Uptravi Triple Combo Delays Disease Progression in PAH Patients, But Fails to Meet Other Trial Goals

Note: This story was updated Sept. 28, 2020, to clarify that Uptravi was being tested as part of an initial triple combination strategy with Opsumit and tadalafil for newly diagnosed patients.

An initial triple combination strategy of the oral therapies Uptravi (selexipag), Opsumit (macitentan), and tadalafil is no better than the combination of Opsumit and tadalafil only at reducing pulmonary vascular resistance in people newly diagnosed with pulmonary arterial hypertension (PAH), a Phase 3b clinical  found.

In addition to failing its primary endpoint (goal), the TRITON trial (NCT02558231) also failed to demonstrate a benefit from Uptravi triple combo in cardiovascular health, disease severity, and other clinical variables.

The Uptravi combination, however, significantly lowered the risk of first disease progression by 41% compared to the standard initial therapy, and showed a trend toward better survival rates.

The findings were shared recently at the European Society of Cardiology Congress, held Aug. 29 to Sept. 1, in an oral presentation titled, “Long-term outcomes in newly diagnosed pulmonary arterial hypertension (PAH) patients receiving initial triple oral combination therapy: Insights from the randomised controlled TRITON study.”

“While the study’s primary endpoint was not met, we observed a signal of reduced risk of disease progression in the initial triple oral combination therapy group as compared to the initial double oral therapy group,” Nazzareno Galiè, MD, professor of cardiology at the University of Bologna, Italy,  and the study’s lead author, said in a press release.

Uptravi, sold by Actelion, is a selective agonist of the prostacyclin receptor, or a molecule that works like prostacyclin, a naturally occurring hormone that regulates blood pressure. It does so by attaching to receptors found on the cells of the blood vessel walls, causing the vessels to relax and dilate (expand).

It was the first prostacyclin receptor agonist approved by regulatory agencies as an oral treatment, after it significantly lowered by 40% the risk PAH progression in patients enrolled in the Phase 3 GRIPHON trial (NCT01106014).

Since its approval, several studies demonstrated that Uptravi could provide significant benefit to PAH patients when added to an endothelin-receptor antagonist (ERA), such as Opsumit, and an phosphodiesterase type 5 inhibitor (PDE-5i), such as tadalafil.

The TRITON study, conducted by Actelion, was designed to test an initial triple combination strategy in 247 newly diagnosed patients who had never received treatment for their PAH.

Enrolled across the U.S., Canada, Australia, and Europe, participants were assigned randomly to receive either a triple combination of Uptravi, Opsumit, and tadalafil, or the double Opsumit-tadalafil combo, for 26 weeks.

TRITON’s main goal was to determine whether this triple combo significantly lowered pulmonary vascular resistance — the resistance to blood flow through pulmonary circulation — in patients.

Secondary measures included improvements in six-minute walk test (6MWT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at week 26, as well as in time until first disease progression.

The 6MWT is a standard measure of cardiovascular health and NT-proBNP is the only validated and widely accepted prognostic marker of changes in cardiovascular function and survival in PAH.

After a median follow-up of more than 75 weeks in both groups, both the double and triple combination therapies had demonstrated improvements in pulmonary vascular resistance (by 52% and 54%, respectively), and in the 6MWT (by 55 and 56 meters, or 60 and 61 yards). No statistical differences were observed between groups.

However, at the time of the analysis, more patients in the double combination group had experienced disease progression (27 patients), compared with 16 patients in the triple combination group. This translated into a 41% reduction in the risk of disease progression.

By the end of the observation period, two patients had died in the triple therapy group (1.7%) and nine (7.1%) in the double therapy group. But researchers note this difference did not reach statistical significance and should be interpreted as exploratory, given that the primary endpoint was not met.

The adverse events, or side effects, reported in the trial remained consistent with the known safety profiles of the medications used in the study.

“Data from the TRITON and pivotal GRIPHON studies reinforce the role of [Uptravi] in the escalation of therapy on top of double oral therapy with an ERA and PDE-5i. These studies reaffirm Janssen’s commitment to innovation and the scientific advancement of PAH treatment and care,” said Alessandro Maresta, MD, a vice president at Actelion.

“We will continue to invest in the science and remain committed to transforming PAH into a long-term, manageable condition so that patients can live a normal life,” Maresta added.