Riociguat: Clinical research and evolving role in therapy

Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud\u27s phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension

EPITOME-2: An open-label study assessing the transition to a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension.

Background Continuous infusion of epoprostenol is the treatment of choice in patients with pulmonary arterial hypertension in functional classes III to IV. However, this treatment's limitations include instability at room temperature. A new epoprostenol formulation offers improved storage conditions and patient convenience. Methods The EPITOME-2 trial was an open-label, prospective, multicenter, single-arm, phase IIIb study. Patients with pulmonary arterial hypertension on long-term, stable epoprostenol therapy were transitioned from epoprostenol with glycine and mannitol excipients (Flolan; GlaxoSmithKline, Durham, NC) to epoprostenol with arginine and sucrose excipients (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland). Patients were followed up for 3 months, and dose adjustments were recorded. Efficacy measures included the 6-minute walk distance, hemodynamics assessed by right heart catheterization, and New York Heart Association functional class. Safety and tolerability of the transition were also evaluated. Quality of life was assessed using the Treatment Satisfaction Questionnaire for Medication. Results Forty-two patients enrolled in the study, and 1 patient withdrew consent before treatment; thus, 41 patients received treatment and completed the study. Six patients required dose adjustments. There were no clinically relevant changes from baseline to month 3 in any of the efficacy end points. Adverse events were those previously described with intravenous prostacyclin therapy. Treatment Satisfaction Questionnaire for Medication scores showed an improvement from baseline to month 3 in the domain of treatment convenience. Conclusions Transition from epoprostenol with glycine and mannitol excipients to epoprostenol with arginine and sucrose excipients did not affect treatment efficacy, raised no new safety or tolerability concerns, and provided patients with an increased sense of treatment convenience

Relationship Between Time From Diagnosis and Morbidity/Mortality in Pulmonary Arterial Hypertension: Results From the Phase III GRIPHON Study

BACKGROUND: Early initiation of pulmonary arterial hypertension (PAH) therapies is associated with improved long-term outcomes, yet data on the early use of prostacyclin pathway agents are limited. In these post hoc analyses of the Prostacyclin (PGI(2)) Receptor Agonist In Pulmonary Arterial Hypertension (GRIPHON) study, the largest randomized controlled trial for PAH to date, the prognostic value of time from diagnosis and its impact on treatment response were examined. RESEARCH QUESTION: How does time from diagnosis impact morbidity/mortality events and response to selexipag treatment in patients with PAH? STUDY DESIGN AND METHODS: The GRIPHON study randomly assigned 1,156 patients with PAH to selexipag or placebo treatment. Patients were categorized post hoc into a time from diagnosis of ≤ 6 months and > 6 months at randomization. Hazard ratios (selexipag vs placebo) were calculated for the primary end point of morbidity/mortality by time from diagnosis using Cox proportional hazard models. RESULTS: Time from diagnosis was ≤ 6 months in 34.9% and > 6 months in 65.1% of patients. Time from diagnosis was prognostic of morbidity/mortality, with newly diagnosed patients having a poorer long-term outcome than patients diagnosed for longer. Compared with placebo, selexipag reduced the risk of morbidity/mortality in patients with a time from diagnosis of ≤ 6 months and > 6 months, with a more pronounced effect in newly diagnosed patients (hazard ratio, 0.45 [95% CI, 0.33-0.63] and 0.74 [95% CI, 0.57-0.96], respectively; P = .0219 for interaction). INTERPRETATION: In the GRIPHON study, newly diagnosed PAH patients had a worse prognosis than patients with a longer time from diagnosis. The benefit of selexipag treatment on disease progression was more pronounced in patients treated earlier than in patients treated later. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01106014; URL: www.clinicaltrials.gov

Long-Term Survival, Safety and Tolerability with Selexipag in Patients with Pulmonary Arterial Hypertension: Results from GRIPHON and its Open-Label Extension

