrhea (15% vs. 9%). Notably, serious adverse events were more common in the riociguat group than in the placebo group (37% vs. 23%), including worsening of interstitial lung disease (8% vs. 7%) and pneumonia (5% vs. 1%). Study discontinuation due to the frequency of adverse events was also more common in the riociguat group than in the placebo group (15% vs. 4%).

During a long-term, open-label extension phase in which all patients switched to riociguat after 26 weeks, adverse events leading to study discontinuation occurred more often in patients switching from placebo to riociguat (11% vs. 3%).

Also during the main study, 11 patients died, including three in the placebo group and eight in the riociguat group. During the long-term extension phase, nine patients who had received riociguat including eight in the former placebo group and one in the riociguat group died.

In terms of efficacy, the researchers observed no improvements in 6-minute walk distance at 26 weeks with riociguat when compared with placebo.

The study, which was terminated after a median of 157 days, enrolled patients aged 18 to 80 years who had idiopathic interstitial pneumonia, an FVC of at least 45%, a 6-minute walk distance of 150 m to 450 m, were WHO functional class II to IV and had precapillary pulmonary hypertension, systolic blood pressure of at least 95 mm Hg and no signs of hypotension. Patients in the riociguat group underwent a 10-week dose adjustment phase during which they received the drug in doses from 0.5 mg to 2.5 mg three times daily in 0.5 mg increments based on clinical signs and measurements followed by a 16-week maintenance phase.

In an accompanying editorial, Keith C. Meyer, MD, from the department of medicine at the University of Wisconsin School of Medicine and Public Health in Madison, noted that the lack of efficacy and the unfavorable risk-benefit profile of riociguat may not be surprising, even after accounting for some of the study’s limitations.

“Although enrolling participants with differing idiopathic interstitial pneumonia diagnoses and potentially failing to exclude a substantial number of patients with combined pulmonary fibrosis and emphysema and extensive emphysema might have represented an Achilles’ heel for this investigation, I suspect that benefit would not have been shown even in a population that consisted entirely of patients with idiopathic pulmonary fibrosis without a combined pulmonary fibrosis and emphysema phenotype,” Meyer wrote.

“Considering the track record of vasoactive agents approved for the treatment of pulmonary arterial hypertension that have been evaluated in clinical trials for fibrotic interstitial lung disease complicated by pulmonary hypertension, one could suggest that if a clinician is tempted to treat such a patient with a vasoactive agent, Hippocrates’ advice, ‘First do no harm,’ should come to mind.” – by Melissa Foster

Disclosures: The study was funded by Bayer AG and Merck. Nathan reports he has received consultant fees from Bayer and Inova Fairfax Hospital received research funding for work pertaining to the RISE-IIP study. Please see the study for all other authors’ relevant financial disclosures. Meyer reports he has received grants from the NIH, Genentech/Roche, InterMune, Parion, Nivalis, Promedior, Biogen and Galapagos.

Editor's note: The headline of this article was updated on Sept. 17, 2019, to specify that the study evaluated the effects of riociguat in patients with idiopathic interstitial pneumonia-associated pulmonary hypertension, not pneumonia-associated hypertension. The Editors regret the error.