RESUMO
BACKGROUND: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).
Assuntos
Hipertensão Arterial Pulmonar , Proteínas Recombinantes de Fusão , Adulto , Humanos , Método Duplo-Cego , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos , Injeções Subcutâneas , Teste de Caminhada , Tolerância ao Exercício/efeitos dos fármacos , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Medicamentos para o Sistema Respiratório/administração & dosagem , Medicamentos para o Sistema Respiratório/efeitos adversos , Medicamentos para o Sistema Respiratório/farmacologia , Medicamentos para o Sistema Respiratório/uso terapêuticoRESUMO
BACKGROUND: Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways. METHODS: In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance. RESULTS: Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm-5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm-5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest. CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.).
Assuntos
Hipertensão Arterial Pulmonar/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Resistência Vascular/efeitos dos fármacos , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Humanos , Injeções Subcutâneas , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Hipertensão Arterial Pulmonar/sangue , Hipertensão Arterial Pulmonar/fisiopatologia , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacologia , Trombocitopenia/induzido quimicamente , Teste de CaminhadaRESUMO
BACKGROUND: In participants with pulmonary arterial hypertension, 24 weeks of sotatercept resulted in a significantly greater reduction from baseline in pulmonary vascular resistance than placebo. This report characterises the longer-term safety and efficacy of sotatercept in the PULSAR open-label extension. We report cumulative safety, and efficacy at months 18-24, for all participants treated with sotatercept. METHODS: PULSAR was a phase 2, randomised, double-blind, placebo-controlled study followed by an open-label extension, which evaluated sotatercept on top of background pulmonary arterial hypertension therapy in adults. Participants originally randomised to placebo were re-randomised 1:1 to sotatercept 0.3 or 0.7â mg·kg-1 (placebo-crossed group); those initially randomised to sotatercept continued the same sotatercept dose (continued-sotatercept group). Safety was evaluated in all participants who received ≥1 dose of sotatercept. The primary efficacy endpoint was change from baseline to months 18-24 in pulmonary vascular resistance. Secondary endpoints included 6-min walk distance and functional class. Two prespecified analyses, placebo-crossed and delayed-start, evaluated efficacy irrespective of dose. RESULTS: Of 106 participants enrolled in the PULSAR study, 97 continued into the extension period. Serious treatment-emergent adverse events were reported in 32 (30.8%) participants; 10 (9.6%) reported treatment-emergent adverse events leading to study discontinuation. Three (2.9%) participants died, none considered related to study drug. The placebo-crossed group demonstrated significant improvement across primary and secondary endpoints and clinical efficacy was maintained in the continued-sotatercept group. CONCLUSION: These results support the longer-term safety and durability of clinical benefit of sotatercept for pulmonary arterial hypertension.
Assuntos
Hipertensão Arterial Pulmonar , Adulto , Humanos , DEAE-Dextrano , Resultado do Tratamento , Hipertensão Pulmonar Primária Familiar , Método Duplo-CegoRESUMO
BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24â weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9â mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7â mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42â mmHg·mL-1·beat-1), PA compliance (0.58â mL·mmHg-1), cardiac efficiency (0.48â mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85â g·m) and RV power (-32.70â mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12â mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39â cm2 and -5.31â cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.
Assuntos
Coração , Hemodinâmica , Humanos , Proteínas Recombinantes de Fusão/uso terapêutico , Cateterismo Cardíaco , Hipertensão Pulmonar Primária FamiliarRESUMO
OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.
Assuntos
Ativadores de Enzimas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Esclerodermia Difusa/tratamento farmacológico , Adulto , Biópsia por Agulha , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Internacionalidade , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Medição de Risco , Esclerodermia Difusa/patologia , Índice de Gravidade de Doença , Falha de TratamentoRESUMO
OBJECTIVES: To determine whether progressive skin fibrosis is associated with visceral organ progression and mortality during follow-up in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: We evaluated patients from the European Scleroderma Trials and Research database with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, valid mRSS at 12±3 months after baseline and ≥1 annual follow-up visit. Progressive skin fibrosis was defined as an increase in mRSS >5 and ≥25% from baseline to 12±3 months. Outcomes were pulmonary, cardiovascular and renal progression, and all-cause death. Associations between skin progression and outcomes were evaluated by Kaplan-Meier survival analysis and multivariable Cox regression. RESULTS: Of 1021 included patients, 78 (7.6%) had progressive skin fibrosis (skin progressors). Median follow-up was 3.4 years. Survival analyses indicated that skin progressors had a significantly higher probability of FVC decline ≥10% (53.6% vs 34.4%; p<0.001) and all-cause death (15.4% vs 7.3%; p=0.003) than non-progressors. These significant associations were also found in subgroup analyses of patients with either low baseline mRSS (≤22/51) or short disease duration (≤15 months). In multivariable analyses, skin progression within 1 year was independently associated with FVC decline ≥10% (HR 1.79, 95% CI 1.20 to 2.65) and all-cause death (HR 2.58, 95% CI 1.31 to 5.09). CONCLUSIONS: Progressive skin fibrosis within 1 year is associated with decline in lung function and worse survival in dcSSc during follow-up. These results confirm mRSS as a surrogate marker in dcSSc, which will be helpful for cohort enrichment in future trials and risk stratification in clinical practice.
