Selexipag in the treatment of pulmonary arterial hypertension: design, development, and therapy.
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SUBMITTER: Hardin EA
PROVIDER: S-EPMC5117890 | biostudies-literature | 2016
REPOSITORIES: biostudies-literature
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Selexipag in the treatment of pulmonary arterial hypertension: design, development, and therapy.
Hardin Elizabeth Ashley EA Chin Kelly M KM
Drug design, development and therapy 20161115
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 pro ...[more]
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Project description: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.
| S-EPMC5593379 | biostudies-literature
Project description:BackgroundThe evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.MethodsAmong consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.ResultsTwenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.ConclusionTriple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.
| S-EPMC7919213 | biostudies-literature
Project description:Aim Selexipag is an oral selective prostacyclin receptor agonist approved for treatment of patients with pulmonary arterial hypertension (PAH). In the present study, we aim to assess the safety and efficacy of selexipag in triple combination therapy with endothelial receptor antagonists (ERAs) and PDE5is for Chinese PAH patients. Methods and results A single center retrospective study was performed on group 1 PAH patients (n = 68) initiating triple combination therapy with selexipag from 1 February 2020 to 31 August 2021 in Qilu Hospital of Shandong University (Shandong, China). Adolescents, children, and PAH patients with unrepaired congenital heart disease were excluded. The French pulmonary hypertension network (FPHN) non-invasive risk assessment, echocardiogram parameters, and clinical data, including tolerability, safety, and death/hospitalization events associated with PAH, were collected. Of the 68 patients, 31 (45.6%) patients had tolerable side effects while only a single patient discontinued selexipag due to severe diarrhea. In the analysis of the efficacy set of 62 patients, the median selexipag treatment time from selexipag initiation to last risk assessment was 27 (21, 33) weeks. Compared to baseline parameters, the percentage of WHO FC III/IV decreased from 77.4% (48) to 24.2% (15) (p = 0.000), median 6-min walk distance (6MWD) increased 82 m [from 398 (318, 450) to 480 (420, 506) m; p = 0.000], and NT-proBNP levels decreased from 1,216 (329, 2,159) to 455 (134, 1,678) pg/mL (p = 0.007). Patients who improved to three low-risk criteria increased from 9.7 to 38.7%. Right ventricular diameter (RV) diameter also decreased and was accompanied by an improved tricuspid annular plane systolic excursion (TAPSE). Patients transitioning from subcutaneous treprostinil to selexipag continued to show improvements in WHO FC, 6MWD (404 ± 94 vs. 383 ± 127 m) and NT-proBNP levels (2,319 ± 2,448 vs. 2,987 ± 3,770 pg/mL). Finally, the 1-year event free survival rate was 96.7% for patients initiating the triple combination therapy within 3 years of PAH diagnosis. Conclusion Triple combination therapy with selexipag was safe and effective in Chinese PAH patients, which was confirmed by acceptable tolerability, and improved exercise capacity, right heart function, risk assessment, and prognosis.
| S-EPMC9530145 | biostudies-literature
Project description:Objective: Adding selexipag to the combined treatment of endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitor (PDE5i) reduces the risk of clinical worsening events in patients with pulmonary arterial hypertension (PAH) but at a considerably higher cost. This study evaluated the cost-effectiveness of adding selexipag to the combined treatment of ERA and PDE5i in patients with PAH from a Chinese healthcare system perspective. Methods: A Markov model was developed to assess costs and quality-adjusted life years (QALYs) of macitentan + tadalafil + selexipag vs. macitentan + tadalafil for the treatment of PAH. Markov states included WHO Functional Class (FC) (I-IV) and death. Transition probabilities were based on data from the TRITON trial. Mortality rates, costs, and utilities were obtained from published literature and public databases. Results: In the base case analysis, compared with macitentan + tadalafil, selexipag + macitentan + tadalafil increased costs ($357,807.588 vs. $116,534.543, respectively) and QALYs (7.234 QALYs vs. 6.666 QALYs, respectively). The resulting incremental cost-effectiveness ratio was $424,746.070 per QALY, which was higher than the willingness-to-pay (WTP) of $38,223.339 per QALY. The results were most sensitive to HR for mortality of patients with FC IV relative to the general population, discount rate, and the cost of selexipag. The probability was greater than 50% for the selexipag + macitentan + tadalafil only if the WTP was more significant than $426,019.200 per QALY. Conclusion: In China, adding selexipag may not be cost-effective for patients with PAH who failed to control their condition after combined treatment of ERA and PDE5i. Results of the analysis can aid discussions on the value and position of selexipag for the combined treatment of PAH.
| S-EPMC10456866 | biostudies-literature
Project description:IntroductionParenteral prostanoids are the most potent therapies for pulmonary arterial hypertension (PAH) but are associated with complications and lifestyle limitations. Carefully selected stable patients may be considered for a transition from parenteral prostanoids to a more convenient oral regimen. We present our experience transitioning patients on parenteral prostanoids to selexipag on an outpatient basis.MethodsThis was a retrospective cohort study of all group 1 PAH patients on parenteral prostanoids who transitioned to selexipag using a standardized outpatient-based protocol. Hospitalization and routine prognostic data were recorded.ResultsFourteen patients were followed for a median of 1,240 (1,052-1,528) days; all were functional class (FC) II (n = 9) or III (n = 5). Thirteen patients completed the transition, including 11 who underwent catheterization 376 (321-735) days after discontinuing parenteral therapy. Three patients had unfavorable transitions requiring reinitiation of parenteral treatment. Overall, pulmonary vascular resistance increased (3.3-4.5 WU, p = 0.01), cardiac index fell (4.0-2.8 L/min/m2, p = 0.01), N-terminal pro-hormone of brain natriuretic peptide worsened (111-205 pg/dL, p = 0.03), but PAH-related hospitalizations improved (27-8, p = 0.02). Cardiac imaging, FC, and 6-min walk distance (6MWD) were unchanged. Patients who failed were older (64 vs. 56 years old) with shorter 6MWD (274 vs. 392 m) and higher REVEAL 2.0 scores (11 vs. 3).ConclusionsTransition from parenteral prostanoids to oral selexipag in carefully selected low-risk patients was well-tolerated in many patients, with up to 5 years of follow-up. Overall, the hemodynamic response to transition is unpredictable and close monitoring, particularly in the first year of follow-up, is recommended. Additional evaluation of potential predictors of success is necessary.
