The Evolving Landscape of Pulmonary Hypertension Treatment: From Vasodilation to Disease Modification

ABSTRACT

Pulmonary hypertension (PH) is a complex disorder associated with significant morbidity and mortality. PH is characterized by an elevated pulmonary vascular load, leading to right ventricular dysfunction and remodeling, with right heart failure and premature death if left untreated. PH is classified into five groups (WHO Groups 1–5) based on etiology and pathophysiology. Group 1 PH, known as pulmonary arterial hypertension (PAH), has seen recent therapeutic advances with life‐extending treatments, including a new therapeutic option that targets the underlying vascular abnormalities. PAH treatment guidelines now emphasize early diagnosis, risk stratification, and targeting multiple pathophysiologic pathways with upfront combination therapy. In contrast to PAH treatment, strategies for other forms of PH remain limited and focus on managing pathophysiologic processes outside the pulmonary vasculature, including left heart disease (Group 2), lung disease and/or hypoxia (Group 3), or pulmonary artery obstructions (Group 4). Nevertheless, advances in research have introduced novel therapeutic targets and investigational agents, offering hope for future expanded treatment options. In this review, we explore recent advances in PH treatments, highlighting the developments poised to expand the therapeutic landscape for this complex disease.

1. Introduction

Pulmonary hypertension (PH) is a complex and life‐threatening disease that affects individuals at all stages of life but is more prevalent in those > 65 years of age [1]. Hemodynamically, PH is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg at rest, as measured by right heart catheterization [1, 2]. Clinically, PH is categorized into five distinct groups (Groups 1–5), reflecting differing underlying pathologies and therapeutic approaches (Figure 1) [1, 2].

FIGURE 1.

Overview of Groups 1–5 PH [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]. ^†Treatment guidelines recommend that patients with idiopathic, heritable, or drug‐ and toxin‐induced PAH undergo acute vasoreactivity testing to identify those who would benefit from treatment with calcium channel blockers. It is important to maintain long‐term hemodynamic and clinical follow‐up in this subgroup. ^‡When assessed using right heart catheterization in symptomatic heart failure patients. ^§Parenchymal diseases not included in Group 5. ALDH2, aldehyde dehydrogenase 2; ASI, activin signaling inhibitor; ATP, adenosine triphosphate; BMP9, bone morphogenetic protein 9; CpcPH, combined pre‐capillary and post‐capillary PH; CTEPH, chronic thromboembolic pulmonary hypertension; ERA, endothelin receptor antagonist; HIF‐1, hypoxia‐inducible factor‐1; HIV, human immunodeficiency virus; IgG1, immunoglobulin G1; IL‐6, interleukin‐6; IpcPH, isolated post‐capillary PH; mTOR, mammalian target of rapamycin; NO, nitric oxide; PAH, pulmonary arterial hypertension; PCA, prostacyclin analog; PCH, pulmonary capillary hemangiomatosis; PDE5, phosphodiesterase‐5; PH, pulmonary hypertension; PRA, prostacyclin receptor agonist; PVOD, pulmonary veno‐occlusive disease; sGC, soluble guanylate cyclase; SGLT2i, sodium–glucose cotransporter‐2 inhibitor; SMURF1, SMAD‐specific E3 ubiquitin protein ligase 1.

This review primarily focuses on treatment advances for Group 1 PH (also termed pulmonary arterial hypertension [PAH]). PAH is an orphan disease [1] and comprises several subgroups (Figure 1), including heritable forms [3]. PAH is characterized by excess proliferation of vascular cells that narrows the pulmonary vessels, thus increasing vascular load and leading to right ventricular dysfunction and maladaptive remodeling, with right heart failure and premature death if untreated (Figure 2) [4]. Significant breakthroughs in understanding the underlying molecular pathways came from identifying genetic causes of heritable PAH. Approximately 80% of patients with heritable PAH (and < 20% with sporadic PAH) carry a mutation in bone morphogenetic protein receptor type 2 (BMPR2), which encodes the BMPR2 receptor of the transforming growth factor β (TGF‐β) signaling superfamily [4]. The central involvement of this vascular remodeling pathway was further confirmed when mutations causing PAH were identified in elements of the downstream TGF‐β signaling pathway and proteins that interact with BMPR2 (activin A receptor type 2‐like 1 [ACVRL1] and endoglin [ENG]) [4, 16].

