selexipag and Hypertension--Pulmonary

Despite the availability of treatments for all subgroups of pulmonary hypertension (PH), the prognosis for PH remains poor. This systematic review and meta-analysis aimed to determine the efficacy and safety of selexipag in patients with PH. A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized controlled trials (RCTs) on treatment of PH with selexipag, compared with placebo or blank, were reviewed. Studies were pooled to weighted mean differences (WMDs) and risk ratios (RRs), with 95% confidence intervals (CIs). Selexipag was safe and significantly improved hospitalization for worsening of PH, WHO FC, mPAP, NT-proBNP, and cardiac index in patients with PH. Selexipag should be considered in patients with pulmonary arterial hypertension or chronic thromboembolic PH.

Topics: Acetamides; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Randomized Controlled Trials as Topic

This meta-analysis was performed to evaluate the effect and safety of selexipag in the treatment of pulmonary hypertension and to explore the effect of selexipag on cardiac function indexes in PAH patients.. Electronic databases, including the Cochrane Library, EMBASE, and PubMed databases, were searched. Endnote software X9 was used for study selection, and the Cochrane Risk of Bias Tool was used for literature screening and quality assessment. Data analysis was performed using RevMan 5.3 software, and GRADE was used to assess the evidence level.. Ten studies were finally selected in accordance with the standard. A total of 10 papers were included. A total of 1322 patients were included, including 723 in the trial group and 599 in the control group. Patients with PAH treated with selexipag were included in the trial group, and patients with PAH treated with placebo were included in the control group. The results of the study showed that selexipag was effective in reducing mortality in patients (WMD=0.70, 95% CI: 0.53-0.94, P = 0.02). Selexipag effectively increased the 6-min walk distance (WMD=33.79, 95% CI: 2.69-64.90, P=0.03). Selexipag also effectively increased the 6-min distance between baseline and follow-up (WMD = 15.28, 95% CI: 7.76-22.80, P < 0.0001). Selexipag effectively reduced PVR (WMD = -230.96, 95% CI: 445.94 to -15.97, P = 0.04). Selexipag significantly reduced PVR between baseline and follow-up (WMD = -139.62, 95% CI: 215.32 to -63.91, P = 0.0003). The adverse reactions of selexipag were mild with headache, diarrhea and nausea reported as the main symptoms.. Selexipag is a new drug with mild adverse reactions and is safe for the treatment of PAH. This drug significantly prolongs the level of 6MWD in PAH patients, reduces the fatality rate, improves WHO FC and reduces PVR. The effects of this drug on CI, mPAP, MRAP, SvO. CRD42021245557.

Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pyrazines; Receptors, Epoprostenol

The comparative efficacy between riociguat and selexipag in patients with pulmonary arterial hypertension (PAH) has never been described in literature. Our aim was to prepare indirect treatment comparison (ITC) to evaluate the cost-effectiveness of riociguat in Czechia.. A systematic literature review identified two relevant trials with comparable endpoints to inform a Bucher ITC of relative and absolute effects. Given the comparable efficacy of riociguat and selexipag, a cost-minimization analysis (CMA) was conducted.. A Bucher ITC provided evidence for the comparable relative efficacy of riociguat defined as the odds of unimproved functional class III 0.761 (95% CI 0.372 to 1.558; p = 0.455) compared to selexipag and a comparable absolute efficacy defined as a difference in the 6-minute walking distance of 10.560 meters (95% CI -10.692 to 31.812; p = 0.330). The CMA identified riociguat as the cost-saving therapy.. Switching to riociguat represents the cost-saving therapy for PAH patients who were inadequately compensated with the PDE5i+ERA therapy. Consequently, riociguat has been introduced to the list of reimbursed medicines in Czechia from October 2021. Based on two global trials, we prepared the first indirect treatment comparison followed with CMA of these therapies that may improve future decision-making for PAH indications.

Topics: Antihypertensive Agents; Costs and Cost Analysis; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension

Selexipag is a first-in-class, oral, long-acting, selective, non-prostanoid agonist of the prostacyclin receptor (IP receptor), indicated for the treatment of symptomatic adult pulmonary arterial hypertension (PAH). It was designed with the objective to surpass the inconveniences associated with standard prostanoid therapy, presenting fewer adverse effects and comparable hemodynamic benefits.. This review describes the pharmacologic properties of selexipag and presents the clinical trials that have been completed or are currently ongoing regarding its clinical efficacy, safety, and tolerability. The pivotal GRIPHON study is extensively presented.. Selexipag is the first IP receptor to reduce the morbidity/mortality composite endpoint of the GRIPHON study, a large, randomized, placebo-controlled study. The TRITON study failed to demonstrate a clear benefit of initial triple oral therapy including selexipag compared to initial double oral therapy. Current guidelines do not provide definitive recommendations regarding the place of selexipag in the treatment algorithm of PAH. Finally, the possibility of transition between the several drugs acting in the prostacyclin pathway, and the potential role of selexipag in chronic thromboembolic pulmonary hypertension and pediatric PAH is currently being examined, possibly expanding its future use.

Topics: Acetamides; Administration, Oral; Adult; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazines; Randomized Controlled Trials as Topic; Treatment Outcome

Prostacyclin is produced in vascular endothelial cells and acts via the IP prostacyclin receptor to cause vasodilation and inhibit smooth muscle cell proliferation and platelet aggregation. Prostacyclin production is reduced in pulmonary arterial hypertension (PAH), and drugs targeting the prostacyclin pathway are one of the pharmacotherapeutic options for PAH. Areas covered: The prostacyclin pathway and drugs that target it are discussed, including synthetic prostacyclin (epoprostenol), prostacyclin analogs (iloprost, treprostinil, beraprost) and selective prostacyclin IP receptor agonists (selexipag). An overview of the development of these therapies, from the earlier agents requiring parenteral administration, through inhaled formulations, to oral products, is provided, together with a summary of data from key clinical trials and registries. Expert commentary: Synthetic prostacyclin and prostacyclin analogs are beneficial for patients with PAH, but they tend to be underused, in part due to the difficulties associated with the administration of parenteral and inhaled formulations. Oral prostacyclin analogs have some limitations with regard to efficacy. The newest agent targeting the prostacyclin pathway, the selective prostacyclin receptor agonist selexipag, is administered orally, and has been shown to reduce a composite morbidity/mortality endpoint. Ongoing studies will help clarify how best to use it in the management of PAH.

Topics: Acetamides; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazines; Receptors, Epoprostenol

To evaluate the data supporting the approval of selexipag and discuss its potential place in therapy for managing pulmonary arterial hypertension (PAH).. A systematic review of the literature for all relevant articles was performed through January 16, 2017, using MEDLINE and SCOPUS. A manual search of references from reports of clinical trials, review articles, and recent conference abstracts was performed to identify additional relevant studies.. Eligible citations included in vitro or in vivo evaluations of selexipag, with no restrictions on patient population or indication. Data related to the patient populations and outcomes of interest were extracted from each citation.. Single phase II and phase III trials have been published evaluating selexipag in patients with PAH. In 43 patients, the phase II trial showed that selexipag significantly reduced pulmonary vascular resistance by 30% versus placebo ( P = 0.0045) and improved 6-minute walk distance by 24 m ( P < 0.05). The larger phase III trial enrolled 1156 patients with PAH, showing that selexipag lowered the incidence of death or PAH-related complications by 40% versus placebo ( P < 0.001). Selexipag also improved 6-minute walk distance and lowered hospitalization risk. Common adverse events included headache, diarrhea, nausea, and jaw pain.. The specific role of selexipag for managing PAH patients is unclear because of its modest efficacy, lack of mortality reduction, and cost similar to intravenous prostacyclins. Additional clinical trials exploring combination therapy as well as its role in other types of pulmonary hypertension are needed.

Topics: Acetamides; Costs and Cost Analysis; Hospitalization; Humans; Hypertension, Pulmonary; Prostaglandins I; Pyrazines

Selexipag is the first oral, non-prostanoid, selective prostacyclin receptor (IP receptor) agonist, approved for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients. Areas covered: This article reviews the clinical pharmacology, efficacy, and safety of selexipag in the treatment of PAH. Expert opinion: Selexipag is the first oral drug that selectively targets the prostacyclin pathway, and has evidence of long-term efficacy and safety. In the global phase 3 study GRIPHON (NCT01106014) in PAH patients, selexipag significantly reduced the risk of the primary composite outcome of morbidity/mortality (M/M). The adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, nausea, jaw pain, and diarrhea. Importantly, selexipag was efficacious and safe irrespective of whether or not patients were already receiving other PAH therapies. With selexipag approval, triple oral combination therapy addressing three important pathways is available for patients with PAH. Selexipag has one major metabolite, ACT-333679, which is also a selective IP receptor agonist, with 37-fold higher potency than selexipag. Pharmacokinetic properties of ACT-333679 permit twice-daily dosing of selexipag, providing a more convenient treatment compared to prostacyclin or its analogs. For patients with moderate hepatic impairment a once-daily regimen is recommended.