Assuntos
Esclerodermia Difusa/mortalidade , Esclerodermia Difusa/patologia , Dermatopatias/mortalidade , Dermatopatias/fisiopatologia , Pele/patologia , Adulto , Estudos de Coortes , Bases de Dados Factuais , Progressão da Doença , Europa (Continente) , Feminino , Fibrose , Humanos , Estimativa de Kaplan-Meier , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Esclerodermia Difusa/complicações , Índice de Gravidade de Doença , Dermatopatias/etiologia , Análise de Sobrevida , Fatores de TempoRESUMO
OBJECTIVES: Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database. METHODS: Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression. RESULTS: Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model. CONCLUSIONS: The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.
Assuntos
Cardiopatias/etiologia , Pneumopatias/etiologia , Escleroderma Sistêmico/epidemiologia , Ensaios Clínicos como Assunto , Progressão da Doença , Métodos Epidemiológicos , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Cardiopatias/epidemiologia , Humanos , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Prognóstico , Estudos Prospectivos , Esclerodermia Difusa , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Índice de Gravidade de Doença , Taxa de Sobrevida/tendênciasRESUMO
Objective: To gain insight into clinical practice regarding referral, early diagnosis and other aspects of the management of patients with dcSSc in Europe and the USA. Methods: Semi-structured interviews were conducted with 84 rheumatologists (or internal medicine physicians) and 40 dermatologists in different countries (the UK, France, Germany, Italy, Spain and the USA). Physicians were asked to identify key steps in the patient pathway relating to patient presentation, diagnosis and referral, in addition to other treatment and follow-up processes. Results: The interviewed physicians reported that late presentation with dcSSc was common, with some patients presenting to primary care physicians after symptoms had persisted for up to 1 year. Awareness of dcSSc is reported to vary widely among primary care physicians. Final diagnosis, generally following guideline-based recommendations, was by rheumatologists in most cases (or internal medicine physicians in France) and they remained responsible for global patient management, with lesser involvement in diagnosis and management by dermatologists. Specialist centres were not well defined and did not exist in all countries. Conclusion: Patients and primary healthcare providers can be unaware of the symptoms of dcSSc, therefore presentation and referral to specialist care are often late. Thus, improved awareness among patients and primary care physicians is necessary to facilitate earlier referral and diagnosis. Once referred, more consistent use of the modified Rodnan skin score at diagnosis and follow-up may help to monitor disease progression. Furthermore, establishing specialist centres may help to promote such changes and improve patient care.
Assuntos
Competência Clínica , Gerenciamento Clínico , Diagnóstico Precoce , Qualidade da Assistência à Saúde/normas , Encaminhamento e Consulta/tendências , Reumatologistas/normas , Esclerodermia Difusa/diagnóstico , Adulto , Europa (Continente) , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Esclerodermia Difusa/terapia , Inquéritos e Questionários , Fatores de TempoRESUMO
BACKGROUND: The 12-week, phase III Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-1 study investigated riociguat in patients with pulmonary arterial hypertension (PAH). Here, we present a prospectively planned analysis of the safety and efficacy of riociguat in the subgroup of patients with PAH associated with connective tissue disease (PAH-CTD). METHODS: Patients with PAH-CTD were further classified post hoc as having PAH associated with systemic sclerosis or PAH-other defined CTD. In PATENT-1, patients received riociguat (maximum 2.5 or 1.5â mg three times daily) or placebo. Efficacy endpoints included change from baseline in 6-minute walking distance (6MWD; primary endpoint), haemodynamics and WHO functional class (WHO FC). In the long-term extension PATENT-2, patients received riociguat (maximum 2.5â mg three times daily); the primary endpoint was safety and tolerability. RESULTS: In patients with PAH-CTD, riociguat increased mean 6MWD, WHO FC, pulmonary vascular resistance and cardiac index. Improvements in 6MWD and WHO FC persisted at 2â years. Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population. CONCLUSIONS: Riociguat was well tolerated and associated with positive trends in 6MWD and other endpoints that were sustained at 2â years in patients with PAH-CTD. TRIAL REGISTRATION NUMBERS: PATENT-1 (NCT00810693), PATENT-2 (NCT00863681).