FIGURE 2.

Overview of Group 1 PH (PAH) pathophysiology and drug targets [1, 4, 5, 11, 12, 13, 14, 15]. ACTRIIA, activin receptor type IIA; BMP, bone morphogenetic protein; BMP9, bone morphogenetic protein 9; BMPR, bone morphogenetic protein receptor; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET, endothelin; GDF, growth differentiation factors; GMP, guanosine monophosphate; GTP, guanosine triphosphate; IgG1, immunoglobulin G1; IP, prostacyclin I2; PAH, pulmonary arterial hypertension; PDE‐5, phosphodiesterase type 5; PH, pulmonary hypertension; RA, right atrium; RV, right ventricle; sGC, soluble guanylate cyclase; SMURF1, SMAD‐specific E3 ubiquitin protein ligase 1; TGF‐β; transforming growth factor‐beta; TKI, tyrosine kinase inhibitor.

Groups 2–5 PH are heterogeneous disease states with diverse pathophysiological causes (Figure 1). Their prognosis varies but remains poor overall. Current approaches focus on reducing risk, improving symptoms, and slowing disease progression. These patients have a significant unmet need for novel effective therapeutic agents, which we also discuss further in this review.

2. Advances in the Therapeutic Management of PAH

For 30 years following the approval of the first medical therapy, treatment for PAH relied on agents targeting the endothelin, nitric oxide (NO), or prostacyclin pathways (Figure 2), with vasodilation thought to be their primary mode of action (Table 1 and Table S1) [1, 5, 18]. Endothelin‐1 binding to endothelin receptors within pulmonary arteries promotes vasoconstriction and proliferation of vascular cells, and this underlies the use of endothelin receptor antagonists (ERAs) such as bosentan, ambrisentan, and macitentan [1]. Several approved therapies target cyclic guanosine monophosphate (cGMP), a secondary messenger downstream in the NO pathway that promotes vascular smooth muscle relaxation. This class of approved medicines includes riociguat, which is a soluble guanylate cyclase (sGC) stimulator (the enzyme that synthesizes cGMP), and sildenafil and tadalafil, which are oral inhibitors of phosphodiesterase‐5 (PDE5), an enzyme that degrades cGMP [1, 4]. Furthermore, prostacyclin analogs (PCAs), including treprostinil, epoprostenol, iloprost, and beraprost, as well as prostacyclin receptor agonists (PRAs), such as selexipag, are approved for the treatment of PAH. The treatment benefit of these compounds is associated with their ability to induce potent vasodilation, inhibit platelet aggregation, and their anti‐proliferative effects [1]. However, as these therapies act primarily as vasodilators, they can impose a substantial burden on patients, with adverse events commonly including headache, dizziness, flushing, congestion, systemic hypotension, and gastrointestinal discomfort [1, 3, 4]. In addition, patients typically receive double or triple combination therapy, often involving therapies with overlapping adverse event profiles [1, 3], which can further contribute to the complexity of PAH management. Although these three therapy classes provide symptomatic relief and delay disease progression, they do not modify the underlying vascular pathology of PAH, and 5‐year rates of survival remain unsatisfactory [19, 20].

TABLE 1.

Approved medications for the treatment of Group 1 PH (PAH).