Topics: Acetamides; Acetates; Administration, Oral; Adult; Animals; Antihypertensive Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Pyrazines

Pulmonary hypertension is defined by a mean pulmonary artery pressure ≥25 mm Hg at rest. Management of pulmonary arterial hypertension (PAH) includes specific drug therapy with calcium channel blockers in vasoreactive patients, or drugs approved for PAH in non-reactive patients that target the endothelin, nitric-oxide and prostacyclin pathways. Areas covered: The review covers receptor selectivity, pharmacokinetics, pharmacodynamics and adverse effects (AEs) of intravenous (IV) epoprostenol (synthetic prostacyclin); the prostacyclin analogs iloprost, beraprost, and treprostinil administered by IV, subcutaneous, inhaled or oral routes; and the oral selective prostacyclin receptor agonist selexipag. Expert commentary: Development of a selective prostacyclin receptor agonist has aimed at identifying compounds with improved pharmacological properties. The high selectivity of selexipag, and its active metabolite ACT-333679, for the prostacyclin receptor, in conjunction with pharmacokinetic properties that reduce peak-trough fluctuations and the up-titration regimen used at the start of treatment, are collectively considered to minimize AEs associated with prostacyclin use. In a large phase 3 study, selexipag-associated AEs were consistent with those observed with drugs that target the prostacyclin pathway, and mainly mild to moderate in severity. The dosing flexibility afforded by oral selexipag may facilitate achieving the maximum therapeutic effect with acceptable tolerability in patients with PAH.

Topics: Acetamides; Acetates; Administration, Oral; Animals; Antihypertensive Agents; Drug Design; Humans; Hypertension, Pulmonary; Pyrazines; Receptors, Epoprostenol

The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosing and administration, and place in therapy of selexipag, an orally administered selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension (PAH), are reviewed.. The first-in-class oral prostacyclin IP receptor agonist selexipag (Uptravi, Actelion Pharmaceuticals) was approved by the Food and Drug Administration in December 2015. Selexipag is rapidly hydrolyzed to a long-acting metabolite that binds with high selectivity to IP receptors, resulting in vasodilation, inhibition of platelet aggregation, and antiinflammatory effects. Results of a long-term, placebo-controlled, clinical outcomes-driven trial showed that selexipag significantly reduced the occurrence of the composite primary outcome (all-cause mortality and development of PAH-related complications). Selexipag is indicated for use in patients with World Health Organization functional class (FC) II or III disease. The recommended initial selexipag dosage is 200 μg twice daily. Like prostanoid analogs, selexipag has a dose-dependent adverse-effect profile that includes nausea, vomiting, diarrhea, headache, and musculoskeletal pain. Although selexipag offers distinct pharmacologic advantages over other agents for the treatment of PAH, important issues of cost and access must be considered.. Selexipag is an oral prostacyclin IP receptor agonist approved for use as monotherapy or in combination with other therapies to slow PAH progression and reduce the risk of hospitalization in patients with FC II or III symptoms. Its stability and relatively long half-life offer conveniences over conventional prostanoid therapies.

Topics: Acetamides; Antihypertensive Agents; Hospitalization; Humans; Hypertension, Pulmonary; Pyrazines; Randomized Controlled Trials as Topic; Treatment Outcome

This review focuses on the treatment of pulmonary arterial hypertension (PAH) with selexipag and compares its drug-related therapeutic effects with those of prostacyclin analogues.. We searched the relevant literature and summarized the current clinical trials concerning selexipag and PAH.. With only few cases per million, PAH is a rare disease, but when untreated it can be life-threatening. PAH is linked to elevated levels of endothelin (ET-1) and decreased levels of nitric oxide (NO) and prostacyclin (PGI2). PAH-specific therapeutic approaches concentrate on these characteristics with drugs targeting the endothelin- receptor (e.g. bosentan), phosphodiesterase-5 (e.g. sildenafil) or the prostacyclin-receptor (e.g. treprostinil). Recently, the new drug selexipag acting as a non-prostanoid IP2-receptor agonist has been approved for PAH therapy. The active form of selexipag (ACT-333679) was designed by the help of a medicinal chemistry program and it was further modified by replacing the terminal carboxyl group with an N-acylsulfonamide group to form the more stable oral drug, selexipag. Selexipag has a high selectivity for the IP2-receptor and differs from conventional prostacyclin analogues in its chemical structure. In the GRIPHON trial selexipag was demonstrated to significantly improve the primary composite endpoint of death or complications related to PAH (hazard ratio 0.6, 99% confidence interval, 0.46 to 0.78; P < 0.001) as well as exercise capacity in the form of the 6-minute walk distance (12.0 m treatment effect, 99% confidence interval, 1 to 24; P = 0.003). However, no significant reduction in all-cause mortality was achieved. Selexipag has also shown promising results in combination therapy with phosphodiesterase-5 inhibitors (PDE-5i) and/or endothelin receptor antagonists (ERA). The most common adverse effects (AEs), associated with selexipag, are headache, diarrhea, jaw pain, and nausea. Nevertheless, Selexipag was generally well tolerated during the GRIPHON trial.. Selexipag is a valuable addition to PAH therapeutics especially by reducing the PAH-related hospitalizations and thus improving quality of life in PAH patients.

Topics: Acetamides; Animals; Antihypertensive Agents; Clinical Trials as Topic; Humans; Hypertension, Pulmonary; Prodrugs; Pyrazines; Treatment Outcome

Pulmonary arterial hypertension (PAH) is a rare disease resulting in progressive remodeling of the pulmonary vasculature and eventual right ventricular failure. Despite the development of 13 therapies for PAH since 2000, the use of continuously infused prostanoids retains a special role. Infused medications present unique challenges, and the search for an efficacious oral prostanoid culminated in the FDA approval of oral treprostinil - a first in class oral prostanoid medication approved to treat pulmonary arterial hypertension (PAH). Areas covered: In this discussion, we review the pharmacologic properties of oral treprostinil, and discuss three original major registration studies that resulted in the approval and widespread use of the drug. We also review several post-approval analyses and transitional studies. We discuss administration issues including side effects, transitioning, cost, and comparative analysis with selexipag. Expert opinion: Though the prospects of harnessing the benefits of continuously infused prostanoid therapy in a pill form are tantalizing, the gap in efficacy between oral and infused treatment is substantial. Major side effects and exorbitant cost are further barriers to broad uptake. Competition from oral prostaglandin receptor agonist selexipag challenges the commercial success of oral treprostinil. The long-term viability of oral treprostinil rests largely on the outcome of the long-term event-driven study of the molecule added to background approved ERA or PDE5 inhibitor monotherapy.

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Clinical Trials as Topic; Drug Approval; Epoprostenol; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pyrazines; Receptors, Prostaglandin; Treatment Outcome

Prostacyclin pathway medications have been shown to be highly efficacious in the treatment of pulmonary arterial hypertension (PAH) through multiple prospective clinical trials and more than two decades of clinical experience. The strongest support for prostacyclin use in PAH management is with parenteral administration. Numerous risks and limitations of parenteral delivery systems as well as significant patient burdens restrict widespread parenteral use. Highly effective and tolerable oral prostacyclin preparations to manage PAH have long been sought. We review the development of the oral prostacyclin agents beraprost, treprostinil, and selexipag and including current indications and limitations. Research into new approaches to the management of PAH, expanding indications for existing agents, and development of novel agents are also discussed.. Two oral prostacyclin pathway medications, oral treprostinil and selexipag, were FDA approved in December 2013 and 2015, respectively. Current guidelines recommend use of selexipag in WHO-FC II and III (class 1, level B recommendation) and oral treprostinil in WHO-FC III (class 2b, level B recommendation). The use of these medications is challenging due to complexity in dosing and their side effect profiles which limit patient tolerability and acceptance. There is a promising role for oral prostacyclin pathway medications in patients with PAH. Future investigations are underway of alternative dose regimens and transitioning from parenteral therapies in order to improve efficacy and tolerability.