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Escleroderma Sistêmico/complicações , Adulto , Idoso , Doenças do Tecido Conjuntivo/complicações , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Resistência Vascular , Teste de CaminhadaRESUMO
BACKGROUND: This study aims to assess the impact of sotatercept on exercise tolerance, exercise capacity, and right ventricular function in pulmonary arterial hypertension. METHODS: SPECTRA (Sotatercept Phase 2 Exploratory Clinical Trial in PAH) was a phase 2a, single-arm, open-label, multicenter exploratory study that evaluated the effects of sotatercept by invasive cardiopulmonary exercise testing in participants with pulmonary arterial hypertension and World Health Organization functional class III on combination background therapy. The primary end point was the change in peak oxygen uptake from baseline to week 24. Cardiac magnetic resonance imaging was performed to assess right ventricular function. RESULTS: Among the 21 participants completing 24 weeks of treatment, there was a significant improvement from baseline in peak oxygen uptake, with a mean change of 102.74 mL/min ([95% CIs, 27.72-177.76]; P=0.0097). Sotatercept demonstrated improvements in secondary end points, including resting and peak exercise hemodynamics, and 6-minute walk distance versus baseline measures. Cardiac magnetic resonance imaging showed improvements from baseline at week 24 in right ventricular function. CONCLUSIONS: The clinical efficacy and safety of sotatercept demonstrated in the SPECTRA study emphasize the potential of this therapy as a new treatment option for patients with pulmonary arterial hypertension. Improvements in right ventricular structure and function underscore the potential for sotatercept as a disease-modifying agent with reverse-remodeling capabilities. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03738150.
Assuntos
Tolerância ao Exercício , Hipertensão Arterial Pulmonar , Função Ventricular Direita , Humanos , Tolerância ao Exercício/efeitos dos fármacos , Masculino , Feminino , Função Ventricular Direita/efeitos dos fármacos , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Adulto , Resultado do Tratamento , Teste de Esforço , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/fisiopatologia , Consumo de Oxigênio/efeitos dos fármacos , Teste de Caminhada , Receptores de Activinas Tipo II/uso terapêutico , Recuperação de Função FisiológicaRESUMO
Sotatercept, a soluble fusion protein comprising the extracellular domain of activin receptor type IIA linked to the Fc portion of human IgG1, is a first-in-class activin signaling inhibitor under development for the treatment of pulmonary arterial hypertension (PAH). We evaluated antidrug antibody (ADA) development and determined the effects of immunogenicity on the pharmacokinetics (PKs), efficacy, and safety of sotatercept in STELLAR, a multicenter, double-blind phase III trial (NCT04576988) wherein participants with PAH were randomized 1:1 to receive sotatercept (starting dose 0.3; target dose 0.7 mg/kg) or placebo subcutaneously every 3 weeks in combination with background therapies for ≤ 72 weeks. ADA-positive (ADA-POS) participants were identified and characterized for neutralizing antibodies (NAbs). PKs, efficacy, and safety were evaluated by ADA and NAb status. Of 162 evaluable participants, 42 (25.9%) were ADA-POS through week 24, of whom 11 (6.8%) were also NAb-POS. Median onset of ADAs was 3.29 weeks (interquartile range (IQR): 3.14-6.14), and median duration was 6 weeks (IQR: 3.14-17.86). No clinically meaningful differences were found across subgroups that were ADA-NEG, ADA-POS/NAb-NEG, and ADA-POS/NAb-POS, in terms of PKs (sotatercept trough concentration over time, mean postdose trough concentration at the end of treatment, and clearance), efficacy (changes from baseline in 6-minute walk distance, pulmonary vascular resistance, and N-terminal pro-B-type natriuretic peptide levels), and safety (incidence of hypersensitivity, anaphylactic reactions, and administration site reactions). We conclude that ADA incidence from sotatercept treatment was 25.9% and did not meaningfully affect the PKs, efficacy, or safety of sotatercept in participants with PAH.