Drug name (generic) and route of administration	Key Phase 3 studies (active studies) †	Potential combination therapy options
ERAs
Bosentan (oral tablet)	BREATHE‐1 BREATHE‐5 (NCT00367770)	✓ PDE5 inhibitor, PCA, PRA, sGCs
Ambrisentan (oral tablet)	ARIES‐1 & ARIES‐2 (NCT00091598) (PAH: TAPE NCT04972656)	✓ PDE5 inhibitor
Macitentan (oral tablet)	SERAPHIN NCT00660179 (PAH: pediatric population, TOMORROW, NCT02932410) (PAH: UNISUS study NCT04273945)	✓ PDE5 inhibitor
PDE5 inhibitors
Sildenafil (IV injection, oral tablet, oral suspension)	SUPER STARTS‐2 (pediatric) NCT00159913	✓ ERA, PCA X sGCs
Tadalafil (oral tablet)	PHIRST‐1 & 2 (NCT00125918)	✓ ERA X sGCs
PCA
Treprostinil (IV or SC injection, inhalation, oral tablet)	SC infusion Oral sustained release: FREEDOM‐C NCT00325442; FREEDOM‐C2 NCT00887978 (PAH: pediatrics, NCT06350032) (PAH or PH‐ILD: liposomal inhalation suspension, NCT04691154) (PAH: treprostinil palmitil inhalation powder, NCT05649748) ‡ (PH‐ILD: treprostinil palmitil inhalation powder, NCT05649722) ‡	✓ ERA, PDE5 inhibitor, sGCs
Epoprostenol (IV injection)	12‐week prospective study (PPH study group)	✓ ERA, PDE5 inhibitor
Iloprost (inhalation)	AIR	✓ ERA, PDE5 inhibitor
Beraprost (oral tablet)	ALPHABET	✓ ERA
PRA
Selexipag (oral tablet, IV injection)	GRIPHON (NCT01106014) (PAH: pediatric population, SALTO, NCT04175600)	✓ ERA, PDE5 inhibitor, sGCs
sGCs
Riociguat (oral tablet)	PATENT‐1 & 2 (NCT00810693) (NCT00863681) (PAH: pediatric population, PATENT‐CHILD, NCT02562235) (PAH; early disease, ESRA NCT05339087)	✓ ERA, PCA X PDE5 inhibitor
Activin signaling inhibitor
Sotatercept (SC injection)	STELLAR (NCT04576988) ZENITH (NCT04896008) HYPERION (NCT04811092) (PAH: pediatric population; MOONBEAM NCT05587712) (PAH: long‐term follow‐up; SOTERIA NCT04796337)	Add‐on therapy for use with individual or combinations of ERA, PDE5 inhibitors, sGCs, PCA, or PRA agents

Abbreviations: ERA, endothelin receptor agonist; ILD, interstitial lung disease; IV, intravenous; PAH, pulmonary arterial hypertension; PCA, prostacyclin analog; PDE5, phosphodiesterase‐5; PH, pulmonary hypertension; PH‐ILD, PH associated with interstitial lung disease; PPH, primary pulmonary hypertension; PRA, prostacyclin receptor agonist; SC, subcutaneous; sGCs, soluble guanylate cyclase stimulator.

^† The summary of ongoing studies focuses on interventional Phase 3 studies in the PH group in which the drug class is approved; additional post‐approval studies are not listed; see Table 2 for ongoing studies in different PH groups.

^‡ Extension studies are listed because they are the first treprostinil palmitil inhalation studies with a Phase 3 component.

In 2024, the first agent in a new therapy class received approval for the treatment of PAH, potentially signaling a transition from drugs that target vascular tone to novel mechanisms of action that may address the underlying remodeling, proliferation, and fibrosis associated with the disease. Activin signaling inhibitors (ASIs) (Table 1 and Table S1) target activin, a type of TGF‐β signaling protein involved in vascular cell dysfunction, including endothelial and smooth muscle cell proliferation, as well as remodeling of the extracellular matrix [21, 22]. Sotatercept, a first‐in‐class ASI approved as add‐on therapy for treatment of PAH, acts as a ligand trap for activins, improving the balance between pro‐ and anti‐proliferative signaling in the pulmonary vasculature (Figure 2) [23, 24]. Multiple placebo‐controlled Phase 3 studies have demonstrated that sotatercept added to background therapy has clinical benefit in PAH [25, 26, 27]. This includes that sotatercept significantly improved 6‐min walk distance (6MWD) versus placebo in STELLAR, the registrational Phase 3 study in participants with PAH at World Health Organization functional class (WHO FC) II or III [25]. Subsequently, in two additional Phase 3 studies in PAH (ZENITH and HYPERION), sotatercept significantly reduced the risk of clinical worsening versus placebo. In ZENITH, conducted in participants at high risk of death (WHO FC III–IV), the risk of morbidity/morbidity decreased by 76% with sotatercept versus placebo [26]. In HYPERION, conducted in participants who were within 1 year of PAH diagnosis (WHO FC II and III) and at intermediate or high risk of mortality, treatment with sotatercept reduced the occurrence of a clinical worsening event by 76% [27]. Safety findings were consistent across the studies, with relatively low rates of treatment discontinuations [25, 26, 27]. Adverse events associated with sotatercept (those that occurred in ≥ 10% of patients receiving sotatercept and in 5% more than placebo) included infections, epistaxis, telangiectasia, diarrhea, headache, rash, increased hemoglobin, dizziness, erythema, and gingival bleeding per the US prescribing information [24]. The US prescribing information also outlines several important warnings and precautions, including erythrocytosis, severe thrombocytopenia, and serious bleeding, and provides guidance on clinical considerations and monitoring to support use of this new therapy [24]. Sotatercept is currently the only ASI approved for PAH and is used as an add‐on to existing PAH therapy, including background double or triple combination therapy [3, 24], rather than as a replacement for established treatment regimens in clinical practice.

