Contemporary Treatment of Pulmonary Arterial Hypertension: A US Perspective.

Pulmonary arterial hypertension (PAH) is a complex fatal condition which requires aggressive treatment with close monitoring. Significant progress has been made over the last three decades in the treatment of PAH but despite this progress, survival has remained unacceptably low. In the quest to improve survival, therapeutic interventions play a central role. In the last few years, there have been remarkable attempts to identify novel treatments. Finally, we have had a breakthrough with the discovery of the fourth treatment pathway in PAH. Activin signaling inhibition distinguishes itself as a potential antiproliferative intervention as opposed to the traditional therapies which mediate their effect primarily by vasodilatation. With this novel treatment pathway, we stand at an important milestone with an exciting future ahead and the natural question of when to utilize Activin signaling inhibitor (ASI) for the treatment of PAH. In this state-of-the-art review, we focus on the placement of this novel agent in the PAH treatment paradigm based on the available evidence, with special focus on the US patient population. This review also provides an expert opinion of the current treatment algorithm on important subgroups of patients with comorbidities from the US perspective.

Emerging therapies in ß-thalassemia: toward a new era in management.

INTRODUCTION: The thalassemias are among the most  common inherited monogenic diseases worldwide, characterized by autosomal recessive inherited defects in the production of hemoglobin. Currently available conventional therapies have many challenges and limitations. Advances in understanding the underlying pathophysiology of ß-thalassemia enabled clinicians and researchers to move toward the development of novel therapeutic modalities. These can be classified into three categories based on their efforts to address different features of the underlying pathophysiology of ß-thalassemia: correction of the globin chain imbalance, addressing ineffective erythropoiesis, and improving iron overload. AREAS COVERED: In this review, we will provide an overview of the novel therapeutic approaches that are currently in development for ß-thalassemia. EXPERT OPINION: A thorough understanding of the pathophysiology and overall disease burden of ß-thalassemia has aided clinicians and scientists to optimize disease management approaches and construct a plan for the development of novel therapies, with ultimate goals of prolonging longevity, reducing symptom burden, improving compliance and adherence for a better quality of life.

Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies.

PURPOSE: Sotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer. METHODS: In study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of ≥1 g/dL from baseline. RESULTS: Both studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of ≥1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of ≥1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon. CONCLUSIONS: Although both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA.

Sotatercept in patients with osteolytic lesions of multiple myeloma.

This phase IIa study evaluated the safety and tolerability of sotatercept, and its effects on bone metabolism and haematopoiesis in newly diagnosed and relapsed multiple myeloma (MM) patients. Patients were randomized (4:1) to receive four 28-d cycles of sotatercept (0·1, 0·3, or 0·5 mg/kg) or placebo. Patients also received six cycles of combination oral melphalan, prednisolone, and thalidomide (MPT). Thirty patients were enrolled; six received placebo and 24 received sotatercept. Overall, 25% of patients received all four sotatercept doses; 71% of sotatercept-treated patients had ≥1 dose interruption mainly due to increases in haemoglobin levels. Grade ≥3 adverse events (AEs) were reported in 17% of patients receiving placebo and 58% receiving sotatercept. Grade 4 AEs in sotatercept-treated patients were neutropenia, granulocytopenia, and atrial fibrillation (one patient each). In patients without bisphosphonate use, anabolic improvements in bone mineral density and in bone formation relative to placebo occurred, whereas bone resorption was minimally affected. Increases in haemoglobin levels, versus baseline, and the duration of the increases, were higher in the sotatercept-treated patients, with a trend suggesting a dose-related effect. Multiple doses of sotatercept plus MPT appear to be safe and generally well-tolerated in MM patients.

Navigating the Sotatercept landscape: A meta-analysis of clinical outcomes.

Pulmonary arterial hypertension (PAH) is a widespread condition that affects around 1% of the global population, with a higher prevalence among older individuals. The approach to managing PAH has undergone significant changes, requiring extensive treatment strategies. Sotatercept, an FDA-approved medication, has recently attracted attention for its potential role in PAH therapy. However, information on its safety and effectiveness is scarce. In this study, we performed a meta-analysis of existing randomized clinical trials to assess the impact of Sotatercept on PAH patients. Our findings revealed that those treated with Sotatercept showed greater improvement in pulmonary vascular resistance and World Health Organization functional class compared with placebo recipients. The occurrence of adverse events was similar between both groups. Importantly, the Sotatercept group displayed a considerably higher number of cases with an increase in hemoglobin levels. Considering that about 33% of PAH patients experience anemia and both anemia and polycythemia can adversely affect disease prognosis, additional research is necessary to establish the potential advantages and disadvantages of Sotatercept as a treatment choice, specifically regarding its erythropoietic properties.

