Riociguat increases the risk of death and serious adverse events in people with pulmonary hypertension (PH) associated with idiopathic interstitial pneumonia (IIP), and should not be prescribed to those patients, final results of a Phase 2 study show.
The study, “Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study,” was published in the journal The Lancet Respiratory Medicine.
IIP is a group of lung disorders of unknown cause characterized by varying degrees of inflammation and fibrosis (scarring). Idiopathic pulmonary fibrosis is the most common among them.
IIP is frequently complicated by PH, which is associated with worse functional status and increased mortality. To date, there are no approved treatments for PH associated with IIP (PH-IIP), classified as Group 3 under the WHO (World Health Organization) classification system.
Adempas (riociguat) is a vasodilator — a molecule that widens blood vessels, reducing blood pressure in the lungs — approved for the treatment of PH symptoms in patients with pulmonary arterial hypertension (PAH, WHO Group 1), and chronic thromboembolic PH (CTEPH, WHO Group 4).
Preclinical studies had shown that riociguat has anti-fibrotic and anti-inflammatory properties, and results from a small open-label Phase 2 study suggested that PH-IIP patients could benefit from this therapy.
The RISE-IIP study (NCT02138825), a randomized, double-blind, placebo-controlled, international Phase 2 trial, sponsored by Bayer Pharmaceuticals (the manufacturer of Adempas), was designed to evaluate the efficacy and safety of riociguat, compared to a placebo, in patients with PH-IIP.
The trial involved 147 adults with PH-IIP (ages 18–80), who were randomly selected to receive riociguat at a dose up to 2.5 mg three times a day (73 patients), or a placebo (74 patients) for 26 weeks. More than 65% of participants were diagnosed with idiopathic pulmonary fibrosis.
The study’s primary goal was to assess changes in patients’ exercise capacity — measured through the six-minute walk test (6MWD) — at week 26. The secondary goal was to assess the time a patient lived without disease progression.
After completing the 26 weeks, participants could enter an open-label extension study in which all patients received riociguat.
In total, 72 patients completed the main study (33 in the riociguat group, and 39 in the placebo group), and 70 patients (32 in the riociguat group, 38 in the former placebo group) received riociguat in the extension study. Median duration of treatment was 157 days.
The recently published final results of the study showed no significant differences in exercise capacity, time to disease progression, and the proportion of patients showing disease progression between those in the riociguat and placebo groups at 26 weeks.
Furthermore, a higher proportion of patients (89–91%) who received riociguat reported adverse and serious adverse events compared with those in the placebo group (86–89%). The frequency of adverse and serious adverse events leading to discontinuation of treatment was also higher in the riociguat group (around 15%) than in the placebo group (4%).
The most common adverse events were swelling of lower legs or hands (22% of patients in the riociguat group versus 9% in the placebo group), and diarrhea (15% versus 9%). The most common serious adverse events were worsening of fibrosis-associated lung disease (8% in the riociguat group versus 7% in the placebo group), and pneumonia (5% versus 1%).
Eleven patients died during the main study — eight in the riociguat group and three in the placebo group. Nine died during the extension study — eight from the former placebo group and one in the riociguat group.
The team noted that no specific cause or common feature among the patients who died was identified, except that many appeared to have more advanced lung disease compared to the general patient population.
Overall, “in patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavorable risk-benefit profile. Riociguat should not be used in patients with PH-IIP,” the team concluded.
The study was ended early in 2016 based on a recommendation from the trial’s Data Monitoring Committee, an independent panel that monitors the safety of patients in ongoing trials, because of riociguat’s unfavorable risk-benefit profile.
“Owing to the absence of efficacy of riociguat in patients with PH-IIP, and the higher number of deaths and serious adverse events with riociguat treatment than with placebo, RISE-IIP was terminated prematurely,” the researchers stated.
According to the team, this study sends “an important message for those who are inclined to treat [PH-IIP] and other forms of lung disease with off-label [PAH] therapies,” including riociguat.