Few Liver Problems With Opsumit in PAH Patients: Real-world Data

Nearly 10% of registry participants had a liver-related side effect during observation period

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Real-world use of Opsumit (macitentan) was generally safe, with few liver-related toxicities seen, according to data from two registries largely made up of pulmonary arterial hypertension (PAH) patients.

Collective data from the two registries met a requirement from the U.S. Food and Drug Administration (FDA) for additional real-world safety data — especially relating to potential liver toxicity — after Opsumit’s regulatory approval.

As in clinical trials, the treatment also appeared to prolong survival and prevent hospitalizations.

The findings “go beyond the setting of clinical trials and capture real‐world use of this medication,” the researchers wrote.

The study, “Safety of macitentan for the treatment of pulmonary hypertension: Real‐world experience from the OPsumit USers Registry (OPUS) and OPsumit Historical USers cohort (OrPHeUS),” was published in Pulmonary Circulation.

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Opsumit is a daily oral therapy designed to slow disease progression and prevent hospitalizations for PAH patients. Belonging to a class of medications called endothelin receptor antagonists, it works to widen the blood vessels that are characteristically narrowed in PAH.

It’s approval was based on findings from the pivotal SERAPHIN Phase 3 trial (NCT00660179), which showed that daily Opsumit was well tolerated and significantly reduced morbidity (e.g. lung transplant), PAH progression, and death.

Although its safety profile was favorable, other medications in the same class have been associated with liver toxicity, prompting the FDA to require a post-marketing safety monitoring program for Opsumit after its U.S. approval in 2013. The agency said the program needed to include 5,000 patients.

OPUS — the OPsumit USers REgistry (NCT02126943) — and OrPHeUS, the OPsumit Historical USers cohort (NCT03197688), were launched at 155 sites in the U.S. to collect real-world safety data from patients starting Opsumit. OPUS ran from April 2014 to June 2020, while OrPHeUS ran from October 2013 to March 2017.

PAH patients, non-PAH patients in OPUS, OrPHeUS

The recent study focuses on the 4,626 PAH patients who were included in either registry as well as 1,024 patients who used Opsumit but didn’t have PAH.

Most (75.5%) of the PAH patients (median age, 62) were female and the most common forms of PAH were idiopathic (no known cause) PAH (54.8%) and PAH with connective tissue disorder (26.8%).

Opsumit was used during follow-up by the entire patient group for a median of 13.6 months and by PAH patients for a median ofr 14.5 months.

Among the PAH patients, Opsumit was usually initiated as part of a dual therapy regimen (48%), but was sometimes given as a single treatment (38%) or as part of a triple therapy (14%). Phosphodiesterase type‐5 inhibitors were the most common type of treatment used with it.

After six months, the proportion of patients using only Opsumit decreased to 30%, whereas the percentages of patients using double or triple therapies increased to 50% and 20%, respectively.

Side effects with Opsumit

The most common side effects seen during OPUS included labored breathing (23.1%), headache (11.6%), and swelling (10.6%).

Throughout the observation period, nearly 10% of all participants in the two registries — 561 of 5,650 people — had at least one liver-related side effect, including 457 people with a PAH diagnosis.

Of the 44% of patients in the overall group who stopped using Opsumit during follow-up, 1,026 did so due to side effects unrelated to the liver and 17 did so due to a liver-related event. Among PAH patients, 790 discontinued treatment due to side effects unrelated to the liver, whereas 15 did so due to a liver-related side effect. In the overall group, the remaining discontinuations were not due to side effects (1,045 people) or the reason wasn’t documented (399 people).

No new safety signals were identified in the study, with side effect profiles generally consistent with SERAPHIN, the researchers noted.

“That 18.1% of patients in this analysis discontinued [Opsumit] for reasons other than an [adverse event] suggests the need to address these factors to ensure optimal outcomes for patients, as low adherence is associated with suboptimal clinical benefits,” the scientists wrote.

An estimated 60% of PAH patients were free from hospitalization after a year of treatment and 36% were hospitalization-free at three years, analyses showed.

There were 697 deaths among PAH patients during the observation period. The estimated survival rate was 90% after a year and 75% after three years. These rates of hospitalization and survival were also consistent with the results from the SERAPHIN trial, the researchers said, noting the findings provided “important evidence to supplement findings from clinical studies.”

The FDA announced in 2019 that data from OPUS/OrPHeUS fulfilled its requirement for additional safety data.

Both registries were sponsored by Opsumit’s developer, Actelion Pharmaceuticals, a Janssen Pharmaceutical company of Johnson and Johnson. Three of the study’s authors are or were employees of Janssen.

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