Population Health Model Predicting the Long-Term Impact of Sotatercept on Morbidity and Mortality in Patients with Pulmonary Arterial Hypertension (PAH).

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).

How We Do It: Using Sotatercept in the Care of Patients with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary microvasculature leading to elevated pre-capillary pulmonary hypertension. Pulmonary vascular remodeling, a characteristic of PAH, is driven by dysfunctions in the signaling between the pulmonary smooth muscle and endothelial cells with abnormalities that affect cell proliferation and immune dysregulation. Sotatercept, an activin signaling inhibitor, has been recently approved by the Food and Drug Administration for the treatment of PAH, based on two pivotal clinical trials. Evidence based clinical trials have provided a framework to guide clinicians treating the disease; however, they are not tailored to the individual patient. Often, recommendations from these data are unclear or too general, due to remaining gaps in knowledge. In this edition of "How I Do It", we provide a case-based discussion of common clinical decisions regarding diagnostic testing, choice of first line agents, escalation of therapy, potential timing of sotatercept, safety awareness, practical use, potential management changes, and the future use of sotatercept in other pulmonary hypertension cohorts.

Treating Pulmonary Arterial Hypertension With Sotatercept: A Meta-Analysis.

Pulmonary arterial hypertension (PAH) results from proliferative remodeling and narrowing of the pulmonary vasculature. Sotatercept is a first-in-class fusion protein that has recently garnered attention for showing improvements in patients with PAH. This meta-analysis of randomized controlled trials (RCTs) assesses the overall efficacy of Sotatercept in treating PAH. PubMed, Google Scholar, and Clinicaltrials.gov were searched using relevant keywords and MeSH terms. Studies were included if RCTs compared Sotatercept with placebo in patients with PAH. Our comprehensive literature search yielded 3,127 results, of which two RCTs with 429 patients were included in this meta-analysis. The patients were on background therapy for PAH. Results of the meta-analysis show that when compared with placebo, Sotatercept improved the six-minute walk distance (mean difference [MD] 34.99; 95% confidence interval [CI] 19.02-50.95; P < 0.0001), the World Health Organization (WHO) functional class (odds ratio [OR] 2.50; 95% CI 1.50-4.15; P = 0.0004), and pulmonary vascular resistance (PVR, MD -253.90; 95% CI -356.05 to -151.75; P < 0.00001). However, reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP, MD -1563.14; 95% CI -3271.93 to 145.65; P = 0.07) was not statistically significant in the Sotatercept group versus placebo. In conclusion, Sotatercept improves the six-minute walk distance, WHO functional class, and PVR in patients with PAH receiving background therapy. However, the effect on NT-proBNP levels was not statistically significant. More research is needed to assess the clinical relevance of these findings.

Nebulisation of Paclitaxel, Sotatercept and Iloprost for pulmonary hypertension for lung cancer. From In vitro to In vivo.

Background: Pulmonary hypertension is common symptom among several diseases. The consequences are severe for several organs. Pulmonary hypertension is usually under-diagnosed and the main symptom observed is dyspnea with or without exercise. Currently we have several treatment modalities administered orally, via inhalation, intravenously and subcutaneously. In advanced disease then heart or lung transplantation is considered. The objective of the study was to investigate the optimum method of aerosol production for the drugs: iloprost, paclitaxel and the novel sotatercept. Materials and Methods: In our experiment we used the drugs iloprost, paclitaxel and the novel sotatercept, in an experimental concept of nebulization. We performed nebulization experiments with 3 jet nebulizers and 3 ultrasound nebulizers with different combinations of residual cup designs, and residual cup loadings in order to identify which combination produces droplets of less than 5µm in mass median aerodynamic diameter. Results: We concluded that paclitaxel cannot produce small droplets and is also still very greasy and possible dangerous for alveoli. However; iloprost vs sotatercept had smaller droplet size formation at both inhaled technologies (1.37<2.23 and 1.92<3.11, jet and ultrasound respectively). Moreover; residual cup designs C and G create the smallest droplet size in both iloprost and sotatercept. There was no difference for the droplet formation between the facemask and cone mouthpieces. Discussion: Iloprost and sotatercept can be administered as aerosol in any type of nebulisation system and they are both efficient with the residual cups loaded with small doses of the drug (2.08 and 2.12 accordingly).