How to best use available PAH therapies, including the relatively recently approved ASI add‐on therapy, is a topic under active discussion. The most recent international PAH treatment guidelines were published in 2022 by the European Society of Cardiology (ESC) and European Respiratory Society (ERS) and thus precede the approval of sotatercept [1]. These recommend stratifying patients based on the initial risk assessment and emphasize combination therapy regimens. The AMBITION study, which investigated initial combination therapy with ambrisentan (an ERA) and tadalafil (a PDE5 inhibitor), had a substantial impact in establishing this as the gold standard for most newly diagnosed cases of PAH [1, 28]. In AMBITION, initial combination therapy (ambrisentan + tadalafil) significantly reduced the risk of a first event of clinical failure compared with either drug given as monotherapy [28]. Consequently, dual combination therapy with an ERA plus PDE5 inhibitor is recommended for many patients at low or intermediate risk (including idiopathic, hereditary, drug‐ and toxin‐associated, and connective tissue disease‐associated PAH). Triple combination therapy is recommended for many patients at higher risk (addition of intravenous [IV] or subcutaneous [SC] PCA) [1]. Risk assessments should be repeated at regular follow‐up intervals, and treatment adjusted and/or escalated unless patients achieve low–risk status; options suggested in 2022 were to add a PRA (selexipag), switch from a PDE5 inhibitor to an sGC stimulator (riociguat), add IV or SC PCA (epoprostenol or treprostinil), or refer for lung transplant evaluation [1]. The combination of a PDE5 inhibitor and sGC stimulator must be avoided owing to excessive NO–sGC–cGMP pathway activation, which increases the risk of hypotension [29].

The first international recommendations that incorporated sotatercept in treatment regimens came from an updated algorithm presented by the 2024 7^th World Symposium on Pulmonary Hypertension (WSPH) [3]. This maintained the overarching principles of the ESC/ERS guidelines, but included the option to escalate by adding an ASI to regimens for patients who do not achieve or maintain low‐risk status [3]. Treatment recommendations are expected to further evolve as more data become available, including consideration of the recent Phase 3 data showing a favorable benefit–risk for early initiation of sotatercept add‐on therapy (within 1 year of PAH diagnosis) [27].

3. Targeted Therapies for the Treatment of Group 2–5 PH

Current treatment guidelines for Groups 2–5 PH focus on managing the underlying pathophysiology. For Group 2 PH (due to left heart disease [LHD]; Figure 1), there are currently no approved medications specifically targeting the underlying pulmonary vascular pathobiology, and its management is focused on the treatment of the LHD [1]. Therapies approved for PAH are not recommended, given that ERAs and PDE5 inhibitors have shown no benefit or potential harm [1, 30, 31]. For Group 3 PH (due to lung diseases and hypoxia), guidelines recommend optimizing the treatment of the underlying lung disease, adding oxygen and non‐invasive ventilation where indicated, as well as pulmonary rehabilitation [1, 32]. While inhaled treprostinil is approved for patients with pulmonary hypertension associated with interstitial lung disease (PH‐ILD) following demonstration of improved exercise capacity [6], it is not approved for other subtypes of Group 3 PH [33]. The PERFECT study of inhaled treprostinil in PH associated with chronic obstructive pulmonary disease (PH‐COPD) terminated prematurely due to unacceptable safety issues [34], raising concerns about off‐target effects and underscoring the need for therapies specifically tailored to the pathophysiology of each subtype.