Topics: Acetamides; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazines

Pulmonary arterial hypertension (PAH) is a relatively rare disease that, due to its chronic nature, has always been difficult to treat effectively. Selexipag is an oral prostacyclin (PGI

Topics: Acetamides; Animals; Antihypertensive Agents; Drug Interactions; Humans; Hypertension, Pulmonary; Pyrazines

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy, inflammation and fibrosis. These three main disease-determining pathways are the target of the currently available treatments used to possibly modify the progression of disease-related manifestations, although this synergy has not been fully applied on SSc joint, skin or lung involvement yet. Areas covered: we describe the current status of SSc treatment/therapy performing a literature search in MEDLINE/Pubmed and Thomson Reuter's Web of Science for articles published until March 2016. Moreover, ongoing registered clinical trials (RCTs) on SSc were searched through clinicaltrials.gov website. Expert commentary: presently, promising drugs are under evaluation to target the different pathogenic pathways of systemic sclerosis: Tocilizumab and Abatacept for skin and lung fibrosis; Riociguat and Selexipag are approved for pulmonary arterial hypertension but promising anti-fibrotic effects are now being studied. Finally, several anti-fibrotic molecules are currently involved in RCTs, such as Nintedanib, IVA-337, Terguride.

Topics: Abatacept; Acetamides; Antibodies, Monoclonal, Humanized; Biological Products; Clinical Trials as Topic; Fibrinolytic Agents; Fibrosis; Humans; Hypertension, Pulmonary; Indoles; Inflammation; Joints; Lisuride; Lung; PubMed; Pyrazines; Pyrazoles; Pyrimidines; Scleroderma, Systemic; Skin

Since the updated pulmonary hypertension (PH) guidelines published in 2015, two major landmark trials have provided additional insight regarding therapeutic algorithms of PH. In this review, we concisely summarized the key findings of peer‑reviewed studies published in the last one year in the field of PH. These studies have enhanced our therapeutic abilities by introducing a new potent agent, selexipag, and by demonstrating the advantage of upfront combination therapy (endothelin receptor antagonist and phosphodiesterase‑5 inhibitor) versus single agent therapy in group 1 PH. The addition of these therapeutic options resulted in mild improvement in certain clinical endpoints. Disappointingly, the improvement in clinical and hemodynamic endpoints was modest, not "across the board" and did not result in a measurable mortality reduction. Similarly, the role of agents traditionally used predominantly for primary PH or PH associated with connective tissues disease were tested in subjects with predominantly left heart failure. The progress in diagnostic modalities and strategies such as evaluation and validation of newer biomarkers, impact of borderline elevated pulmonary pressure and the role of various imaging modalities is briefly discussed but these investigations bears no groundbreaking amendments in current diagnostic algorithms.

Topics: Acetamides; Algorithms; Guidelines as Topic; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Pyrazines; Vasodilator Agents

Topics: Acetamides; Antihypertensive Agents; Clinical Trials as Topic; Gastrointestinal Diseases; Headache; Humans; Hypertension, Pulmonary; Pyrazines

Prostacyclin (PGI2) is a prostaglandin derived from arachidonic acid in the endothelium and smooth muscle which causes vasodilation, inhibits platelet aggregation, and has anti-inflammatory, anti-thrombotic and anti-proliferative effects. In pulmonary arterial hypertension (PAH), PGI2 levels and PGI2 synthase expression are reduced, contributing to the vasoconstriction and vascular smooth muscle cell proliferation seen in the disease. Based on these findings, PGI2 analogues were developed to target this pathway. Epoprostenol was the first targeted therapy available for treating PAH. Due to the short half-life of this drug, it requires administration via a continuous intravenous infusion, and therefore it carries the risks of central line infections and thrombosis. However, it remains the treatment of choice in patients with severe PAH as it has a proven survival benefit as well as improved functional class and exercise capacity. Subsequently, several other PGI2 analogues have been developed with differing modes of administration and varying degrees of efficacy. Beraprost is an oral PGI2 analogue for which a sustained efficacy has not been demonstrated. Iloprost is a nebulised PGI2 analogue that requires administration six to nine times a day and leads to improved functional class, exercise capacity and haemodynamics. There are inhaled, oral, subcutaneous and intravenous forms of treprostinil. Subcutaneous treprostinil avoids the risks of a continuous intravenous administration; however, this drug can cause intractable pain at the injection site. Selexipag is the new oral non-prostanoid IP prostacyclin receptor agonist that has shown improved haemodynamics and good tolerance in a phase II study. Initial results of the phase III trial are promising. Comparison of the different PGI2 agents is limited by a lack of head-to-head clinical trials. However, the development of PGI2 analogues has improved survival in patients with PAH and remains the main treatment option in advanced disease. While PGI2 analogues have good efficacy in PAH, they are not interchangeable, and their delivery systems have many limitations; in particular, they are associated with significant deleterious consequences. In the future, it is hoped that the elusive goal of developing an effective oral PGI2 analogue will be achieved. This would increase the number of people who could benefit from the treatment while reducing the associated adverse events, and as a result improve the survival an

Topics: Acetamides; Epoprostenol; Humans; Hypertension, Pulmonary; Prostaglandins I; Pyrazines; Randomized Controlled Trials as Topic; Receptors, Prostaglandin

Selexipag (Uptravi(®)) is a highly selective, long-acting, nonprostanoid, prostacyclin receptor agonist that is being developed by Actelion Pharmaceuticals Ltd and Nippon Shinyaku. Oral selexipag is approved in the USA for the treatment of pulmonary arterial hypertension (PAH; WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. It has subsequently been approved in Canada for the long-term treatment of PAH, and received a positive opinion in the EU for the treatment of PAH in adult patients with WHO functional class II-III. Selexipag received orphan drug designation for the treatment of PAH in Japan in 2014 and is in undergoing regulatory review in several countries for use in this indication. In the large, event-driven, phase III GRIPHON trial, selexipag reduced the risk of the primary composite endpoint of death or a complication related to PAH (whichever occurred first) by 40 % compared with placebo in patients with PAH (80 % were also receiving stable dosages of an endothelin receptor antagonist and/or a phosphodiesterase 5 inhibitor). This article summarizes the milestones in the development of selexipag leading to this first approval for PAH.

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Clinical Trials as Topic; Drug Approval; Humans; Hypertension, Pulmonary; Pyrazines; Receptors, Prostaglandin

Pulmonary arterial hypertension (PAH) was previously considered a uniformly fatal disease, with patients succumbing to right heart failure and death at an average of 3 years after diagnosis. The past 20 years, however, have seen the development of numerous targeted therapies that have changed the natural history of PAH. As more pharmacologic agents have been approved and utilized, further advances in the design of and endpoints for clinical trials. This study will review some of these notable developments.. The successful design and completion of long-term, event-driven trials is exemplified in three recent studies: SERAPHIN, GRIPHON, and AMBITION. SERAPHIN and GRIPHON evaluated the newer agents, macitentan, an endothelin receptor antagonist, and selexipag, a prostacyclin receptor agonist, respectively. Both trials were large-scale studies that, in addition to showing marked effect on the primary endpoint of morbidity/mortality, clearly demonstrated that assessment of long-term effects of PAH therapies is feasible for new compounds. The AMBITION study evaluated a treatment strategy, namely up-front combination therapy with tadalafil and ambrisentan compared with monotherapy and showed the combination approach to be superior at decreasing the likelihood of clinical failure.. The evolution of clinical trials in PAH has direct implications for care of these patients. The short and long-term benefits of combination regimens suggest that the multidrug approach to PAH should, in fact, be standard of care for this disease.

Topics: Acetamides; Antihypertensive Agents; Clinical Trials as Topic; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Inositol 1,4,5-Trisphosphate Receptors; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyrazines; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides

Targeted pulmonary vasoactive substances are the cornerstone of treatment in pulmonary arterial hypertension (PAH). Approved drugs act on various receptors and molecules within the pulmonary arteries, mainly causing pulmonary vasodilation and potentially reversing remodeling with consequent improvement of right ventricular function. A key role is attributed to the prostacyclin pathway and especially the prostacyclin receptor (IP). Selexipag is a recently developed, non-prostanoid, oral IP receptor agonist for the treatment of PAH which has been approved in countries/regions including the USA and Europe.. We review the discovery and development of drugs targeting IP receptors in PAH and describe preclinical and phase I studies of selexipag. Furthermore, we review important phase II and III selexipag studies and place them into the clinical context of previously approved prostanoids.. Oral selexipag offers a promising therapeutic option within the class of available drugs targeting IP receptors. However, its role as first-line therapy based on its efficacy/side-effect profile in current studies is questionable. Most likely, selexipag will be used in combination with other PAH-specific oral drugs. The potential of selexipag to replace or postpone the use of inhaled or parenteral prostanoids needs to be investigated in future trials.