A Lifelike guided journey through the pathophysiology of pulmonary hypertension-from measured metabolites to the mechanism of action of drugs.

Introduction: Pulmonary hypertension (PH) is a pathological condition that affects approximately 1% of the population. The prognosis for many patients is poor, even after treatment. Our knowledge about the pathophysiological mechanisms that cause or are involved in the progression of PH is incomplete. Additionally, the mechanism of action of many drugs used to treat pulmonary hypertension, including sotatercept, requires elucidation. Methods: Using our graph-powered knowledge mining software Lifelike in combination with a very small patient metabolite data set, we demonstrate how we derive detailed mechanistic hypotheses on the mechanisms of PH pathophysiology and clinical drugs. Results: In PH patients, the concentration of hypoxanthine, 12(S)-HETE, glutamic acid, and sphingosine 1 phosphate is significantly higher, while the concentration of L-arginine and L-histidine is lower than in healthy controls. Using the graph-based data analysis, gene ontology, and semantic association capabilities of Lifelike, led us to connect the differentially expressed metabolites with G-protein signaling and SRC. Then, we associated SRC with IL6 signaling. Subsequently, we found associations that connect SRC, and IL6 to activin and BMP signaling. Lastly, we analyzed the mechanisms of action of several existing and novel pharmacological treatments for PH. Lifelike elucidated the interplay between G-protein, IL6, activin, and BMP signaling. Those pathways regulate hallmark pathophysiological processes of PH, including vasoconstriction, endothelial barrier function, cell proliferation, and apoptosis. Discussion: The results highlight the importance of SRC, ERK1, AKT, and MLC activity in PH. The molecular pathways affected by existing and novel treatments for PH also converge on these molecules. Importantly, sotatercept affects SRC, ERK1, AKT, and MLC simultaneously. The present study shows the power of mining knowledge graphs using Lifelike's diverse set of data analytics functionalities for developing knowledge-driven hypotheses on PH pathophysiological and drug mechanisms and their interactions. We believe that Lifelike and our presented approach will be valuable for future mechanistic studies of PH, other diseases, and drugs.

Sotatercept for Pulmonary Arterial Hypertension in the Inpatient Setting.

Patients with pulmonary arterial hypertension (PAH) who are admitted to the hospital pose a challenge to the multidisciplinary healthcare team due to the complexity of the pathophysiology of their disease state and PAH-specific medication considerations. Pulmonary arterial hypertension is a progressive disease that may lead to death as a result of right ventricular (RV) failure. During acute on chronic RV failure it is critical to decrease the pulmonary vascular resistance with the goal of improving RV function and prognosis; therefore, aggressive PAH-treatment based on disease risk stratification is essential. Pulmonary arterial hypertension treatment for acute on chronic RV failure can be impacted by end-organ damage, hemodynamic instability, drug interactions, and PAH medications dosage and delivery. Sotatercept, a first in class activin signaling inhibitor that works on the bone morphogenetic protein/activin pathway is on track for Food and Drug Administration approval for the treatment of PAH based on results of recent trials in where the medication led to clinical and hemodynamic improvements, even when added to traditional PAH-specific therapies. The purpose of this review is to highlight important considerations when starting or continuing sotatercept in patients admitted to the hospital with PAH.

[Heritable pulmonary arterial hypertension]. / Hereditäre pulmonal-arterielle Hypertonie.

Heritable pulmonary arterial hypertension (PAH) can be triggered by at least 18 genes. The most frequently altered gene is the bone morphogenetic protein receptor 2 (BMPR2). Further genes from the same pathway are also well known PAH-causing genes. Genetic testing can aid to confirm differential diagnoses such as a pulmonary veno-occlusive disease. It also enables the testing of healthy family members. In addition to the PAH patient population particularly served by genetic testing, this article touches on the mode of inheritance and provides insights into the first treatments soon on the market that rebalance the BMPR2 signaling pathway.