Group 4 PH (PH associated with pulmonary artery obstructions) is typically treated with a multimodal approach [1, 35]. Riociguat is approved for persistent/recurrent chronic thromboembolic PH (CTEPH) after surgery or inoperable cases to improve exercise capacity and WHO FC [36]. Treatment guidelines recommend considering off‐label use of PAH therapies in patients who are symptomatic and have inoperable CTEPH; treprostinil may also be considered for patients with inoperable disease at WHO FC III–IV or patients with persistent/recurrent PH after pulmonary endarterectomy [1]. Group 5 PH can be due to a wide range of conditions with unclear and/or multifactorial mechanisms, and treatment recommendations focus on the underlying condition [1].

4. Advances in PH Medical Therapy

Translating vascular remodeling findings from preclinical models to clinical efficacy in PH is challenging and remains a barrier to therapeutic discovery and development. In vitro models exist to capture downstream target inhibition‐driven pharmacodynamic impact, but evidence of robust vascular remodeling typically requires in vivo experiments lasting multiple weeks. While these in vivo data are considered pivotal to early therapeutic development, the models struggle to capture the complex biological fingerprint of clinical PH. For example, in animal models, vascular remodeling is typically assessed under controlled conditions with homogeneous disease drivers and relatively short disease duration, enabling clear demonstration of structural reversal (e.g., reduced medial hypertrophy and muscularization) [22]. However, in patients, vascular pathology is heterogeneous, chronic, and often accompanied by irreversible changes, such as plexiform lesions and fibrosis, which may not be fully captured or reversed. Moreover, clinical endpoints rely largely on functional and hemodynamic measures (e.g., mPAP, pulmonary vascular resistance [PVR], 6MWD) rather than direct histologic assessment of remodeling, making it challenging to directly link mechanistic effects observed preclinically to patient benefit [25, 37]. Consequently, while the effect of sotatercept on vascular remodeling is supported by the TGF‐β superfamily biology [23, 24], preclinical evidence [21, 22], and robust clinical improvements in hemodynamics [25, 37], establishing the extent and durability of true vascular remodeling in humans remains an important translational gap.

There is a wide range of drugs currently in development for PH (Table 2 and Table S2), which demonstrates the diversity of research efforts and potential for new disease‐modifying therapies. Emerging evidence of key molecular pathways is driving a shift in PH management from traditional vasodilator‐focused strategies to targeted pathway‐specific approaches [5]. PAH is the most active area of drug development (Figure 1), with key agents, such as seralutinib, in Phase 3 development. Seralutinib is an inhaled tyrosine kinase inhibitor (TKI) that targets several different pathways (proliferative, inflammatory, and fibrotic) involved in remodeling of the pulmonary vasculature [11, 12], and the Phase 2 TORREY study demonstrated significant improvements in PVR compared with placebo [38]. The PROSERA study (NCT05934526) investigated seralutinib in adults with PAH; however, the primary endpoint did not meet the prespecified threshold for statistical significance [39]. Results from the exploratory substudy of PROSERA evaluating computed tomography (CT) functional respiratory imaging were statistically significant and correlated with clinical outcomes; therefore, a New Drug Application is expected to be submitted for seralutinib for the treatment of PAH in September 2026 [40]. Other therapies that target growth factor pathways include imatinib, a TKI that targets BRC‐ABL, PDGFR, and c‐KIT [5] and is continuing in clinical development for PAH in the PIPAH study (NCT04416750), although a previous study (NCT05036135) was terminated owing to a lack of efficacy at tested doses. Agents in early development for PAH include PF‐07868489, a novel bone morphogenetic protein 9 (BMP9) inhibitor [13], and LTP001, a SMAD‐specific E3 ubiquitin protein ligase 1 (SMURF1) inhibitor that modulates the degradation of TGF‐β pathway components [5, 14]. Potential future research for the treatment of PAH may also explore stem cell therapy, gene therapy, microRNAs, and agents that target epigenetic mechanisms [41, 42].