Topics: Acetamides; Administration, Oral; Animals; Drug Approval; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazines

In recent years, there have been major changes in the landscape of pulmonary arterial hypertension therapy with the introduction of novel agents and innovative treatment strategies for this progressive disease. The aim of this review is to discuss the evolution in trial design in this field and highlight the salient features of recently published studies. We also summarize our approach to therapy selection in this chronic disease and identify areas for future exploration. The therapeutic armamentarium now includes 13 approved therapies. While most of these agents have been studied in small, short-term trials using the 6-min walk distance as a primary endpoint, there has been a shift in recent years toward larger, long-term, event-driven trials that utilize combined morbidity and mortality endpoints. The SERAPHIN and GRIPHON trials were two such studies, which led to the approval of the dual endothelin-receptor antagonist macitentan and the selective prostacyclin receptor antagonist selexipag, respectively. Other event-driven trials, like AMBITION and COMPASS-2, have provided valuable insight into the use of combined oral therapies in symptomatic patients. In conclusion, despite being a more manageable disease in the modern treatment era, pulmonary hypertension is still associated with considerable morbidity and much more work remains to be done in this field. Important questions remain about the most optimal way to manage patients and conduct trials going forward.

Topics: Acetamides; Antihypertensive Agents; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Pyrazines; Pyrimidines; Sulfonamides

Pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis if not treated. Pharmacological treatment options for PAH have increased significantly over the past 10 years, with availability of intravenous, oral and inhaled drugs targeting the nitric oxide, endothelin and prostacyclin pathways. Treatment with these therapies in specialised pulmonary hypertension centres has resulted in reductions in patient symptoms, disease progression and mortality, and improved exercise capacity. Recognition of chronic thromboembolic pulmonary hypertension is important, as this cause of pulmonary hypertension may be amenable to surgical treatment. Several new oral drugs, including macitentan, riociguat and selexipag, some of which have novel modes of action, and the use of combinations of PAH drugs have recently been shown to be beneficial in treating PAH and are likely to change treatment for this condition in the future.

Topics: Acetamides; Antihypertensive Agents; Australia; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Pyrazines; Pyrazoles; Pyrimidines; Sulfonamides; World Health Organization

Management of pulmonary arterial hypertension (PAH) remains challenging even in the contemporary era. Intravenous prostacyclin therapy, while associated with decreased mortality, has practical limitations and requires significant lifestyle modifications. The recently approved long-acting oral IP prostacyclin receptor agonist for treatment of PAH, selexipag, is a non-prostanoid agent that vasodilates, impacts remodeling (anti-proliferative), reduces endothelial cell dysfunction, inhibits platelet aggregation (anti-thrombotic), and increases right heart inotropy. Areas covered: This review discusses the limitations of non-oral prostacyclin therapy for PAH and describes the factors which led to successful development of selexipag in in vitro and preclinical studies. We review the pharmacokinetics and pharmacodynamics of selexipag. We further discuss the methodology and results of phase II and III trials, which led to approval of selexipag for PAH management. Expert opinion: As compared to previously developed oral prostacyclins, selexipag has limited adverse effects despite similar or better efficacy. Its final place in the treatment paradigm is not yet clear but it does represent a significant advance in the area of oral PAH therapy.

Topics: Acetamides; Administration, Oral; Animals; Antihypertensive Agents; Delayed-Action Preparations; Drug Evaluation, Preclinical; Humans; Hypertension, Pulmonary; Pyrazines; Treatment Outcome

Pulmonary arterial hypertension is characterized by abnormalities in the small pulmonary arteries including increased vasoconstriction, vascular remodeling, proliferation of smooth muscle cells, and in situ thrombosis. Selexipag, a novel, oral prostacyclin receptor agonist, has been shown to improve hemodynamics in a phase II clinical trial and reduce clinical worsening in a large phase III clinical trial involving patients with pulmonary arterial hypertension. In this paper, we describe the prostacyclin signaling pathway, currently available oral prostanoid medications, and the development and clinical use of selexipag.

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Clinical Trials as Topic; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pyrazines; Tachyphylaxis

Selexipag is a first-in-class orally available selective non-prostanoid IP receptor agonist. This review was based on a PubMed search and focuses on the potential role of selexipag in the treatment of pulmonary arterial hypertension (PAH).. Selexipag is rapidly hydrolyzed to an active metabolite, ACT-333679. Both selexipag and its metabolite are highly selective for the IP receptor compared with other prostanoid receptors. This selectivity for the IP receptor offers the potential for improved tolerability with selexipag, as side effects (e.g., nausea and vomiting) that might result from activation of the other prostanoid receptors may be minimized. In addition, the selexipag metabolite has a half-life of 7.9 h, thus permitting oral dosing twice daily. Selexipag showed effects on pharmacodynamic end points obtained with right heart catheterization in a Phase II trial in patients with PAH, and is being evaluated in the ongoing Phase III trial (GRIPHON trial, Clinicaltrials.gov NCT01106014).. The signal of a beneficial effect of selexipag on disease progression may become more robust for long term under prolonged exposure. Pending the GRIPHON trial results, selexipag could provide a convenient first-line prostacyclin treatment option for patients with PAH.

Topics: Acetamides; Acetates; Administration, Oral; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Prostaglandins I; Pyrazines; Receptors, Prostaglandin; Signal Transduction

It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options. This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.

Topics: Acetamides; Animals; Antihypertensive Agents; Benzamides; Clinical Trials as Topic; Drugs, Investigational; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Epoprostenol; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Lisuride; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Serotonin Antagonists; Sulfonamides

Reduced daily life physical activity (DLPA) in pulmonary arterial hypertension (PAH) contributes to a poor quality of life.. Can actigraphy be used to assess changes in DLPA in patients with PAH receiving selexipag or placebo?. Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension (TRACE) was a prospective, multicenter, randomized, placebo-controlled, double-blind, exploratory phase 4 study enrolling patients with PAH in World Health Organization functional class II/III, receiving stable endothelin receptor antagonist with/without phosphodiesterase type 5 inhibitor background therapy. Primary end points were change from baseline to Week 24 in actigraphy-assessed DLPA (recorded by using an accelerometer), including daily time spent in nonsedentary physical activity (NSPA), daily time spent in moderate to vigorous physical activity (MVPA), daily volume of activity, and daily number of steps.. At baseline, patients (N = 108) were prevalent, on stable background PAH therapy, and at low risk of disease progression. Patients showed high compliance with wear of the accelerometer throughout the study. From baseline to Week 24, mean daily time spent in NSPA increased by 1.1 min and decreased by 16.7 min in the selexipag and placebo groups (treatment difference [95% CI], 17.8 [-6.0, 41.6] min); mean time spent in MVPA increased by 0.3 min and was reduced by 2.0 min in the selexipag and placebo groups (treatment difference [95% CI], 2.3 [-10.8, 15.4] min); and mean number of daily steps decreased by 0.3 and 201.9 in the selexipag and placebo groups (treatment difference [95% CI], 201.6 [-243.0, 646.2]).. TRACE enrolled a prevalent population on background therapy and at low risk of disease progression. Changes in DLPA were small and highly variable, with no statistically significant differences between treatment groups. This patient-centric study was the first randomized trial in PAH to capture high-quality actigraphy data and to describe DLPA in terms of mean/median and variability, which may inform the design of future studies.. ClinicalTrials.gov; No.: NCT03078907; URL: www.. gov.

Topics: Actigraphy; Antihypertensive Agents; Disease Progression; Exercise; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Prospective Studies; Pulmonary Arterial Hypertension; Quality of Life

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.. 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.. 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.. 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.. ClinicalTrials.gov Identifiers: NCT01106014 and NCT01112306.

Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazines

The number of pulmonary arterial hypertension (PAH) patients with comorbidities is increasing and there are limited data on response to PAH-targeted therapies in this population. These post hoc analyses explored the effect of selexipag in PAH patients with cardiovascular comorbidities in the GRIPHON study.. Selexipag reduces the risk of a morbidity/mortality event vs. placebo irrespective of patient comorbidity status, suggesting that comorbidity status does not influence the treatment effect of selexipag.

Topics: Acetamides; Antihypertensive Agents; Comorbidity; Double-Blind Method; Heart Failure; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazines

Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remain limited. Selexipag, an oral selective IP prostacyclin receptor agonist approved for pulmonary arterial hypertension, is a potential treatment option for CTEPH.. In this multicentre, randomised, double-blind, placebo-controlled study, 78 Japanese patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and/or balloon pulmonary angioplasty were randomly assigned to receive placebo or selexipag. The primary end-point was the change in pulmonary vascular resistance (PVR) from baseline to week 20. Secondary end-points were changes in other haemodynamic parameters: 6-min walk distance (6MWD), Borg dyspnoea scale score, World Health Organization (WHO) functional class, EuroQol five-dimension five-level tool and N-terminal pro-brain natriuretic peptide.. The change in PVR was -98.2±111.3 dyn·s·cm. Selexipag significantly improved PVR and other haemodynamic variables in patients with CTEPH, although exercise capacity remained unchanged. Further large-scale investigation is necessary to prove the role of selexipag in CTEPH.