Idiopathic pulmonary fibrosis: Addressing the current and future therapeutic advances along with the role of Sotatercept in the management of pulmonary hypertension.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by irreversible scarring of the lungs. The cause of IPF is unknown, but it is thought to involve a combination of genetic and environmental factors. There is no cure for IPF, and treatment is focused on slowing disease progression and relieving symptoms. AIMS: We aimed in this review to investigate and provide the latest insights into IPF management modalities, including the potential of Saracatinibas a substitute for current IPF drugs. We also investigated the therapeutic potential of Sotatercept in addressing pulmonary hypertension associated with IPF. MATERIALS AND METHODS: We conducted a comprehensive literature review of relevant studies on IPF management. We searched electronic databases, including PubMed, Scopus, Embase, and Web of science. RESULTS: The two Food and Drug Administration-approved drugs for IPF, Pirfenidone, and Nintedanib, have been pivotal in slowing disease progression, yet experimental evidence suggests that Saracatinib surpasses their efficacy. Preclinical trials investigating the potential of Saracatinib, a tyrosine kinase inhibitor, have shown to be more effective than current IPF drugs in slowing disease progression in preclinical studies. Also, Sotatercept,a fusion protein, has been shown to reduce pulmonary vascular resistance and improve exercise tolerance in patients with PH associated with IPF in clinical trials. CONCLUSIONS: The advancements discussed in this review hold the promise of improving the quality of life for IPF patients and enhancing our understanding of this condition. There remains a need for further research to confirm the efficacy and safety of new IPF treatments and to develop more effective strategies for managing exacerbations.

From bench to bedside: The promise of sotatercept in hematologic disorders.

Sotatercept (ACE-011) is an activin receptor IIA-Fc (ActRIIA-Fc) fusion protein currently under investigation for its potential in the treatment of hematologic diseases. By impeding the activities of the overexpressed growth and differentiation factor 11 (GDF11), activin A, and other members of the transforming growth factor-ß (TGF-ß) superfamily, commonly found in hematologic disorders, sotatercept aims to restore the normal functioning of red blood cell maturation and osteoblast differentiation. This action is anticipated to enhance anemia management and hinder the progression of myeloma. Simultaneously, comprehensive research is ongoing to investigate sotatercept's pharmacokinetics and potential adverse reactions, thus laying a robust foundation for its prospective clinical use. In this review, we provide a detailed overview of TGF-ß pathways in physiological and hematologic disorder contexts, outline the potential mechanism of sotatercept, and delve into its pharmacokinetics and clinical research advancements in various hematologic diseases. A particular emphasis is given to the relationship between sotatercept dosage and its efficacy or associated adverse reactions.

Pharmacotherapy of refractory pulmonary arterial hypertension.

INTRODUCTION: Treatment of refractory pulmonary arterial hypertension (PAH) is challenging and rarely the focus of reviews. The purpose of this review is to discuss current treatment options of refractory PAH, along with the state of research of several new medications. AREAS COVERED: We conducted a comprehensive PubMed search on the relevant literature on treating PAH, with a focus on approved and investigational interventions for high-risk patients. Our strategy used keywords 'Treatment' AND 'Pulmonary Hypertension,' without date restrictions, ensuring a thorough survey of available literature for our review. EXPERT OPINION: By utilizing serial risk assessment to identify patients remaining intermediate or high-risk, more patients are likely to survive longer. This is done by earlier use of combination or triple therapy with prostacyclin drugs. Current medications for PAH are all essentially vasodilators that improve physiology, but do not truly modify the disease process. The potential application of new investigational medications is exciting as they work by novel pathways likely to change the landscape of refractory PAH treatment.

Is sotatercept, which traps activins and growth differentiation factors, a new dawn in treating pulmonary arterial hypertension (PAH)?

