Uptravi Aids Blood Flow in Resistant CTEPH, But Not Exercise Capacity
Treatment with Uptravi (selexipag) significantly improved blood flow parameters in people with inoperable or persistent chronic thromboembolic pulmonary hypertension (CTEPH) in a Phase 3 clinical trial, although its use did not significantly affect measures of physical abilities.
Full trial results are in “Selexipag for the treatment of chronic thromboembolic pulmonary hypertension,” published in the European Respiratory Journal. The study was funded by Uptravi’s developers, Nippon Shinyaku and Janssen.
Uptravi, an oral medicine, works by mimicking the action of a signaling molecule called prostacyclin, which prompts blood vessels to relax and widen to lower blood pressure. It is approved in countries that include the U.S. and Japan, where this trial took place, to treat pulmonary arterial hypertension (PAH). CTEPH is a form of pulmonary hypertension caused by blood clots in the lungs.
This clinical trial (JapicCTI: 163279) enrolled 78 people with CTEPH, ages 20 to 85, at 42 institutions across Japan. Surgery to remove the clots is a usual first-line treatment for CTEPH, and most of these patients were not eligible for surgery. The others had CTEPH that persisted following surgery. About 60% of the patients were taking the approved CTEPH medication Adempas (riociguat).
Half of the participants were randomly assigned to treatment with Uptravi for 20 weeks, while the other 39 patients took a placebo. Uptravi was started at a dose of 200 micrograms (ug) twice daily. Over the study’s first 12 weeks, the treatment’s dose was slowly increased, based on tolerability, up to a maximum of 1,600 ug twice daily. One-third of the Uptravi-group patients moved to this maximum dose.
Phase 3 trial’s safety and efficacy findings
Safety data from were generally in line with findings from prior studies of Uptravi: the most common side effects included headache (53.8%), diarrhea (41.0%), nausea (33.3%), malaise (23.1%), jaw pain (20.5%), decreased appetite (20.5%), muscle pain (15.4%), vomiting (15.4%), and joint pain (10.3%). Three people in the Uptravi group stopped the treatment due to side effects.
“The incidence of adverse events characteristic of prostacyclin drugs is high, and the safety profile seen in this study is similar to those seen in other selexipag [Uptravi] studies in PAH,” the researchers wrote.
The study’s met its main goal, that of treatment easing pulmonary vascular resistance (PVR), a measure of the internal resistance to blood flow in the lungs’ blood vessels. After 20 weeks, PVR values were significantly lower in patients given Uptravi compared with those on placebo.
“All subgroup analyses indicated a consistent beneficial effect of selexipag on PVR,” the researchers noted.
Other parameters related to blood flow and heart function, such as cardiac index, total pulmonary resistance, and mixed venous oxygen saturation — measuring the oxygen content of blood returning to the heart from the body — also significantly improved with Uptravi relative to placebo over the trial’s 20 weeks.
However, no significantly differences in measures of physical abilities, including six-minute walk distance (6MWD) and the World Health Organization (WHO) functional class, were evident between the treatment and placebo groups. Scores on a standardized measure of life quality called the EQ-5D-5L also did not differ between the groups.
Researchers suggested the trial may have been too small to detect a significant difference in these measures. They also noted the group’s relatively well-preserved exercise tolerance at study start, possibly due to previous treatments like balloon pulmonary angioplasty or pulmonary hypertension medications, “might have attenuated [weakened] the treatment effect” on 6MWD and WHO functional class.
“Furthermore, a ceiling effect of 6MWD might mask efficacy in mild symptomatic PH [pulmonary hypertension] patients who have high baseline [starting] 6MWD” scores, the team added, stressing that larger studies are needed to evaluate Uptravi’s effect on physical function in people with CTEPH.
“The results of this study suggest that selexipag is well tolerated and safe, and that it improves pulmonary haemodynamics [blood flow] in CTEPH patients who cannot undergo [surgery] or those with persistent or recurrent PH after [surgery]. No improvement was observed in exercise capacity,” the researchers concluded.
Notably, Uptravi’s approval in Japan was extended to cover the treatment of inoperable or persistent/recurrent CTEPH after surgery last year by the country’s Ministry of Health, Labor and Welfare.
In an accompanying editorial, Hossein-Ardeschir Ghofrani, MD, a professor at Universities of Giessen and Marburg Lung Center in Germany, argued that the trial’s meeting its primary goal of improved PVR without improvements seen in functional capacity “simply isn’t enough.”
“Though this study met its primary endpoint and oral selexipag was approved as a treatment for inoperable CTEPH patients in Japan, the overall results and scope of this study do not justify a valid position for selexipag” among treatments available for this patient group, Ghofrani wrote.