Topics: Acetamides; Antihypertensive Agents; Chronic Disease; Dyspnea; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazines; Treatment Outcome

Patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) after defect correction have a poor prognosis compared with other CHD-PAH patients. Therefore, it is important that these patients are treated as early and effectively as possible. Evidence supporting the use of PAH therapies in patients with corrected CHD-PAH from randomised controlled trials is limited. The purpose of these analyses was to characterise the corrected CHD-PAH patients from the GRIPHON study and examine the response to selexipag.. Out of the 110 patients diagnosed with corrected CHD-PAH, 55 had atrial septal defects, 38 had ventricular septal defects, 14 had persistent ducti arteriosus, and 3 had defects not further specified. Hazard ratios (HR) and 95% confidence intervals (CI) for the primary composite endpoint were calculated using Cox proportional hazard models. Compared with the non-CHD patients from GRIPHON, patients with corrected CHD-PAH were slightly younger, with a greater proportion being treatment-naive and in World Health Organization functional class I/II. The rate of the primary composite endpoint of morbidity/mortality was lower in patients with corrected CHD-PAH who were treated with selexipag compared with those treated with placebo (HR 0.58; 95% CI 0.25, 1.37). The most common adverse events were those known to be related to selexipag.. These post-hoc analyses of GRIPHON provide valuable information about a large population of patients with corrected CHD-PAH, and suggest that selexipag may delay disease progression and was well-tolerated in patients with corrected CHD-PAH.

Topics: Acetamides; Adult; Antihypertensive Agents; Cardiac Surgical Procedures; Disease Progression; Double-Blind Method; Drug Monitoring; Early Medical Intervention; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Middle Aged; Proportional Hazards Models; Pyrazines; Treatment Outcome

Parenteral prostacyclin analogs that target the prostacyclin pathway have been used to treat pulmonary arterial hypertension (PAH) since the 1990s. Abrupt discontinuation of parenteral prostacyclin analogs can be associated with acute deterioration of PAH. Less is known about temporary interruption of oral therapies that target the prostacyclin pathway, such as selexipag.. We evaluated the frequency, duration, reasons, and consequences of temporary selexipag interruptions among PAH patients enrolled in the Prostacyclin (PGI. At least 1 treatment interruption occurred in 111 of 574 patients (19.3%) in the selexipag group and in 58 of 582 (10.0%) in the placebo group. Baseline characteristics were similar between patients with and without an interruption. Of the 111 patients in whom selexipag was temporarily interrupted, 94 (85%) were receiving background PAH therapy. Adverse events were the most common reason for selexipag interruption. Selexipag interruptions and reinstitution of treatment were well tolerated. There were no episodes of acute deterioration during treatment interruption.. Based on observations from GRIPHON, selexipag interruptions can be expected in clinical practice. However, temporarily interrupting selexipag was well tolerated and manageable.

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazines; Receptors, Epoprostenol; Time Factors; Withholding Treatment

In pulmonary arterial hypertension (PAH), combination therapy is an important treatment strategy. Although randomized controlled trial data are available to support the combination of two therapies, data regarding triple combination therapy are few.. The phase III GRIPHON trial enrolled 1156 patients with PAH, including 376 receiving background double combination therapy. We evaluated the efficacy and safety of selexipag as a third agent in these patients and further analyzed this subgroup according to symptom burden at baseline as indicated by World Health Organization (WHO) functional class (FC).. In this post hoc analysis, hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using Cox proportional-hazard models to determine response to selexipag versus placebo on the composite primary endpoint of morbidity/mortality. Baseline characteristics and adverse events were summarized descriptively.. Of 376 patients receiving background endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE-5i) therapy, 115 had WHO FC II symptoms and 255 had WHO FC III symptoms at baseline. The impact on the primary endpoint of adding selexipag versus placebo to double combination therapy was consistent with the effect in the overall population (HR 0.63; 95% CI 0.44-0.90) as well as in patients with WHO FC II and III symptoms. Compared with the overall population, discontinuations due to an adverse event were higher when selexipag was added to background double combination therapy; no safety concerns were identified.. The addition of selexipag to background double combination therapy with an ERA and PDE-5i provides an incremental benefit similar to that seen in the overall population, including in patients with WHO FC II or III symptoms at baseline. CLINICALTRIALS.. NCT01106014.

Topics: Acetamides; Adult; Aged; Antihypertensive Agents; Diarrhea; Double-Blind Method; Drug Delivery Systems; Drug Therapy, Combination; Epoprostenol; Female; Headache; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazines; Signal Transduction

Selexipag is an orally available prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. In this open-label Phase II trial, the efficacy and safety of selexipag in Japanese patients with pulmonary arterial hypertension (PAH) is examined.Methods and Results:Selexipag was administered at 200 μg twice daily and titrated up to 1,600 μg by increments of 200 μg in 37 subjects to reach the individual maximum tolerated dose. At 16 weeks, in 33 patients comprising the per-protocol set, the pulmonary vascular resistance (PVR; primary endpoint) decreased from 683.2±237.3 to 560.3±238.7 dyn·s/cm. The efficacy and tolerability of selexipag in Japanese PAH patients was confirmed by improvement in pulmonary hemodynamics, exercise capacity, symptoms. Selexipag is an efficacious treatment option for Japanese PAH patients. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111532].).

Topics: Acetamides; Adult; Aged; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Pyrazines; Receptors, Epoprostenol

Selexipag (Uptravi) is an oral selective IP prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal GRIPHON study was the largest clinical study ever conducted in PAH patients, providing long-term data from 1,156 patients. PAH comedication did not affect exposure to selexipag, while exposure to its active metabolite ACT-333679 was reduced by 30% when taken in combination, clinically not relevant in the context of individual dose up-titration. Using log-linear regression models linking model-predicted steady-state exposure to pharmacodynamics (PD), exposure to selexipag and ACT-333679 showed some statistically significant, albeit not clinically relevant, effects on exercise capacity, laboratory values, and the occurrence of prostacyclin-related adverse events, but not on vital signs or adverse events denoting hemorrhage. Using suitable modeling techniques, the GRIPHON study yielded clinically relevant data with limited burden of pharmacokinetics (PK) blood sampling, demonstrating that PK/PD modeling enables firm conclusions even with sparse PK and PD sampling.

Topics: Acetamides; Acetates; Adult; Antihypertensive Agents; Bilirubin; Double-Blind Method; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Leukocyte Count; Male; Models, Biological; Natriuretic Peptide, Brain; Peptide Fragments; Pyrazines; Treatment Outcome

Patients with connective tissue disease-associated pulmonary arterial hypertension (PAH-CTD) have a poor prognosis compared with other aetiologies. The underlying CTD can influence treatment response and outcomes. We characterised the GRIPHON study PAH-CTD subgroup and evaluated response to selexipag.Of 334 patients with PAH-CTD, PAH was associated with systemic sclerosis (PAH-SSc) in 170, systemic lupus erythematosus (PAH-SLE) in 82 and mixed CTD/CTD-other in 82. For the primary composite endpoint of morbidity/mortality, hazard ratios (HR) and 95% CI were calculated using Cox proportional hazard models.Compared with the overall GRIPHON population, the CTD subgroup was slightly older with a greater proportion of females and shorter time since diagnosis. Patients with PAH-SSc appeared to be more impaired at baseline, with a more progressive disease course. The converse was observed for PAH-SLE. Selexipag reduced the risk of composite morbidity/mortality events in patients with PAH-CTD by 41% (HR 0.59; 95% CI 0.41-0.85). Treatment effect was consistent irrespective of baseline PAH therapy or CTD subtype (interaction p=0.87 and 0.89, respectively). Adverse events were predominately prostacyclin-related and known for selexipag treatment.GRIPHON has allowed the comprehensive characterisation of patients with PAH-CTD. Selexipag delayed progression of PAH and was well-tolerated among PAH-CTD patients, including those with PAH-SSc and PAH-SLE.

