The GRIPHON study was a multicentre, double-blind, placebo-controlled, event-driven Phase 3 trial.^[1]

BID, twice daily; FC, functional class; PAH, pulmonary arterial hypertension; 6MWD, 6-minute walk distance; WHO, World Health Organization

The GRIPHON study assessed the safety and efficacy of UPTRAVI^® across a broad range of patients with PAH.^[1]

CHD, congenital heart disease; CTD, connective tissue disease; ERA, endothelin receptor antagonist; FC, functional class; HIV, human immunodeficiency virus; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; PDE-5i, phosphodiesterase type-5 inhibitor; WHO, World Health Organization
*9 patients were in FC I, 11 patients in FC IV.
†Other aetiologies included drug- or toxin-induced PAH (2%) and HIV-PAH (1%).
‡Patients with repaired congenital systemic-to-pulmonary shunts.

Evidence for the long-term efficacy of UPTRAVI^® is based on GRIPHON primary endpoint data showing a 40% reduction of the risk of morbidity-mortality* vs placebo. The treatment effect of UPTRAVI^® was consistent across prespecified subgroups, including aetiology and as monotherapy, in combination with an ERA or a PDE-5 inhibitor, or triple combination with both an ERA and a PDE-5 inhibitor.^[1][2][3][4]

Adapted from Sitbon et al. 2015^[1]>
CI, confidence interval; ERA, endothelin receptor antagonist; HR, hazard ratio; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase type 5
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in disease progression and hospitalisations due to PAH; they do not apply to mortality on its own.

Consistent with the primary endpoint in the overall population, UPTRAVI^® reduced the risk of a morbidity-mortality event* vs placebo in patients with CHD-PAH† by 42% (HR 0.58; 95% CI: 0.25–1.37)^[2] and in patients with CTD-PAH by 41% (HR 0.59; 95% CI : 0.41–0.85).‡^[3]

The treatment effect with UPTRAVI^® was consistent in patients with CTD-PAH across the CTD subtypes. Compared with placebo, UPTRAVI^® reduced the risk of morbidity-mortality* by 44% in patients with SSc-PAH, by 34% in patients with SLE-PAH and by 32% in patients with MCTD-PAH/other-CTD-PAH.^[3]

Adapted from Gaine et al. 2017^[3]
CHD, congenital heart disease; CI, confidence interval; CTD, connective tissue disease; HR, hazard ratio; MCTD, mixed connective tissue disease; PAH, pulmonary arterial hypertension; SLE, systemic lupus erythematosus; SSc, systemic sclerosis
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in disease progression and hospitalisations due to PAH; they do not apply to mortality on its own.
†Patients with repaired congenital systemic-to-pulmonary shunts.
‡Patients with MCTD-PAH and other-CTD-PAH (HR 0.68; 95% CI: 0.31–1.47).

Adapted from Gaine et al. 2017^[3]
CI, confidence interval; HR, hazard ratio; PAH, pulmonary arterial hypertension; SLE, systemic lupus erythematosus
*As measured by a composite primary morbidity-mortality endpoint . Results were driven by a decrease in disease progression and hospitalisations due to PAH; they do not apply to mortality on its own.

UPTRAVI^® reduced the risk of morbidity-mortality* vs placebo by 37% in patients receiving double oral combination therapy with an ERA and a PDE-5i.^[4]

Adapted from Coghlan et al. 2018^[4]
CI, confidence interval; ERA, endothelin receptor antagonist; HR, hazard ratio; PAH, pulmonary arterial hypertension; PDE-5i, phosphodiesterase type-5 inhibitor
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in disease progression and hospitalisations due to PAH; they do not apply to mortality on its own.

The effect of UPTRAVI^® was consistent with the primary endpoint for all background therapy subgroups. UPTRAVI^® reduced the risk of morbidity-mortality* vs placebo by 43% in patients not receiving any therapy at baseline (HR 0.57; 99% CI: 0.32–1.03; p=0.0068), by 42% in patients receiving PDE-5i monotherapy at baseline (HR 0.58; 99% CI: 0.37–0.91; p=0.0008) and by 34% in patients receiving ERA monotherapy at baseline (HR 0.66; 99% CI: 0.32–1.35; p=0.655).^[5]

Addition of UPTRAVI^® to double oral combination therapy reduced the risk of a morbidity-mortality event* in WHO FC II and FC III patients. The benefit of adding UPTRAVI^® was seen early and was sustained throughout the long term.^[4]

Adapted from Coghlan et al. 2018^[4]
CI, confidence interval; ERA, endothelin receptor antagonist; FC, functional class; HR, hazard ratio; PAH, pulmonary arterial hypertension; PDE-5i, phosphodiesterase type-5 inhibitor; WHO, World Health Organization
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in disease progression and hospitalisations due to PAH; they do not apply to mortality on its own.

When added to double combination therapy, UPTRAVI^® reduced the risk of morbidity-mortality* vs placebo by 26% in WHO FC III patients (HR 0.74; 95% CI: 0.50–1.10).^[4]