| S-EPMC9710435 | biostudies-literature
Project description:AimsThe 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.Methods and resultsRandomized patients (n = 1156) were classified using three methods: (i) by subgroups defined according to previously published comorbidity count and restrictive haemodynamic criteria: Subgroup A (<3 comorbidities and haemodynamic criteria met; n = 962) and Subgroup B (≥3 comorbidities and/or haemodynamic criteria not met; n = 144); comorbidities included body mass index ≥30 kg/m2 , essential hypertension, diabetes, history of coronary artery disease; (ii) by number of comorbidities, with addition of atrial fibrillation (0, 1, 2, 3, 4, or 5); (iii) by presence of individual comorbidities. Selexipag to placebo hazard ratios (HR) and 95% confidence intervals (CI) for morbidity/mortality (primary composite endpoint) were estimated using Cox regression adjusting selexipag effect for baseline covariates. Approximately half of the patients in GRIPHON (n = 584; 50.5%) had comorbidities. Selexipag reduced the risk of a morbidity/mortality event compared with placebo in both Subgroup A (HR 0.66, 95% CI 0.53, 0.82) and Subgroup B (HR 0.50, 95% CI 0.26, 0.96), with no evidence of an inconsistent treatment effect between subgroups (interaction p = 0.432). Consistent results were observed in analyses by number and by specific type of comorbidity.ConclusionSelexipag 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.
| S-EPMC9298818 | biostudies-literature
Project description:Selexipag is an orally available selective IP prostacyclin-receptor agonist licensed since 2016 for the therapy of pulmonary arterial hypertension (PAH). We aimed to describe real-life data of patients with pulmonary hypertension (PH) treated with selexipag. We analyzed all patients initiated with selexipag from July 2016 to April 2018 at the Department of Internal Medicine V, University of Munich. Non-invasive and invasive parameters corresponding to the risk assessment were collected at baseline and follow-up (FU). Furthermore, we recorded tolerability. Twenty-six patients were treated with selexipag, of whom 23 had PAH and three had chronic thromboembolic PH. At baseline, most patients were in function class (FC) II or III (42% and 54%, respectively). All patients were under medical treatment for PH, mostly dual therapy (92%). One or more side effects were noted in 19 patients, while seven reported no side-effects. FU assessment was available in 20 patients after 149 ± 80 days of treatment. Nt-proBNP (median, baseline 1641 pg/mL, FU 1185 pg/mL, P = 0.05) and PVR (mean ± SD, baseline 8.5 ± 4.3 WU, FU 5.6 ± 1.1 WU; P < 0.05) improved significantly. At FU, at least one risk assessment parameter improved in nine patients (45%), all parameters remained in the same risk group in seven patients (35%), and at least one parameter deteriorated in four patients (20%). Interestingly, patients with any side effect throughout the dose titration had a better treatment response than those without any side effects. In our real-life cohort, the majority of patients with PH treated with selexipag showed a stable or improved risk assessment at FU.
| S-EPMC6381437 | biostudies-literature
Project description:BackgroundSelexipag is an oral selective prostacyclin IP receptor agonist approved in patients with low- and intermediate-risk pulmonary hypertension (PH); evidence in patients at high risk is lacking.Case summaryA 42-year-old woman with worsening dyspnoea (World Health Organization functional class III-IV) and suspected PH at echocardiographic examination was evaluated in our Pulmonary Hypertension Centre. Right heart catheterization showed pre-capillary PH with reduced cardiac index and increased pulmonary vascular resistance. High-resolution computed tomography excluded parenchymal lung disease and ventilation/perfusion (V/Q) lung scan was negative for mismatched perfusion defects so the conclusive diagnosis was high-risk idiopathic pulmonary arterial hypertension (PAH). The patient refused an initial combination therapy including a parenteral prostacyclin analogue (PCA) in accordance with the ESC/ERS guidelines, so an off-label triple oral combination therapy including a phosphodiesterase-5 inhibitor, an endothelin receptor antagonist, and selexipag was started. At 3- and 6-month follow-up we found a clinical and haemodynamic improvement, so the patient was reclassified as low risk. Her clinical condition is currently stable.DiscussionDespite the benefit of parenteral PCAs in high-risk PAH, low adherence to treatment may be explained by adverse side effects related to the intravenous route of administration. Given the potential effect seen in our patient, upfront triple oral combination therapy in PAH high-risk patients should be further evaluated in a controlled clinical trial.
| S-EPMC7649462 | biostudies-literature
Project description: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.
| S-EPMC5529739 | biostudies-literature
Project description:AimsPatients 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.Methods and resultsOut 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.ConclusionsThese 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.
| S-EPMC6607487 | biostudies-literature