Assuntos
Antineoplásicos , Hipertensão Arterial Pulmonar , Humanos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Proteínas Recombinantes de Fusão/efeitos adversos , Anticorpos Neutralizantes , Resultado do TratamentoRESUMO
Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic (PopPK) model was developed using data from two phase 1 studies in healthy participants, and two phase 2 studies and one phase 3 study in participants with PAH. The pooled sotatercept PK data encompassed single intravenous (IV) or subcutaneous (SC) doses ranging from 0.01 to 3.0 mg/kg, as well as multiple SC doses ranging from 0.03 to 1.0 mg/kg, with PK samples collected up to a maximum of ~150 weeks following Q3W and Q4W dosing regimens. The final PopPK analysis included 350 participants, with 30 and 320 participants receiving sotatercept IV and SC, respectively. A two-compartment model with a first-order absorption rate constant and a linear disposition from central compartment well-described sotatercept PK. The estimated bioavailability is ~66%; bioavailability, clearance (CL), and central volume (VC) have low to moderate inter-individual variability. Time-varying body weight and baseline albumin concentration were statistically significant predictors of PK; CL and VC were predicted to increase with increasing body weight, while CL was predicted to decrease with increasing baseline albumin concentration. However, the magnitude of covariate effects is not predicted to meaningfully alter the disposition of sotatercept. Altogether, the PopPK modeling results demonstrate favorable PK characteristics (low to moderate variability and typical bioavailability), supporting sotatercept as a SC biological agent for the treatment of patients with PAH.
Assuntos
Modelos Biológicos , Hipertensão Arterial Pulmonar , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Hipertensão Arterial Pulmonar/tratamento farmacológico , Adulto Jovem , Voluntários Saudáveis , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/administração & dosagem , Disponibilidade Biológica , Idoso , Injeções Subcutâneas , AdolescenteRESUMO
INTRODUCTION: Pulmonary arterial hypertension (PAH) is a rare, progressive disease associated with significant morbidity and mortality. The phase 3 STELLAR trial tested sotatercept plus background therapy (BGT) versus placebo plus BGT. BGT was comprised of mono-, double-, or triple-PAH targeted therapy. Building on STELLAR findings, we employed a population health model to assess the potential long-term clinical impact of sotatercept. METHODS: Based on the well-established ESC/ERS 4-strata risk assessment approach, we developed a six-state Markov-type model (low risk, intermediate-low risk, intermediate-high risk, high risk, lung/heart-lung transplant, and death) to compare the clinical outcomes of sotatercept plus BGT versus BGT alone over a lifetime horizon. State-transition probabilities were obtained from STELLAR. Risk stratum-adjusted mortality and lung/heart-lung transplant probabilities were based on COMPERA PAH registry data, and the post-transplant mortality probability was obtained from existing literature. Model outcomes were discounted at 3% annually. Sensitivity analyses were conducted to examine model robustness. RESULTS: In the base case, sotatercept plus BGT was associated with longer life expectancy from model baseline (16.5 vs 5.1 years) versus BGT alone, leading to 11.5 years gained per patient. Compared with BGT alone, sotatercept plus BGT was further associated with a gain in infused prostacyclin-free life years per patient, along with 683 PAH hospitalizations and 4 lung/heart-lung transplant avoided per 1000 patients. CONCLUSIONS: According to this model, adding sotatercept to BGT increased life expectancy by roughly threefold among patients with PAH while reducing utilization of infused prostacyclin, PAH hospitalizations, and lung/heart-lung transplants. Real-world data are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04576988 (STELLAR).