Topics: Acetamides; Adult; Antihypertensive Agents; Disease Progression; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Male; Middle Aged; Outcome Assessment, Health Care; Pyrazines; Risk Assessment; Scleroderma, Systemic; Survival Analysis

Topics: Acetamides; Administration, Oral; Adolescent; Adult; Aged; Double-Blind Method; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazines; Survival Rate; Treatment Outcome; Young Adult

In a phase 2 trial, selexipag, an oral selective IP prostacyclin-receptor agonist, was shown to be beneficial in the treatment of pulmonary arterial hypertension.. In this event-driven, phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned 1156 patients with pulmonary arterial hypertension to receive placebo or selexipag in individualized doses (maximum dose, 1600 μg twice daily). Patients were eligible for enrollment if they were not receiving treatment for pulmonary arterial hypertension or if they were receiving a stable dose of an endothelin-receptor antagonist, a phosphodiesterase type 5 inhibitor, or both. The primary end point was a composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period (defined for each patient as 7 days after the date of the last intake of selexipag or placebo).. A primary end-point event occurred in 397 patients--41.6% of those in the placebo group and 27.0% of those in the selexipag group (hazard ratio in the selexipag group as compared with the placebo group, 0.60; 99% confidence interval, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of the events. The effect of selexipag with respect to the primary end point was similar in the subgroup of patients who were not receiving treatment for the disease at baseline and in the subgroup of patients who were already receiving treatment at baseline (including those who were receiving a combination of two therapies). By the end of the study, 105 patients in the placebo group and 100 patients in the selexipag group had died from any cause. Overall, 7.1% of patients in the placebo group and 14.3% of patients in the selexipag group discontinued their assigned regimen prematurely because of adverse events. The most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhea, nausea, and jaw pain.. Among patients with pulmonary arterial hypertension, the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower with selexipag than with placebo. There was no significant difference in mortality between the two study groups. (Funded by Actelion Pharmaceuticals; GRIPHON ClinicalTrials.gov number, NCT01106014.).

Topics: Acetamides; Aged; Disease Progression; Double-Blind Method; Drug Administration Schedule; Female; Hospitalization; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Prodrugs; Pyrazines

In this phase 2 proof-of-concept study we examined the safety and efficacy of selexipag, an orally available, selective prostacyclin receptor (IP receptor) agonist, as a treatment for pulmonary arterial hypertension (PAH). 43 adult patients with symptomatic PAH (receiving stable endothelin receptor antagonist and/or a phosphodiesterase type-5 inhibitor therapy) were randomised three to one to receive either selexipag or placebo. Dosage was up-titrated in 200-μg increments from 200 μg twice daily on day 1 to the maximum tolerated dose by day 35 (maximum allowed dose of 800 μg twice daily). Change in pulmonary vascular resistance at week 17 expressed as a percentage of the baseline value was the primary efficacy end-point, and was analysed in the per protocol set first and then in the all-treated set to assess robustness of results. A statistically significant 30.3% reduction in geometric mean pulmonary vascular resistance was observed after 17 weeks' treatment with selexipag compared with placebo (95% confidence limits -44.7- -12.2; p=0.0045, Wilcoxon rank sum test). This was supported by a similar result from the all-treated set. Selexipag was well tolerated with a safety profile in line with the expected pharmacological effect. Our results encourage the further investigation of selexipag for the treatment of PAH.

Topics: Acetamides; Administration, Oral; Adult; Aged; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazines; Receptors, Epoprostenol; Receptors, Prostaglandin; Treatment Outcome; Vascular Resistance; Vasodilator Agents

This study aimed to investigate the safety, tolerability, and efficacy of selexipag in children and young adults with idiopathic and heritable pulmonary arterial hypertension.. This retrospective cohort study included clinical data from five children and six young adults with pulmonary arterial hypertension receiving selexipag as add-on therapy or as a transition from beraprost sodium or epoprostenol infusion therapy. Clinical efficacy was evaluated by measuring improvement in clinical variables from baseline, including hemodynamic parameters.. Of the 11 patients, 6 were switched from beraprost sodium to selexipag and one paediatric patient transitioned from epoprostenol to selexipag. The median maintenance dose of selexipag in children was 80 μg/kg/day. In nine patients undergoing repeat catheterisation, statistically significant improvements were observed after the initiation of selexipag in terms of mean pulmonary arterial pressure (p < 0.01), pulmonary vascular resistance index (p < 0.05), and cardiac index (p < 0.01). None of the patients had clinical worsening after selexipag during follow-up, but one young adult patient discontinued treatment due to severe headache. The most common side effect profiles were headache, nausea, abdominal pain, jaw pain, myalgia, and diarrhoea.. Selexipag may have a favourable safety profile and potential efficacy in children and young adults with pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Child; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Retrospective Studies; Treatment Outcome; Young Adult

Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazines

Intravenous (i.v.) prostacyclin is the cornerstone treatment in high-risk pulmonary arterial hypertension (PAH) patients. Selexipag is an orally available prostacyclin receptor agonist. Limited data are available regarding the feasibility of transitioning from i.v. epoprostenol to selexipag. A 50-year-old woman with idiopathic PAH was diagnosed in a World Health Organization (WHO) Functional Class (FC) IV. She improved with upfront triple combination therapy, including i.v. epoprostenol. Over 2 years of follow-up, the patient remained at low risk and expressed strong preference towards oral therapies. After careful risk-benefit clinical consideration, she was transitioned from i.v. epoprostenol to selexipag. Selexipag was started at dosage of 200 μg twice daily (b.i.d.) and titrated up to 1600 μg b.i.d. over 8 weeks (up-titration of 200 μg b.i.d. every week). Simultaneously, i.v. epoprostenol was down-titrated 3.0 ng/kg/min every week from a dosage of 27.5 ng/kg/min. The transition occurred under strict medical surveillance and was well tolerated. One year after discontinuation of epoprostenol, the patient remains in WHO FC I and has no signs of clinical deterioration. Although not generalizable to most PAH patients, this case highlights that a carefully planned transition from epoprostenol to selexipag is feasible in selected low-risk patients within a shared medical decision-making framework.

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Arterial Hypertension

Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil.. ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions.. Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging.. Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients.

Topics: Administration, Oral; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Prospective Studies; Pulmonary Arterial Hypertension; Registries

Topics: Acetamides; Heart Failure; Humans; Hypertension, Pulmonary; Pyrazines

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

Topics: Acetamides; Adult; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Lupus Erythematosus, Systemic; Pulmonary Arterial Hypertension; Pyrazines; Quality of Life

Optimizing an individual dose with careful management of adverse events (AEs) is essential in the treatment with selexipag approved for pulmonary arterial hypertension (PAH). This study aims to identify real-world practice patterns and AE characteristics of selexipag.. This multicenter, longitudinal, observational study included Korean patients with PAH who initiated with selexipag and were followed up to 24 weeks. The dose-titration pattern, AE incidences by dosing and time course, recovery pattern from AEs, and relationship between doses and AE incidences were evaluated.. Data for 113 patients were included in the analysis. The individual maintenance dose ranged between 200 and 3,200 µg/day. More often AEs were occurred in the titration phase than maintenance phase. There was no significant difference in AE incidences according to the distribution of titration and maintenance doses. The four most common AEs were diarrhea, headache, nausea/vomiting, and myalgia without showing a dose-dependent trend in either frequency or severity. The recovery rates were between 65.0% and 76.9% with a median time to recovery of 15-70 days (range, 2-233).. Our finding that AE incidence did not increase with increasing dose of selexipag would provide supportive real-world evidence on the management of optimal dose and safety.

Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Republic of Korea

Topics: Acetamides; Humans; Hypertension, Pulmonary; Pyrazines

PTTM is a rare but fatal disease, characterized by endothelial intimal proliferation and pulmonary hypertension due to micro-vascular remodeling. In view of the poor prognosis, new effective strategies are urgently required.. A 51-year-old woman was admitted to hospital for acute progressive dyspnea and dry cough. Clinical tests revealed hypercoagulable state and signs of severe pulmonary hypertension, without evidence of pulmonary embolism on contrast-enhanced CT. CT showed interlobular septal thickening and diffuse ground-glass opacity. Lung perfusion scan indicated multiple segment defect. Further right heart catherization proved a significant increase in pulmonary vascular resistance.. A combination therapy of apatinib and selexipag was administered for treatment of PTTM. The conventional therapies of ventilation, anticoagulation and diuretic medicines were initiated after admission.. Symptoms of PTTM were ameliorated with a reduction in pulmonary artery pressure. The resolution of interlobular septal thickening and ground-glass opacity on CT constituted the clinical benefits from treatment.. Patient with PTTM will benefit from the combination strategy of apatinib, a VEGF-receptor antagonist, and selexipag, an oral prostacyclin receptor agonist.