TABLE 2.

Drugs in Phase 2 or 3 investigation for PH.

Drug name/number	Mechanism of action	Phase of development	Ongoing studies (Key completed trials)
2‐HOBA (2‐Hydroxybenzylamine)	Scavenger of reactive dicarbonyl species	Phase 2	PAH: NCT06176118
APL‐9796	ZIP12 monoclonal antibody	Phase 2	PAH or PH‐ILD ViTAL‐PH study NCT06846554
AZD3427	Long‐acting relaxin‐2 mimetic	Phase 2	PH due to left heart disease (WHO Group 2): RE‐PHIRE study NCT05737940
DNIC‐GS (Oxacom)	Dinitrosyl iron complex (NO donor)	Phase 2/3	PAH: OXA‐PAH‐1 NCT06683040
Dapagliflozin	SGLT2i	Phase 1/2	PAH: DAPAH study NCT05179356
			PH (effect on RV function); Phase 1; NCT06612086
DHEA	Adrenal steroid	Phase 2	PAH: EDIPHY study NCT03648385
Empagliflozin	SGLT2i	Phase 1/2	PAH: EmPATH study NCT06992440
			RV function; Phase 1; NCT06554301
			(Idiopathic PAH: Phase 2 safety and efficacy, Emphower PoC NCT05493371)
Frespaciguat (MK‐5475)	Soluble guanylate cyclase stimulator	Phase 2	PH‐COPD: INSIGNIA‐PH‐COPD (NCT05612035)
Imatinib	Tyrosine kinase inhibitor	Phase 2	PAH: PIPAH NCT04416750
			(PAH: Phase 2/3 IMPAHCT † NCT05036135)
LAM‐001 (inhaled dry‐powder formulation of sirolimus)	mTOR inhibitor	Phase 2	PH Group 1 or 3: NCT05798923
LTP001	SMURF1 inhibitor	Phase 1/2	PAH: NCT06649110
			(PAH: NCT05135000)
Mirivadelgat/FP‐045	Oral small‐molecule ALDH2 activator	Phase 2	PH‐ILD: WINWARD NCT06475781
Mosliciguat (BAY1237592)	Inhaled sGC activator	Phase 2	PH‐ILD: PHocus NCT06635850
PF‐07868489	Recombinant IgG1 inhibiting BMP9 signaling	Phase 1/2	PAH: NCT06137742
Ralinepag (APD‐811)	Selective prostacyclin receptor agonist	Phase 3	PAH: ADVANCE OUTCOMES (ROR‐PH‐301) NCT03626688
			(PAH: Phase 2, open label, safety and efficacy NCT02279745)
Satralizumab	IL‐6 receptor antagonist	Phase 2	PAH: SATISFY‐JP open‐label study of Japanese population NCT05679570
Seralutinib (GB002)	Tyrosine kinase inhibitor targeting PDGFRα/β, CSF1R, and c‐KIT	Phase 3	PAH: PROSERA Study (NCT05934526)
			PH‐ILD: SERANATA Study (NCT07181382)
			(PAH: TORREY study NCT04456998)
Sotatercept	Activin signaling inhibitor	Phase 2	(Group 2 PH: CADENCE NCT04945460)
Tadalafil	PDE5 inhibitor	Not stated ‡	(Group 2 PH: NCT06350773)
		Phase 2	(PH‐COPD – BETTER COPD‐PH NCT05937854)
		Phase 3	(PH‐COPD: ERASE PH‐COPD NCT05844462)
TNX‐103/levosimendan	Calcium sensitizer and potassium ATP channel activator	Phase 3	PH‐HFpEF: LEVEL NCT05983250
TX000045/TX45	Long‐acting Fc–relaxin fusion protein	Phase 2	PH‐HFpEF: APEX study NCT06616974 (Phase 1a study [17])
Valsartan	ARB	Phase 2	PAH: REVAMP‐PH study NCT06053580
Vardenafil/RT234	PDE5 inhibitor	Phase 2b	PAH: VIPAH‐PRN 2B NCT04266197

Note: The table does not include agents that no longer have an active trial in a PH indication.