Assuntos
Hipertensão Arterial Pulmonar , Humanos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Proteínas Recombinantes de Fusão/efeitos adversos , Medição de Risco , MorbidadeRESUMO
Purpose: Systemic sclerosis is a rare multi-organ autoimmune rheumatic disease, resulting in progressive fibrosis of the skin/internal organs. This study aimed to understand the impact of diffuse cutaneous systemic sclerosis symptoms and disease burden from the patient's perspective. Methods: This was a mixed methodology, market research study involving ethnography, structured interviews, video diaries, and patient tasks. Patients had been diagnosed with diffuse cutaneous systemic sclerosis for ⩾ 6 months and were recruited via healthcare professionals or patient associations (France, Italy, the United Kingdom, and the United States). Patients filmed short (~15 min) daily video diaries about their lives over 7 days and participated in ethnographic sessions, patient tasks, and structured video interviews. In Germany and Spain, patients participated in 60-min telephone interviews. Results: Twenty-three patients (mean age: 54 years; 83% women; minimum disease duration: 6 months) participated in the study. Time to diagnosis was prolonged, as patients overlooked their symptoms and some healthcare professionals attributed symptoms to other causes. Patients rarely received additional information or support services at diagnosis. Importantly, although patients were aware of the seriousness of organ involvement, they reported that skin changes, pain, and fatigue impaired their ability to perform routine tasks. Patients had a high prescription treatment burden (mean: 10 tablets/day; up to >25 tablets/day) with additional non-prescription medication taken for other comorbidities. Treatment discontinuation was common due to side effects. Patients experienced diffuse cutaneous systemic sclerosis as a loss of independence and self-esteem. Moreover, patients tended to have small support networks, and emotional support services were not offered as standard care. Conclusion: Patients with diffuse cutaneous systemic sclerosis had high treatment and disease burdens, with skin changes, pain, and fatigue profoundly affecting their lives. There is an unmet need for patient information at the time of diagnosis and emotional support services throughout the patient's journey with diffuse cutaneous systemic sclerosis. Based on the results of this study, we provide recommendations for improving diffuse cutaneous systemic sclerosis care.
RESUMO
PURPOSE: To compare the anatomical structure and the presence of growth factors and cytokines of amniotic membrane preserved in glycerol/MEM (1:1) or undiluted dimethyl sulfoxide through electron microscopy. METHODS: Amniotic membrane preserved in glycerol/MEM (1:1) or undiluted dimethyl sulfoxide were processed for transmission and scanning electron microscopy. As control, freshly collected amniotic membrane was fixed and processed for electron microscopy. The cytokines and growth factors assessed were: TGF-beta (transforming growth factor beta); TGF-beta activ (activated transforming growth factor beta); EGF (epidermal growth factor); FGF-4 (fibroblast growth factor 4); bFGF (basic fibroblast growth factor); IL-4 (interleukin 4); PGE2 (prostaglandin E2); IL-10 (interleukin 10); KGF (keratinocyte growth factor); HGF (hepatocyte growth factor). RESULTS: Amniotic membrane from the control group showed intact epithelium, with surface microvilli and junctional complexes between the cells and the basal membrane. Glycerol/MEM preserved amniotic membrane had similar aspect to the control, with higher epithelial cells. Those amniotic membranes preserved in dimethyl sulfoxide disclosed less intercellular junction and detachment of the epithelium from the basal membrane. The cytokines and growth factors did not disclose significant differences, except for FGF-4, bFGF, PGE2 and KGF. CONCLUSIONS: Amniotic membrane preserved in glycerol/MEM showed a better tissue structure, with less detachment of the epithelium from the basal membrane, in comparison to undiluted dimethyl sulfoxide. The majority of the growth factors and cytokines were kept with both techniques of preservation.
Assuntos
Âmnio/metabolismo , Âmnio/ultraestrutura , Criopreservação/métodos , Crioprotetores/farmacologia , Dimetil Sulfóxido/farmacologia , Glicerol/farmacologia , Âmnio/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/ultraestrutura , Humanos , Microscopia Eletrônica de Transmissão , Fator de Crescimento Transformador beta/metabolismoRESUMO
RISE-SSc is a randomized, double-blind, placebo-controlled phase 2 study investigating the efficacy and safety of riociguat in patients with diffuse cutaneous systemic sclerosis (dcSSc). Based on positive results from riociguat trials in patients with pulmonary hypertension and chronic thromboembolic pulmonary hypertension in combination with the known antiproliferative and antifibrotic effects seen in animal models, patients with SSc may benefit from treatment with riociguat. Patients with SSc meeting the ACR/EULAR systemic sclerosis classification criteria with diffuse cutaneous SSc (dcSSc) subset per LeRoy criteria, and a disease duration of less than or equal to 18 months will be randomized to placebo or riociguat 0.5 mg (up-titrated to a maximum dose of 2.5 mg TID over 10 weeks) and maintained on therapy for a total of 52 weeks. During the first 10 weeks of the long-term extension phase, placebo subjects will be up-titrated on riociguat, and all patients will be followed for up to 6 years. The primary endpoint of change in modified Rodnan skin score (mRSS) from baseline will be assessed at 52 weeks, as will be secondary endpoints such as mRSS progression and regression rates, patient quality of life, digital ulcer burden, and change in forced vital capacity and carbon monoxide diffusing capacity. This review will further define the clinical rationale for the use of riociguat in the treatment of SSc and provide details on study protocol, design, and outcome reporting. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02283762.