Topics: Acetamides; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Lung Neoplasms; Middle Aged; Pulmonary Artery; Pyrazines; Pyridines; Receptors, Epoprostenol; Receptors, Vascular Endothelial Growth Factor; Stomach Neoplasms; Thrombotic Microangiopathies

In 2019, the European Paediatric Pulmonary Vascular Disease Network (EPPVDN) developed a PH risk score to assess the risk and severity of pulmonary hypertension (PH) in children and young adults. We conducted a prospective observational study to validate the EPPVDN paediatric PH risk score by means of cardiac magnetic resonance imaging (CMR) and echocardiography.. During the same inpatient stay, the invasive and noninvasive EPPVDN PH risk scores were determined, and a protocol-driven CMR study was performed on 20 PAH children. Subsequently, we correlated the risk scores with imaging variables derived from CMR and echocardiography, including strain. Further, we applied the risk score to nine children with PAH who received add-on selexipag therapy. Before and approximately six months after selexipag start, the risk score and echocardiographic RV strain were determined and delta changes of both were correlated.. We found strong correlations of conventional CMR (r = 0.69-0.88), CMR strain (r = 0.71-0.88), advanced echocardiographic (r = 0.65-0.88) and echocardiographic strain variables (r = 0.67-0.86) with the EPPVDN PH risk scores (p < .006). In the selexipag cohort, the change in echo-derived RV free wall strain correlated well with the change in the invasive higher risk score (r = 0.72, p = .028).. We demonstrate strong correlations of outcome-relevant CMR and echocardiographic variables with the EPPVDN PH risk scores, and thus validated the score via independent methods. To achieve broad and easy access, we developed a calculator for the risk score as a web application (www.pvdnetwork.org/pedphriskscore). The novel EPPVDN PH risk score will be useful in routine clinical care and can now be applied in larger paediatric PH studies.

Topics: Acetamides; Child; Echocardiography; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Pyrazines; Risk Factors; Young Adult

Pulmonary arterial hypertension is a progressive, debilitating condition characterized by increased resistance in the pulmonary arterial circulation. Current treatments for pulmonary arterial hypertension include endothelin receptor antagonists such as bosentan, sitaxentan, ambrisentan, macitentan, and oral prostacyclin receptor agonists such as selexipag. Endothelin receptor antagonists have been associated with liver injury, while hepatotoxicity was not reported for selexipag. Although genetic variability has been indisputably associated with variability in drug response, no study has been designed until now to assess its effects on the pharmacokinetics of endothelin receptor antagonists or selexipag.. We report the case of a 58-year-old female Caucasian patient with a dramatic increase in plasma levels of transaminases after treatment with macitentan and selexipag, drugs whose risk of causing liver injury has so far been considered limited. After therapy discontinuation, plasma levels of transaminases returned to baseline, thus suggesting a role of these drugs in the observed hepatotoxicity. After pharmacological counseling, we decided to introduce ambrisentan for the patient's treatment. After 7 months of treatment, no liver injury has been reported. To evaluate the role of genetic factors in the observed hepatotoxicity, we genotyped the patient for single-nucleotide polymorphisms previously associated with macitentan, ambrisentan, or selexipag metabolism. We found a genetic profile associated with a poor metabolizer (PM) phenotype for CYP2C8 and CYP2C9, key enzymes for elimination of both macitentan and selexipag. The reported results suggest that an allelic profile associated with low activity for CYP2C8 and CYP2C9 enzyme could be a potential risk factor for macitentan and selexipag-induced liver injury and could provide a possible marker for early identification of subjects at higher risk of developing hepatotoxicity.. A multidisciplinary approach based on clinical evaluation, as well as pharmacological counseling and evaluation of the patient's genetic profile, might be useful for identification of patients with a high chance of drug-induced liver injury, avoiding unnecessary risks in therapy selection and prescription.

Topics: Bosentan; Counseling; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C9; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Arterial Hypertension; Receptors, Epoprostenol; Transaminases

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance that can lead to right ventricular failure and death. The use of medications that affect the prostacyclin pathway is an important treatment strategy in PAH. Inhaled iloprost is a prostacyclin analogue, and selexipag is an oral, non-prostanoid, prostacyclin IP receptor agonist. Data are limited on transitioning patients from inhaled iloprost to selexipag. In this case report, we describe the successful transition of a 57-year-old female with heritable PAH from inhaled iloprost to selexipag over 8 weeks in an out-patient setting. After initiation of selexipag, the patient's inhaled iloprost dose was gradually reduced and eventually discontinued. The patient tolerated the transition well with stable symptoms, 6-minute walk distance, and pulmonary hemodynamics. Additional studies are needed to better define the comparative efficacy and safety of inhaled iloprost and selexipag.

Topics: Acetamides; Antihypertensive Agents; Female; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Pulmonary Arterial Hypertension; Pyrazines

Pulmonary hypertension is a rare and complex disease with poor prognosis. Paediatric cases are infrequent and usually associated with congenital heart disease. Management is problematical due to the limited therapy available and poor evidence of efficacy. Recently a new medication, selexipag (UptraviR), a prostacyclin receptor agonist, has been approved for the treatment of pulmonary artery hypertension in adults. We report our experience using selexipag in four paediatric patients with pulmonary hypertension associated with congenital heart disease.

Topics: Acetamides; Adult; Antihypertensive Agents; Child; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Pyrazines

Topics: Acetamides; Anemia, Sickle Cell; Antihypertensive Agents; Child; Female; Humans; Hypertension, Pulmonary; Prodrugs; Pulmonary Wedge Pressure; Pyrazines

Selexipag is an oral nonprostanoid IP prostacyclin receptor agonist that is indicated for treatment of pulmonary arterial hypertension (PAH). In patients with continued symptoms of PAH despite maximized oral therapy with selexipag and other oral therapies, a transition to parenteral prostacyclin may be warranted. There is a paucity of data regarding how to safely transition from oral selexipag to parenteral treprostinil. We describe rapid transition from oral selexipag to parenteral treprostinil in this case report.. A 65-year-old female with mixed-etiology PAH as result of pulmonary fibrosis related to polymyositis was admitted to the intensive care unit to be transitioned from selexipag to treprostinil due to dyspnea at rest despite therapy with selexipag 1,600 mg twice daily and macitentan 10 mg daily for 3 years. At baseline the patient required oxygen support (4 L/min) at rest to maintain oxygen saturation at or above 90%. Right heart catheterization performed 8 weeks prior to admission revealed severe PAH, with a pulmonary arterial pressure of 73/27 mm Hg and pulmonary vascular resistance of 10 Wood units. On the day of admission the patient was given selexipag 800 µg at 9 am and simultaneously started on intravenous (i.v.) treprostinil at a dose of 2 ng/kg/min. The treprostinil dose was increased by 2 ng/kg/min every 3 hours until a target dose of 22 ng/kg/min was achieved, at which point the patient had experienced dyspnea improvement. She experienced a mild headache and flushing during rapid treprostinil dose escalation. After 30 hours of i.v. treprostinil infusion, the patient was transitioned to subcutaneous treprostinil therapy and discharged.. In this case the patient was rapidly transitioned from oral selexipag to i.v. and then subcutaneous treprostinil therapy over a 30-hour period, with minimal adverse effects.

Topics: Acetamides; Administration, Intravenous; Administration, Oral; Aged; Antihypertensive Agents; Blood Pressure; Drug Substitution; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Pyrazines; Time Factors

Topics: Acetamides; Double-Blind Method; Humans; Hypertension, Pulmonary; Japan; Pyrazines

Topics: Acetamides; Administration, Oral; Cardiac Catheterization; Drug Substitution; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Pyrazines

Topics: Acetamides; Antihypertensive Agents; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pyrazines

Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pyrazines; Risk Evaluation and Mitigation

Safe transition of patients with pulmonary arterial hypertension (PAH) from parenteral treprostinil to oral selexipag therapy in both inpatient and outpatient settings is described.. There is a paucity of published data on how to safely transition patients to oral therapy in the event of complications and problems during parenteral administration of prostacyclins, which can include bloodstream infections, injection-site pain (with use of subcutaneous treprostinil), infusion pump malfunction, and dosing errors due to incorrect dose preparation. This case series describes the transition of 4 patients with World Health Organization (WHO) group I PAH (WHO functional classes II-IV) from i.v. (. Four patients with WHO group I PAH who were not candidates for continued parenteral treprostinil therapy were safely transitioned to oral selexipag in both inpatient and outpatient settings.