Abbreviations: ALDH2, aldehyde dehydrogenase 2; ARB, angiotensin II receptor blocker; ATP, adenosine triphosphate; BMP9, bone morphogenetic protein 9; CSF1R, colony‐stimulating factor 1 receptor; DHEA, dehydroepiandrosterone; DNIC‐GS, dinitrosyl iron complex with glutathione; Fc, fragment crystallizable; IgG1, immunoglobulin G1; IL‐6, interleukin‐6; mTOR, mammalian target of rapamycin; NO, nitric oxide; PAH, pulmonary arterial hypertension; PDE5, phosphodiesterase‐5; PDGFRα/β, platelet‐derived growth factor receptor alpha/beta; PH, pulmonary hypertension; PH‐COPD, pulmonary hypertension associated with chronic obstructive pulmonary disease; PH‐HFpEF, pulmonary hypertension associated with heart failure with preserved ejection fraction; PH‐ILD, pulmonary hypertension associated with interstitial lung disease; RV, right ventricle; sGC, soluble guanylate cyclase; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SMURF1, SMAD‐specific E3 ubiquitin protein ligase 1; WHO, World Health Organization.

^† Study terminated; while inhaled imatinib was well tolerated, it did not prove to be efficacious at the evaluated doses.

^‡ Study phase was not provided as part of the registration details.

Advancements in other PH groups have lagged, owing to the wide variety of often complex pathophysiologies, diagnostic challenges, and challenges in clinical trial design [1]; nevertheless, several studies in Group 2 PH have promise. The Phase 2 CADENCE study (NCT04945460) investigated the ASI sotatercept in participants with combined pre‐capillary and post‐capillary PH (CpcPH) due to heart failure with preserved ejection fraction (HFpEF), which is characterized by structural abnormalities in the pulmonary vasculature (caused by chronic pressure overload [7]). It is hypothesized that the ability of sotatercept to re‐balance pro‐ and antiproliferative signaling would produce clinical benefits such as those demonstrated in PAH [24, 25]. In CADENCE, sotatercept was generally well tolerated, reduced PVR in the target population, and showed mechanistic evidence of both pulmonary vascular and cardiac benefits [43]. Relaxin is known to have vasodilatory and anti‐fibrotic effects in the lungs [44], and two investigational agents that target this pathway are in active development. The Phase 2 APEX study (NCT06616974) is evaluating TX000045, a long‐acting Fc–relaxin fusion protein, in patients with PH due to HFpEF. The Phase 2b RE‐PHIRE study (NCT05737940) was assessing AZD3427, a long‐acting relaxin‐2 mimetic, in patients with HF (no restrictions by left ventricular ejection fraction) and PH‐LHD [45]; however, the program was terminated due to underwhelming efficacy [46]. Research is continuing for AZD5462 [46], an oral relaxin receptor agonist, which was investigated in the Phase 2b LUMINARA study (NCT06299826) in patients with chronic HF [47]. Also in Group 2 PH, levosimendan, a calcium sensitizer and potassium‐ATP channel activator, is being investigated in patients with PH associated with HFpEF. This agent has a unique dual mechanism of action; calcium sensitization can produce inotropic effects, while potassium‐ATP channel activation is potentially cardioprotective (acting in cardiac cells) and promotes vasodilation in the pulmonary and systemic circulation (acting in vascular smooth muscle cells) [48]. A Phase 3 study of levosimendan (LEVEL; NCT05983250) is ongoing and additional studies are planned.

There are also active investigations for new therapies for Group 3 PH. In Q4 2025, the first sites for SERANATA (NCT07181382), a global Phase 3 clinical trial of seralutinib for the treatment of PH‐ILD (Group 3 PH), were activated [49]. Unfortunately, Groups 4 and 5 remain underrepresented and with limited recent successes. In CTEPH, a Phase 3 study of selexipag (SELECT; NCT03689244) was terminated owing to a lack of efficacy, while a Phase 3 study of macitentan (MACiTEPH study; NCT04271475) was terminated early owing to futility following the pre‐planned interim analysis.

