Treatment effect of selexipag on time to disease progression when initiated early in pulmonary arterial hypertension (PAH) patients: GRIPHON and TRITON pooled analysis
Authors: Coghlan G J , Gaine S , Channick R N , Chin K M , Du Roure C , Gibbs J S R , Hoeper M M , Lang I M , Mathai S C , McLaughlin V V , Mitchell L , Simonneau G , Sitbon O , Tapson V , Galie N 
Published: October 2021

Abstract

Background
In PAH clinical practice, drugs targeting the prostacyclin pathway, including the oral prostacyclin receptor agonist selexipag, are often initiated years after diagnosis. The GRIPHON (NCT01106014) and TRITON (NCT02558231) randomised controlled trials examined the impact of selexipag on disease progression, primary and secondary endpoints, respectively. In GRIPHON, selexipag significantly reduced the risk of disease progression (composite primary endpoint) in a PAH population (N=1156) with a mean time from diagnosis of 2.4 years, as part of an oral triple, double or monotherapy regimen versus placebo. In TRITON, a potential signal for reduced risk of disease progression was observed with initial triple oral therapy (selexipag, macitentan, tadalafil) versus initial double oral therapy (placebo, macitentan, tadalafil) in a population of 247 newly diagnosed, treatment naïve patients.

Purpose
To investigate the impact of initiating selexipag within 6 months of diagnosis on disease progression in a large PAH population.

Methods
We selected patients from GRIPHON and TRITON diagnosed within 6 months of randomization and compared those on active therapy with selexipag (selexipag group) versus those on control therapy with placebo (control group). Disease progression endpoints were defined as in the GRIPHON and TRITON studies, respectively. Hazard ratios (HR) and 95% CI for time to first disease progression event up to end of double-blind treatment (selexipag/placebo) + 7 days were estimated using a Cox regression model which included treatment as a factor, and baseline prognostic factors and study as covariates.

Results
Overall, 649 patients met the criteria (diagnosis ≤6 months) for these analyses: 329 in the selexipag group (207 from GRIPHON and 122 from TRITON) and 320 in the control group (197 from GRIPHON and 123 from TRITON). Patient characteristics at baseline and treatment regimens were balanced between the treatment groups. With respect to treatment regimen, selexipag/placebo was given as part of triple therapy in 44%, double therapy in 32% and monotherapy in 24% of patients. The median (range) exposure to study treatment was 510 (4–1280) and 409 (3–1318) days in the selexipag and control groups, respectively. There were 67 (20%) and 116 (36%) patients who experienced a disease progression event in the selexipag and control groups, respectively. Selexipag reduced the risk of disease progression (first event) by 52% compared to control (HR 0.48 [95% CI 0.35, 0.66]) (Figure).

Conclusions
This post-hoc pooled analysis of GRIPHON and TRITON patients diagnosed within 6 months suggests that targeting the prostacylin pathway with selexipag within a short time after diagnosis may reduce the risk of disease progression in a broad PAH population.

Funding Acknowledgement
Type of funding sources: Other. Main funding source(s): Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson