RARE DISEASE
Idiopathic pulmonary arterial hypertension
Idiopathic pulmonary arterial hypertension
Idiopathic pulmonary arterial hypertension
Synonyms: IPAH, Primary pulmonary arterial hypertension
Synonyms: IPAH, Primary pulmonary arterial hypertension
Synonyms: IPAH, Primary pulmonary arterial hypertension
Drug discovery
9
drugs
With orphan designations
Overview
Idiopathic pulmonary arterial hypertension (IPAH) is a rare, progressive disease of small pulmonary arteries characterized by vascular remodeling, elevated pulmonary vascular resistance (>2 Wood units), and mean pulmonary arterial pressure >20 mmHg [1][6]. It leads to right ventricular failure and premature death, with nonspecific presenting symptoms like exertional dyspnea, fatigue, and syncope [1][4][6]. Diagnosis requires exclusion of secondary causes [1][6]. Treatment combines vasodilators, antiproliferative agents, and advanced interventions [3][8][13], though prognosis remains guarded without transplantation [10][16].
Categories: rare genetic diseases, rare respiratory diseases, rare transplant-related disorders
Research Papers
3,541 drug discovery papers about Idiopathic pulmonary arterial hypertension, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,541 drug discovery papers about Idiopathic pulmonary arterial hypertension, with 3 first-in-class and 11 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | Efficacy, Safety, and Pharmacokinetics of Macitentan in Japanese Pediatric Patients With Pulmonary Arterial Hypertension: Prospective, Multicenter, Open-Label Study.
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), imposing an increased workload on the right ventricle and ultimately leading to right heart failure. Macitentan is a potent dual endothelin receptor antagonist that blocks both endothelin receptor subtypes A and B, and is approved for adult patients with PAH, but evidence in pediatric PAH patients is limited. This was an open-label, multicenter, Phase III study enrolling Japanese pediatric PAH patients aged ≥3 months to <15 years. A total of 7 patients were enrolled. Efficacy was evaluated by assessing pulmonary hemodynamics after 24 weeks of treatment, and safety was assessed over a 52-week period. The geometric mean fold change in PVR index (PVRI) at Week 24 was 59.43%, which met the prespecified success criterion of ≤81.6% (primary endpoint). Other pulmonary hemodynamic parameters, including mean PAP, mean right atrial pressure, and total pulmonary resistance, also showed improvement. Additionally, at Week 52, functional outcomes such as 6-minute walk test performance and quality-of-life reports, demonstrated a trend toward improvement. Safety findings were favorable, with no unexpected concerns among the 7 treated participants. Most adverse events were mild to moderate in severity, and none were considered related to macitentan. Macitentan showed clinically meaningful reduction in PVRI and improved pulmonary hemodynamics in Japanese pediatric patients with PAH, with a favorable safety profile over 52 weeks of treatment.
2026-08-07 | Improved Outcomes with Early Aggressive Therapy in Pediatric Pulmonary Hypertension.
Pediatric pulmonary arterial hypertension (PAH) carries high mortality with 81% 5-year transplant-free survival. The global Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension-2 (TOPP-2; NCT02610660) registry was created to assess the treatments and outcomes of newly diagnosed pediatric PAH patients. This study evaluates real-world treatment strategies and their relationship with outcomes. Within TOPP-2, 445 subjects with newly diagnosed, catheterization-confirmed WSPH Group 1 pediatric PAH were enrolled. Treatment regimens were classified as none, calcium channel blocker monotherapy, PAH-targeted Monotherapy (Mono), Dual, Triple (enteral/inhaled only), or triple including parenteral prostanoid (TripleX). Baseline treatment strategy was defined as medications received three months following diagnosis. Primary clinical endpoint was death or lung transplantation. Dual therapy was the most common baseline treatment regimen (40.2%), followed by Monotherapy (29.0%). Phosphodiesterase type 5 inhibitors were the most common class of PAH-targeted therapy (72.4%) followed by endothelin receptor antagonists (59.3%). Adjusting for disease severity at diagnosis, baseline Dual patients had lesser hazard of death/transplant than Mono patients escalating to Dual by year one (HR=0.30, 95% CI=0.16-0.56, p<0.001). Baseline TripleX patients had lesser hazard of death/transplant than those started on enteral/inhaled therapy only and escalated to parenteral by year one (HR=0.28, 95% CI=0.15-0.50, p<0.001). A wide range of pediatric PAH initial medication strategies were observed in the TOPP-2 registry. Therapy regimen escalation within the first year, to Dual for lower-risk patients or to TripleX for higher-risk patients, was associated with worse outcomes compared to those treated more aggressively upfront, supporting upfront over sequential combination therapies.
2026-08-01 | Effects of riociguat on right ventricular size and function in pulmonary arterial hypertension (RIVER II): a prospective, phase IV study.
Pulmonary arterial hypertension (PAH) is characterized by right ventricular (RV) pressure overload, dilatation and dysfunction, which are key prognostic determinants. While riociguat improves exercise capacity and hemodynamics, prospective data on reverse remodeling remain limited. This prospective, phase IV study evaluated the effects of riociguat on right-heart size, function, hemodynamics, exercise capacity and safety in PAH patients. Treatment-naïve or pretreated PAH patients were enrolled. Patients receiving phosphodiesterase-5 inhibitors (PDE5i) could be switched to riociguat upon clinical indication. The primary endpoint was the change in right atrial (RA) and RV area at 24 weeks. Secondary endpoints included additional echocardiographic, clinical, exercise, hemodynamic and laboratory parameters, as well as quality-of-life (QoL) and safety. Thirty patients (61.2 ± 14.5 years; 76.7% male; 24 PDE5i-pretreated) were enrolled. Marked right-heart dilatation and impaired RV function were prominent at baseline. At week 24, riociguat significantly reduced RA (Δ -3.17 ± 5.91 cm²; p = 0.006) and RV area (Δ -6.00 ± 3.80 cm²; p < 0.0001). Furthermore, RV-fractional area change, 6-minute walking distance and functional class improved significantly. In patients with invasive follow-up, cardiac index increased significantly, with favorable trends in further parameters. N-terminal pro-brain natriuretic peptide and QoL remained unchanged. The study terminated early following the decision by the supplier Merck/MSD; the termination was not safety related. Riociguat was generally well tolerated with no new safety concerns. Riociguat therapy resulted in a statistically significant improvement in right ventricular and atrial size and function with further improvements in exercise capacity and functional class. This prospective trial confirms the findings of previous retrospective studies and supports riociguat as an effective treatment option to improve RV geometry and performance. This trial was registered on clinicaltrials.gov with the ClinicalTrials.gov ID NCT04954742.
2026-08-01 | Poly-Pharmacologic Disruption of the Proliferative-to-Mesenchymal Fate Branch Point Reverses EndMT and Pulmonary Hypertension.
Endothelial-to-mesenchymal transition (EndMT) drives the vascular remodeling in pulmonary arterial hypertension (PAH), yet the regulators that commit endothelial cells to this fate and whether they are pharmacologically addressable remain poorly defined. We report TK22, a small molecule that selectively erases the EndMT-competent endothelial state and reverses experimental pulmonary hypertension. TK22 was developed by structure-based design as an ATP-competitive CDK5 inhibitor (IC50 181 nM). Unbiased profiling across 394 kinases, however, revealed that TK22 inhibits the interphase cell-cycle kinases CDK2/3/4/6 node as well as a pro-mesenchymal node of AMPK-related kinases (NUAK1 and SIK1/2/3) together with PDGFRβ and MLK3, placing its activity at the intersection of proliferative and EndMT control rather than at a single node. Owing to this dual-node action, TK22 produced a strikingly clean cellular phenotype. In primary murine lung endothelial cells, TK22 reversed TGF-β1-induced EndMT across morphological, proteomic, and functional readouts, normalizing α-SMA, SM22, and Calponin, restoring angiogenic tube formation, abolishing acquired smooth-muscle-like contractility, and returning TGF-β1-driven hyperproliferation to baseline without suppressing normal endothelial growth. Single-cell RNA sequencing resolved the basis of this precision: TGF-β1 redirected a cycling Mki67+ endothelial subpopulation into an EndMT-committed state (Tnnt2, Ptgs2, Serpine1) and induced an associated metabolic-stress program (Egln3, Pfkfb3, Pdk1, Bnip3). Cross-validated PHATE and Monocle3 trajectory inference defined a directional proliferative-to-mesenchymal fate transition, and kernel density estimation revealed a stable EndMT cell-state attractor. TK22 selectively eliminated the EndMT-competent and metabolic-stress subpopulations while leaving the remaining endothelial landscape intact. This population-level precision of TK22 is consistent with its dual engagement of the anti-cell-cycle and anti-mesenchymal kinase nodes. In the Su5416/hypoxia rat PH model, TK22 normalized right ventricular systolic pressure, Fulton index, and cardiac function. Together, these findings reframe pharmacologic EndMT control: inhibition at the proliferative-to-mesenchymal fate branch point, through coordinated suppression of cell-cycle and mesenchymal kinases, achieves high selectivity for erasing a pathological endothelial fate state. These findings propose TK22 as a mechanistically precise agent for EndMT-driven vascular disease and establish single-cell trajectory analysis as an essential readout of cellular target engagement and cell-state precision.