INTRODUCTION: In the event-driven GRIPHON randomised-controlled trial, the oral prostacyclin receptor agonist selexipag significantly reduced the risk of disease progression (composite primary endpoint of morbidity/mortality), compared with placebo, in patients with pulmonary arterial hypertension (PAH). The ongoing open-label extension study (GRIPHON OL) collects further data on long-term safety, tolerability, and survival of PAH patients treated with selexipag. METHODS: Patients randomised to selexipag or placebo in GRIPHON could enter GRIPHON OL either after experiencing a morbidity event during double-blind treatment or at the end of the study. Patients were followed for adverse events (AE) and survival from selexipag initiation up to 3 days and 30 days after end of treatment, respectively. Data are presented up to a cut-off date of 1 September 2019. RESULTS: Overall, 953 patients in GRIPHON and GRIPHON OL were treated with selexipag. At the time of selexipag initiation, 81.2% of patients were receiving background PAH therapy. Median (min, max) exposure to selexipag was 31.7 months (0, 106), corresponding to a total of 3054.4 patient-years. The most frequently reported AEs were related to known prostacyclin-related effects or underlying disease. There were 305 (32.0%) patients who experienced an AE leading to treatment discontinuation. Survival during GRIPHON and GRIPHON OL was assessed for the 574 patients randomised to selexipag in GRIPHON. Kaplan-Meier survival estimates (95%CI) at 1, 3, 5 and 7 years were 92.0% (89.4, 94.0), 79.3% (75.4, 82.6), 71.2% (66.5, 75.3) and 63.0% (57.4, 68.1), respectively. CONCLUSIONS: These results provide the longest follow-up period published to date for a PAH therapy. The safety profile of selexipag over this extended treatment period was consistent with that observed in GRIPHON. A large proportion of the population was receiving background therapy at selexipag initiation, providing further insight into the long-term safety of selexipag as part of a combination therapy regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306

Three- Versus Two-Drug Therapy for Patients With Newly Diagnosed Pulmonary Arterial Hypertension

BACKGROUND: In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy. OBJECTIVES: TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH. METHODS: Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week 26. RESULTS: Patients were assigned to initial triple (n = 123) or initial double therapy (n = 124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P = 0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died. CONCLUSIONS: In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy

ERS International Congress 2021: highlights from the Pulmonary Vascular Diseases Assembly

This article aims to summarise the latest research presented at the virtual 2021 European Respiratory Society (ERS) International Congress in the field of pulmonary vascular disease. In light of the current guidelines and proceedings, knowledge gaps are addressed and the newest findings of the various forms of pulmonary hypertension as well as key points on pulmonary embolism are discussed.Despite the comprehensive coverage of the guidelines for pulmonary embolism at previous conferences, discussions about controversies in the diagnosis and treatment of this condition in specific cases were debated and are addressed in the first section of this article.We then report on an interesting pro–con debate about the current classification of pulmonary hypertension.We further report on presentations on Group 3 pulmonary hypertension, with research exploring pathogenesis, phenotyping, diagnosis and treatment; important contributions on the diagnosis of post-capillary pulmonary hypertension are also included.Finally, we summarise the latest evidence presented on pulmonary vascular disease and COVID-19 and a statement on the new imaging guidelines for pulmonary vascular disease from the Fleischner Society

risk assessment in pulmonary arterial hypertension insights from the griphon study

BACKGROUND Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH. METHODS GRIPHON randomized 1,156 patients with PAH to selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide RESULTS Both the number of low-risk criteria and the REVEAL 2.0 risk category were prognostic for morbidity/mortality at baseline and any time-point during the study. Patients with 3 low-risk criteria at baseline had a 94% reduced risk of morbidity/mortality compared to patients with 0 low-risk criteria and were all categorized as low-risk by REVEAL 2.0. The treatment effect of selexipag on morbidity/mortality was consistent irrespective of the number of low-risk criteria or the REVEAL 2.0 risk category at any time-point during the study. Selexipag-treated patients were more likely to increase their number of low-risk criteria from baseline to week 26 than placebo-treated patients (odds ratio 1.69, p = 0.0002); similar results were observed for REVEAL 2.0 risk score. CONCLUSIONS These results support the association between risk profile and long-term outcome and suggest that selexipag treatment may improve risk profile