There is also ongoing work to optimize use of currently approved therapies, to either minimize inconvenience for patients and/or improve delivery to the pulmonary circulation; the latter can potentially increase efficacy and reduce side effects from systemic activity. While these strategies currently focus on therapies for PAH, successful approaches are likely to translate to the treatment of other groups too. An inhaled formulation of treprostinil (which is associated with a reduced risk of systemic side effects versus oral administration) is already available for patients with PAH [50]. A treprostinil palmitil inhalation powder (TPIP) is currently in Phase 3 development for both PAH (NCT05649748) and in PH‐ILD (NCT05649722) after recent positive results from a Phase 2b study that met its primary and all secondary efficacy endpoints [51]. TPIP is administered once daily, which is more convenient for patients than the four‐times‐daily dosing of the existing inhaled treprostinil formulation [50]. There are two inhaled sGC‐targeted drugs currently in clinical development for Group 3 PH (mosliciguat, an sGC activator [NCT06635850], and frespaciguat, an sGC stimulator [NCT05612035]). Moreover, in addition to the development of inhaled drug formulations, patients with PH are expected to benefit from advances in drug delivery technology, such as smart inhalers and ultrasonic or vibrating mesh nebulizers.

The current trial landscape increasingly reflects a shift toward mechanistically targeted group‐specific therapies, underscoring the evolving paradigm in PH treatment (Table 2). The Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics (PVDOMICS; NCT02980887) initiative is a large National Institutes of Health‐/National Heart, Lung, and Blood Institute‐sponsored study aimed at redefining PH based on molecular and physiological phenotyping across a broad patient population versus the traditional WHO groupings. PVDOMICS has the potential to support earlier and more accurate diagnosis and to refine assessment of interventions for PH [52]. This approach may also enable the development of more effective, precision‐based therapeutic strategies tailored to individual patients [52]. It is also likely that patients will benefit from combination regimens with drugs that target multiple pathways.

The diversity of PH patient populations necessitates careful selection of trial participants to examine group‐specific interventions that, in turn, must be balanced against recruitment challenges due to the relatively low frequency of some PH subtypes. This includes that several PH groups (or subgroups) are rare, including PAH for which orphan drug designation remains crucial for new drug development. Moreover, accurate diagnosis and classification according to PH group can be challenging, with misclassification of patients likely to affect clinical trial results (dilute efficacy signals or introduce safety risks). This is especially acute in developing countries, which often lack specialist expertise and facilities for PH.

Accurate evaluation of new therapies requires clinical trials with endpoints that reliably measure clinical benefit. Common efficacy endpoints include 6MWD and time to clinical worsening for registrational trials, and PVR and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels for early phase studies [53, 54]. 6MWD, although commonly used [53], is influenced by factors such as age and may not detect clinical worsening/improvement for all PH groups or predict mortality benefit [53]. In addition, evidence is still lacking on whether time to clinical worsening is a valid surrogate for mortality [53]. NT‐proBNP correlates with myocardial stress and right ventricular dysfunction [1, 53, 55]; however, it is not specific and selective for PH [1, 55], highlighting the need for alternative predictive biomarkers. Patient‐reported outcomes are important to consider and complement efficacy and safety endpoints [56]. With the development of new therapies with disease‐modifying potential, treatment goals may transition from maintaining ‘low risk’ status to achieving remission and ultimately cure [57]. Accordingly, validated endpoints and thresholds capable of defining these outcomes will be essential.

5. Conclusions

Combined medical therapies that target multiple pathways are now the cornerstone of treatment for PAH (Group 1 PH), both improving clinical outcomes and delaying disease progression. While the development of new medicines for Groups 2–5 PH is progressing relatively slowly, new drug classes are in development for the treatment of PAH. The research into the pathobiology of these populations is ongoing and important to identify new targets that allow rational drug design.

The relatively large number of PAH drugs in development raises hope for a shift from agents primarily acting on vascular tone to those that treat the underlying molecular causes of abnormal vascular remodeling. In turn, this offers the hope of long‐term disease stabilization and possibly remission in some patients, and a model for how new agents can be developed for other PH groups.

Funding

This review was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, New Jersey, USA.

Conflicts of Interest

All authors are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, New Jersey, USA, and may own stock and/or hold stock options in Merck & Co. Inc., Rahway, New Jersey, USA.

Supporting information

Appendix S1: cts70685‐sup‐0001‐supinfo.docx.