2026-07-28 | Repurposing Heart Failure Therapies in Pulmonary Arterial Hypertension: Mechanistic Rationale, Translational Evidence, and Clinical Perspectives for SGLT2 Inhibitors and Mineralocorticoid Receptor Antagonists.
Pulmonary arterial hypertension (PAH) is a progressive and life-threatening condition characterized by elevated pulmonary vascular resistance eventually causing right ventricular failure and premature death. Despite advances in targeted therapies, morbidity and mortality levels remain high, highlighting the need for additional treatment strategies that address the disease's multifactorial pathophysiology. Attention has recently centred on two pharmacological groups with proven roles in other cardiovascular settings: sodium-glucose cotransporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRAs). SGLT2 inhibitors have demonstrated robust clinical benefits in heart failure (HF), type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), extending survival and reducing hospitalizations. Although their primary actions involve renal glucose and sodium handling, accumulating evidence suggests they may also exert favourable effects on the pulmonary vasculature, endothelial function, and right ventricular performance. In parallel, elevated aldosterone levels have been implicated in vascular remodelling, inflammation, and fibrosis in PAH, suggesting a potential therapeutic role for MRAs. However, the strength and clinical significance of these associations remain under investigation. The aim of this review is to synthesize and critically appraise the current evidence regarding the potential role of SGLT2 inhibitors and MRAs in the treatment of pulmonary arterial hypertension, exploring their mechanistic rationale, preclinical findings, and available clinical data to determine whether these agents may offer additional therapeutic benefit in PAH management.
2026-08-11 | Efficacy, Safety, and Pharmacokinetics of Macitentan in Japanese Pediatric Patients With Pulmonary Arterial Hypertension: Prospective, Multicenter, Open-Label Study.
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), imposing an increased workload on the right ventricle and ultimately leading to right heart failure. Macitentan is a potent dual endothelin receptor antagonist that blocks both endothelin receptor subtypes A and B, and is approved for adult patients with PAH, but evidence in pediatric PAH patients is limited. This was an open-label, multicenter, Phase III study enrolling Japanese pediatric PAH patients aged ≥3 months to <15 years. A total of 7 patients were enrolled. Efficacy was evaluated by assessing pulmonary hemodynamics after 24 weeks of treatment, and safety was assessed over a 52-week period. The geometric mean fold change in PVR index (PVRI) at Week 24 was 59.43%, which met the prespecified success criterion of ≤81.6% (primary endpoint). Other pulmonary hemodynamic parameters, including mean PAP, mean right atrial pressure, and total pulmonary resistance, also showed improvement. Additionally, at Week 52, functional outcomes such as 6-minute walk test performance and quality-of-life reports, demonstrated a trend toward improvement. Safety findings were favorable, with no unexpected concerns among the 7 treated participants. Most adverse events were mild to moderate in severity, and none were considered related to macitentan. Macitentan showed clinically meaningful reduction in PVRI and improved pulmonary hemodynamics in Japanese pediatric patients with PAH, with a favorable safety profile over 52 weeks of treatment.
2026-08-07 | Improved Outcomes with Early Aggressive Therapy in Pediatric Pulmonary Hypertension.