Topics: Acetamides; Administration, Intravenous; Administration, Oral; Adult; Antihypertensive Agents; Drug Substitution; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Middle Aged; Pyrazines

Pulmonary Arterial Hypertension (PAH) is a chronic rare disease that can lead to serious cardiovascular problems and death. Additional treatments that increase effectiveness, that are safe and with a convenient administration that improve outcomes and quality of life for patients are needed. The aim of this study was to assess the value contribution of the new, oral prostacyclin receptor agonist, selexipag, for PAH treatment in Spain through reflective Multicriteria Decision Analysis (MCDA) methodology.. A comprehensive literature review was performed to develop an evidence matrix, composed of twelve quantitative criteria and four contextual criteria, based on an EVIDEM MCDA framework adapted to orphan drugs evaluation by the Spanish region of Catalonia. Quantitative performance scores, qualitative impact of contextual criteria and individual reflections from stakeholders were collected for each MCDA framework criteria. The value contribution of selexipag to PAH treatment compared to inhaled iloprost was calculated.. Oral selexipag for PAH treatment was considered as a treatment which adds value, compared to iloprost, in the following MCDA quantitative criteria: comparative efficacy, patient reported outcomes, preventive benefit, therapeutic benefit, other medical costs and other non-medical costs, without significant differences in safety profile but with a higher acquisition cost than inhaled iloprost.. Selexipag was considered to provide value to PAH treatment. It was perceived as an intervention indicated for a severe rare disease with high unmet needs, supported by high quality clinical evidence. When compared to inhaled iloprost, oral selexipag has demonstrated improvements in efficacy and patient reported outcomes, with a similar safety profile and some additional costs. Reflective MCDA provided a standardised, transparent approach to evaluate multiple criteria relating to the overall value contribution of selexipag to PAH treatment facilitating decision-making.

Topics: Acetamides; Decision Making; Decision Support Techniques; Humans; Hypertension, Pulmonary; Pyrazines; Quality of Life; Rare Diseases; Spain

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.

Topics: Acetates; Administration, Oral; Animals; Biological Availability; Carbamates; Drug Discovery; Hypertension, Pulmonary; Rats; Receptors, Prostaglandin; Structure-Activity Relationship

Prostacyclin (PGI

Topics: Acetamides; Acetates; Animals; beta-Arrestins; Cell Proliferation; CHO Cells; Contractile Proteins; Cricetinae; Cricetulus; Cyclic AMP; Epoprostenol; Extracellular Matrix; Humans; Hypertension, Pulmonary; Iloprost; Male; Muscle Contraction; Muscle Relaxation; Pyrazines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Epoprostenol

Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when pulmonary emboli fail to resolve with anticoagulation. For patients with inoperable or residual CTEPH, riociguat is currently the only therapy approved by the United States Food and Drug Administration. However, some patients with CTEPH may require therapy beyond riociguat, such as intravenous prostacyclins, which can present significant administration challenges in patients with complex comorbid conditions. We describe a 42-year-old man with T12 paraplegia complicated by CTEPH (functional class IV with substantial right ventricular dysfunction) and severe pressure ulcers. In order to facilitate goals of care (hospital discharge to a skilled nursing facility where parenteral prostanoids could not be administered), he underwent rapid transition from intravenous treprostinil to oral selexipag in the form of a cross-taper over 6 days. The patient required readmission due to worsening symptoms and was transitioned back to intravenous treprostinil; he tolerated conversion to oral treprostinil for approximately 4 months, but it was subsequently discontinued due to nausea and modified goals of care. The patient underwent transition to hospice care 3 months later and eventually died from clinical deterioration. To our knowledge, this is the first report to describe transition from intravenous treprostinil to selexipag as well as conversion from parenteral treprostinil to oral treprostinil in a patient with CTEPH and illustrates the approaches to and potential issues with prostanoid transitions. Additional observations are necessary to better understand the relative roles of selexipag and oral treprostinil regarding comparative efficacy and tolerability.

Topics: Acetamides; Administration, Oral; Adult; Antihypertensive Agents; Chronic Disease; Epoprostenol; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Paraplegia; Pyrazines; Severity of Illness Index; Ventricular Dysfunction, Right

Pulmonary arterial hypertension (PAH) is a rare and progressive disorder. Current treatment in the pediatric population includes phosphodiesterase 5 inhibitors (PDE-5i), endothelin receptor antagonists (ERA), and both inhaled and intravenous prostacyclin pathway agonists. As of December 22, 2015 the first oral prostacyclin pathway agonist, selexipag (Uptravi

Topics: Acetamides; Adolescent; Antihypertensive Agents; Child; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Pyrazines; Treatment Outcome; Walk Test; Young Adult

Topics: Acetamides; Child; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazines

The endothelin (ET), nitric oxide (NO) and prostacyclin (PGI2) pathways are involved in pulmonary arterial hypertension (PAH) pathogenesis. While ET and NO are targeted early in the disease process, limitations of current pharmacotherapies that target the PGI2 pathway (PGI2 or PGI2 analogues) result in them not being used or delayed. Selexipag is a novel oral, selective agonist of the PGI2 (IP) receptor. Activation of the IP receptor induces vasodilation in the pulmonary circulation and inhibits the proliferation of vascular smooth muscle cells, key factors in PAH pathogenesis. By combining oral dosing with improved receptor selectivity, selexipag may enable earlier combination therapy targeting the three-molecular pathways of PAH with anticipated improvements in daily- and long-term clinical function and outcome in PAH.

Topics: Acetamides; Antihypertensive Agents; Humans; Hypertension, Pulmonary; Pyrazines

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Drug Interactions; Humans; Hypertension, Pulmonary; Pyrazines; Randomized Controlled Trials as Topic; Receptors, Epoprostenol; Receptors, Prostaglandin; Tablets; Treatment Outcome

Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogues is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agonist potency were optimized through modification of the linear side chain. Compound 12b (MRE-269, ACT-333679) was identified as a potent and highly selective prostacyclin receptor agonist. Replacement of the terminal carboxyl group with an N-acylsulfonamide group yielded parent compound 26a (selexipag, NS-304, ACT-293987), which is orally active and provides sustained plasma exposure of 12b. Compound 26a was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial.

Topics: Acetamides; Acetates; Administration, Oral; Animals; CHO Cells; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Cricetulus; Dogs; Double-Blind Method; Haplorhini; Humans; Hypertension, Pulmonary; Myocytes, Smooth Muscle; Platelet Aggregation Inhibitors; Pulmonary Artery; Pyrazines; Randomized Controlled Trials as Topic; Rats; Receptors, Epoprostenol; Structure-Activity Relationship

{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI(2)) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI(2) analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E(3) (EP(3)) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP(3) receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP(3) receptor antagonist (2E)-3-(3',4'-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP(3) receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.

Topics: Acetamides; Acetates; Alprostadil; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Epoprostenol; Hypertension, Pulmonary; In Vitro Techniques; Male; Pulmonary Artery; Pyrazines; Rats; Rats, Wistar; Receptors, Epoprostenol; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Benzamides; Drug Therapy, Combination; Early Medical Intervention; Epoprostenol; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Piperazines; Pyrazines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides

2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304) is an orally available, long-acting nonprostanoid prostacyclin receptor (IP receptor) agonist prodrug. In a rat model of pulmonary hypertension induced by monocrotaline (MCT), NS-304 ameliorated vascular endothelial dysfunction, pulmonary arterial wall hypertrophy, and right ventricular hypertrophy, and it elevated right ventricular systolic pressure and improved survival. {4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), the active form of NS-304, is much more selective for the IP receptor than are the prostacyclin analogs beraprost and iloprost, which also have high affinity for the EP(3) receptor. To investigate the effect of receptor selectivity on vasodilation of the pulmonary artery, we assessed the relaxant response to these IP agonists in rats. MRE-269 induced vasodilation equally in large pulmonary arteries (LPA) and small pulmonary arteries (SPA), whereas beraprost and iloprost induced less vasodilation in SPA than in LPA. An EP(3) agonist, sulprostone, induced SPA and LPA vasoconstriction, and an EP(3) antagonist attenuated the vasoconstriction. Beraprost showed EP(3) agonism and induced LPA and SPA vasoconstriction, whereas the EP(3) antagonist inhibited this vasoconstriction and enhanced beraprost- and iloprost-induced SPA vasodilation. These findings suggest that the EP(3) agonism of beraprost and iloprost interfered with the SPA vasodilation resulting from their IP receptor agonism. Endothelium removal markedly attenuated the vasodilation induced by beraprost, but not that induced by MRE-269 or iloprost. Moreover, the vasodilation induced by beraprost and iloprost, but not that induced by MRE-269, was more strongly attenuated in LPA from MCT-treated rats than from normal rats. NS-304 is a promising alternative medication for pulmonary arterial hypertension with prospects for good patient compliance.

Topics: Acetamides; Acetates; Animals; Antihypertensive Agents; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Humans; Hypertension, Pulmonary; In Vitro Techniques; Male; Prodrugs; Pulmonary Artery; Pyrazines; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Vasodilation