INTRODUCTION: Although the prevalence of pulmonary arterial hypertension (PAH) is low, mortality is high. In PAH, there is a down-regulation of the bone morphogenetic protein receptor type 2 pathway, leading to a prominence of the upregulation pathway that is mediated by activins and growth differentiation factors acting at the receptor type IIA (ActRIIA). Sotatercept is an ActRIIA fusion protein. STELLAR was a phase 3 study of sotatercept for the treatment of PAH. AREAS COVERED: STELLAR. The primary endpoint of STELLAR was change from baseline at 24 weeks in the 6-minute walking distance, which was increased by 34.4 m by sotatercept compared to 1 m in the placebo group. Epistaxis/nosebleed, telangiectasia, and dizziness were more common with sotatercept than placebo. EXPERT OPINION: By targeting the remodeling in PAH, sotatercept is providing a new approach to the treatment of PAH and has the potential to slow or reverse cardiovascular remodeling in other conditions, e.g. left heart failure. However, the development of sotatercept for the treatment of PAH still requires a consideration of the appropriate dose and a longer-term assessment of the benefits and safety. If sotatercept becomes available for self-administration, it will be of interest to assess whether this affects adherence and benefits.

Emerging biologics for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare pulmonary vascular disorder, wherein mean systemic arterial pressure (mPAP) becomes abnormally high because of aberrant changes in various proliferative and inflammatory signalling pathways of pulmonary arterial cells. Currently used anti-PAH drugs chiefly target the vasodilatory and vasoconstrictive pathways. However, an imbalance between bone morphogenetic protein receptor type II (BMPRII) and transforming growth factor beta (TGF-ß) pathways is also implicated in PAH predisposition and pathogenesis. Compared to currently used PAH drugs, various biologics have shown promise as PAH therapeutics that elicit their therapeutic actions akin to endogenous proteins. Biologics that have thus far been explored as PAH therapeutics include monoclonal antibodies, recombinant proteins, engineered cells, and nucleic acids. Because of their similarity with naturally occurring proteins and high binding affinity, biologics are more potent and effective and produce fewer side effects when compared with small molecule drugs. However, biologics also suffer from the limitations of producing immunogenic adverse effects. This review describes various emerging and promising biologics targeting the proliferative/apoptotic and vasodilatory pathways involved in PAH pathogenesis. Here, we have discussed sotatercept, a TGF-ß ligand trap, which is reported to reverse vascular remodelling and reduce PVR with an improved 6-minute walk distance (6-MWDT). We also elaborated on other biologics including BMP9 ligand and anti-gremlin1 antibody, anti-OPG antibody, and getagozumab monoclonal antibody and cell-based therapies. Overall, recent literature suggests that biologics hold excellent promise as a safe and effective alternative to currently used PAH therapeutics.

Current Management and Future Directions for Pulmonary Arterial Hypertension Associated with Congenital Heart Disease.

Current management of patients with congenital heart disease has increased their survival into adulthood. This is accompanied by potential cardiac complications, including pulmonary hypertension associated with congenital heart disease (PAH-CHD). PAH-CHD constitutes a challenging subgroup of pulmonary hypertension and requires expert management to improve quality of life and prognosis. Novel agents have shown a significant improvement in morbidity and mortality in patients with pulmonary arterial hypertension. However, the long-term effects of these medications on PAH-CHD patients remain somewhat uncertain, necessitating treatment plans largely founded on the clinical experience of the healthcare providers. The aim of this review is to summarize the current evidence and future perspectives regarding treatment strategies for PAH-CHD to help better guide management of this complex disease.

Emerging pharmacotherapies for the treatment of pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Approved treatment options currently primarily target abnormal cell signaling pathways involved in vasoconstriction and proliferation, such as those mediated by prostacyclin, cyclic guanosine monophosphate, and endothelin. AREAS COVERED: Recent advancements have led to new applications and modes of delivery of currently approved PAH medications. At the same time, novel drugs targeting specific molecular pathways involved in PAH pathogenesis have been developed and are being investigated in clinical trials. This review summarizes investigational drug trials for PAH gathered from a comprehensive search using PubMed and ClinicalTrials.gov between 2003 and 2023. It includes both currently approved medications studied at different doses or new administration forms and experimental drugs that have not yet been approved. EXPERT OPINION: Approved treatments for PAH target imbalances in pulmonary vasoactive pathways that work primarily on enhancing pulmonary vasodilation with less salient effects on pulmonary vascular remodeling. The advent of more locally acting inhaled medications offers additional therapeutic options that may improve the ease of drug delivery and reduce adverse systemic effects. The more recent emphasis on developing and applying therapeutics that directly impact the aberrant signaling pathways implicated in PAH appears more likely to advance the treatment of this devastating disease.