Pediatric pulmonary arterial hypertension (PAH) carries high mortality with 81% 5-year transplant-free survival. The global Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension-2 (TOPP-2; NCT02610660) registry was created to assess the treatments and outcomes of newly diagnosed pediatric PAH patients. This study evaluates real-world treatment strategies and their relationship with outcomes. Within TOPP-2, 445 subjects with newly diagnosed, catheterization-confirmed WSPH Group 1 pediatric PAH were enrolled. Treatment regimens were classified as none, calcium channel blocker monotherapy, PAH-targeted Monotherapy (Mono), Dual, Triple (enteral/inhaled only), or triple including parenteral prostanoid (TripleX). Baseline treatment strategy was defined as medications received three months following diagnosis. Primary clinical endpoint was death or lung transplantation. Dual therapy was the most common baseline treatment regimen (40.2%), followed by Monotherapy (29.0%). Phosphodiesterase type 5 inhibitors were the most common class of PAH-targeted therapy (72.4%) followed by endothelin receptor antagonists (59.3%). Adjusting for disease severity at diagnosis, baseline Dual patients had lesser hazard of death/transplant than Mono patients escalating to Dual by year one (HR=0.30, 95% CI=0.16-0.56, p<0.001). Baseline TripleX patients had lesser hazard of death/transplant than those started on enteral/inhaled therapy only and escalated to parenteral by year one (HR=0.28, 95% CI=0.15-0.50, p<0.001). A wide range of pediatric PAH initial medication strategies were observed in the TOPP-2 registry. Therapy regimen escalation within the first year, to Dual for lower-risk patients or to TripleX for higher-risk patients, was associated with worse outcomes compared to those treated more aggressively upfront, supporting upfront over sequential combination therapies.
2026-08-01 | Effects of riociguat on right ventricular size and function in pulmonary arterial hypertension (RIVER II): a prospective, phase IV study.
Pulmonary arterial hypertension (PAH) is characterized by right ventricular (RV) pressure overload, dilatation and dysfunction, which are key prognostic determinants. While riociguat improves exercise capacity and hemodynamics, prospective data on reverse remodeling remain limited. This prospective, phase IV study evaluated the effects of riociguat on right-heart size, function, hemodynamics, exercise capacity and safety in PAH patients. Treatment-naïve or pretreated PAH patients were enrolled. Patients receiving phosphodiesterase-5 inhibitors (PDE5i) could be switched to riociguat upon clinical indication. The primary endpoint was the change in right atrial (RA) and RV area at 24 weeks. Secondary endpoints included additional echocardiographic, clinical, exercise, hemodynamic and laboratory parameters, as well as quality-of-life (QoL) and safety. Thirty patients (61.2 ± 14.5 years; 76.7% male; 24 PDE5i-pretreated) were enrolled. Marked right-heart dilatation and impaired RV function were prominent at baseline. At week 24, riociguat significantly reduced RA (Δ -3.17 ± 5.91 cm²; p = 0.006) and RV area (Δ -6.00 ± 3.80 cm²; p < 0.0001). Furthermore, RV-fractional area change, 6-minute walking distance and functional class improved significantly. In patients with invasive follow-up, cardiac index increased significantly, with favorable trends in further parameters. N-terminal pro-brain natriuretic peptide and QoL remained unchanged. The study terminated early following the decision by the supplier Merck/MSD; the termination was not safety related. Riociguat was generally well tolerated with no new safety concerns. Riociguat therapy resulted in a statistically significant improvement in right ventricular and atrial size and function with further improvements in exercise capacity and functional class. This prospective trial confirms the findings of previous retrospective studies and supports riociguat as an effective treatment option to improve RV geometry and performance. This trial was registered on clinicaltrials.gov with the ClinicalTrials.gov ID NCT04954742.
2026-08-01 | Poly-Pharmacologic Disruption of the Proliferative-to-Mesenchymal Fate Branch Point Reverses EndMT and Pulmonary Hypertension.
Endothelial-to-mesenchymal transition (EndMT) drives the vascular remodeling in pulmonary arterial hypertension (PAH), yet the regulators that commit endothelial cells to this fate and whether they are pharmacologically addressable remain poorly defined. We report TK22, a small molecule that selectively erases the EndMT-competent endothelial state and reverses experimental pulmonary hypertension. TK22 was developed by structure-based design as an ATP-competitive CDK5 inhibitor (IC50 181 nM). Unbiased profiling across 394 kinases, however, revealed that TK22 inhibits the interphase cell-cycle kinases CDK2/3/4/6 node as well as a pro-mesenchymal node of AMPK-related kinases (NUAK1 and SIK1/2/3) together with PDGFRβ and MLK3, placing its activity at the intersection of proliferative and EndMT control rather than at a single node. Owing to this dual-node action, TK22 produced a strikingly clean cellular phenotype. In primary murine lung endothelial cells, TK22 reversed TGF-β1-induced EndMT across morphological, proteomic, and functional readouts, normalizing α-SMA, SM22, and Calponin, restoring angiogenic tube formation, abolishing acquired smooth-muscle-like contractility, and returning TGF-β1-driven hyperproliferation to baseline without suppressing normal endothelial growth. Single-cell RNA sequencing resolved the basis of this precision: TGF-β1 redirected a cycling Mki67+ endothelial subpopulation into an EndMT-committed state (Tnnt2, Ptgs2, Serpine1) and induced an associated metabolic-stress program (Egln3, Pfkfb3, Pdk1, Bnip3). Cross-validated PHATE and Monocle3 trajectory inference defined a directional proliferative-to-mesenchymal fate transition, and kernel density estimation revealed a stable EndMT cell-state attractor. TK22 selectively eliminated the EndMT-competent and metabolic-stress subpopulations while leaving the remaining endothelial landscape intact. This population-level precision of TK22 is consistent with its dual engagement of the anti-cell-cycle and anti-mesenchymal kinase nodes. In the Su5416/hypoxia rat PH model, TK22 normalized right ventricular systolic pressure, Fulton index, and cardiac function. Together, these findings reframe pharmacologic EndMT control: inhibition at the proliferative-to-mesenchymal fate branch point, through coordinated suppression of cell-cycle and mesenchymal kinases, achieves high selectivity for erasing a pathological endothelial fate state. These findings propose TK22 as a mechanistically precise agent for EndMT-driven vascular disease and establish single-cell trajectory analysis as an essential readout of cellular target engagement and cell-state precision.
2026-07-28 | Repurposing Heart Failure Therapies in Pulmonary Arterial Hypertension: Mechanistic Rationale, Translational Evidence, and Clinical Perspectives for SGLT2 Inhibitors and Mineralocorticoid Receptor Antagonists.
Pulmonary arterial hypertension (PAH) is a progressive and life-threatening condition characterized by elevated pulmonary vascular resistance eventually causing right ventricular failure and premature death. Despite advances in targeted therapies, morbidity and mortality levels remain high, highlighting the need for additional treatment strategies that address the disease's multifactorial pathophysiology. Attention has recently centred on two pharmacological groups with proven roles in other cardiovascular settings: sodium-glucose cotransporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRAs). SGLT2 inhibitors have demonstrated robust clinical benefits in heart failure (HF), type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), extending survival and reducing hospitalizations. Although their primary actions involve renal glucose and sodium handling, accumulating evidence suggests they may also exert favourable effects on the pulmonary vasculature, endothelial function, and right ventricular performance. In parallel, elevated aldosterone levels have been implicated in vascular remodelling, inflammation, and fibrosis in PAH, suggesting a potential therapeutic role for MRAs. However, the strength and clinical significance of these associations remain under investigation. The aim of this review is to synthesize and critically appraise the current evidence regarding the potential role of SGLT2 inhibitors and MRAs in the treatment of pulmonary arterial hypertension, exploring their mechanistic rationale, preclinical findings, and available clinical data to determine whether these agents may offer additional therapeutic benefit in PAH management.
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Drug Discovery Landscape
9 orphan drug designations for Idiopathic pulmonary arterial hypertension.
9 orphan drug designations for Idiopathic pulmonary arterial hypertension.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
prodrug of imatinib | small molecules | FDA | 2026-07-16 | — | Inhibikase Therapeutics, Inc. |
treprostinil palmitil | small molecules | FDA | 2026-01-26 | — | Insmed Incorporated |
human anti-PDGF-B monoclonal IgG4 antibody | antibodies | FDA | 2025-11-10 | — | Regeneron Pharmaceuticals, Inc. |
tetrathiomolybdate | small molecules | FDA | 2025-03-18 | — | Artin Bioscience Inc. |
peroxiredoxin 2 mimetic, a tricyclic compound containing disulfide bond as a pharmacophore | small molecules | FDA | 2024-11-25 | — | Vasthera Co. |
a novel, next-generation, selective ligand trap in the form of a heavy chain fragment (Fc) fusion protein consisting of a modified extracellular domain of the human Activin Type 2B Receptor (ActRIIB) fused to a stabilized human immunoglobulin G4 Fc by a peptide linker. | proteins | FDA | 2024-11-18 | — | AliveGen USA, Inc. |
N-(tert-butylcarbamoyl)-5-cyano-2-((4'-(difluoromethoxy)-[1,1'-biphenyl]-3-yl)oxy)benzenesulfonamide | small molecules | FDA | 2018-03-01 | — | ATXA Therapeutics Limited |
Macitentan [Opsumit] | small molecules | EMA | 2011-09-27 | — | Janssen Cilag International |
Beraprost sodium | small molecules | EMA | 2008-07-10 | — | IDEA Innovative Drug European Associates (Ireland) Limited |
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