Sotatercept for pulmonary arterial hypertension on background therapy: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background

Pulmonary arterial hypertension (PAH) is a progressive condition that leads to right ventricular failure and reduced survival. Sotatercept, a fusion protein targeting the activin signaling pathway, may offer disease-modifying benefits.

Objective

This study aimed to evaluate the efficacy and safety of sotatercept compared to placebo in adults with PAH receiving background therapy.

Methods

A systematic literature search was conducted through April 2025 to identify randomized controlled trials (RCTs) comparing sotatercept with placebo in PAH. Data were pooled using risk ratios (RR) or mean differences (MD) with 95% confidence intervals, analyzed using R software.

Results

Three RCTs including 601 patients were analyzed. Sotatercept significantly improved 6-minute walk distance (MD: 38.4 m, P < 0.001), reduced NT-proBNP levels (MD: −852.85 pg/mL, P = 0.02), and lowered pulmonary vascular resistance (MD: −200.25 dyn·s·cm⁻⁵, P < 0.001). World Health Organization functional class improved (RR: 2.04, P < 0.001), and mortality, right ventricular failure, and treatment discontinuation decreased. Overall adverse events were similar between groups (RR: 1.01, P = 0.65), but class-related events such as bleeding and hematologic abnormalities were more frequent.

Conclusion

Sotatercept significantly improves clinical outcomes in PAH but requires close monitoring for bleeding and hematologic adverse events.

Pulmonary arterial hypertension (PAH) is a rare progressive disease characterized by elevated pulmonary arterial pressure and increased pulmonary vascular resistance (PVR), eventually leading to right ventricular (RV) failure and death if left untreated.¹ Hemodynamically, PAH is defined by a mean pulmonary artery pressure >20 mm Hg, a pulmonary artery wedge pressure ≤15 mm Hg, and PVR ≥2 Wood units, as measured by right heart catheterization.^2,3 While its prevalence is low, PAH imposes clinical burden due to its high morbidity and limited survival, with contemporary data reporting a 5-year survival rate of approximately 60% despite advances in medical therapy.^4,5

Over the past two decades, PAH treatment has focused on pharmacologic modulation of three key vasodilatory pathways: endothelin, nitric oxide, and prostacyclin signaling cascades (3). Agents such as endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs have been shown to improve functional capacity, reduce symptoms, and delay clinical deterioration.^3,6 However, these therapies do not sufficiently target the underlying pathophysiological mechanisms driving disease progression: vascular remodeling, inflammation, and excessive cellular proliferation in the pulmonary arterioles. This limitation has stressed the need for therapies that can modify the disease course by reversing or halting vascular pathology.⁷

Advances in molecular biology have identified the bone morphogenetic protein receptor type 2 (BMPR2) signaling axis, part of the transforming growth factor-beta (TGF-β) superfamily, as central to PAH pathogenesis. Loss of function mutations in BMPR2 are present in 70% to 80% of heritable PAH cases and 10% to 20% of idiopathic cases.^8,9 Impaired BMPR2 signaling reduces antiproliferative and proapoptotic control within the pulmonary vasculature, leading to uncontrolled vascular cell proliferation. Compounding this balance is increased signaling via activins and growth differentiation factors (GDF8 and GDF11) through the activin receptor type IIA (ActRIIA), which contributes to pathological vascular remodeling.^10,11

Sotatercept is a first-in-class recombinant fusion protein that acts as a ligand trap for ActRIIA ligands, including activin A, GDF8, and GDF11. By neutralizing these proproliferative factors, sotatercept restores the balance between the antiproliferative BMPR2–Smad1/5/8 and pro-proliferative ActRIIA–Smad2/3 pathways.^12,13​​​​ In preclinical models, sotatercept has demonstrated the ability to reverse pulmonary vascular remodeling, reduce inflammation, and improve RV function​.^14,15 These findings suggest that sotatercept represents a paradigm shift in PAH treatment by targeting the root molecular drivers of vascular remodeling rather than focusing solely on vasodilation. The drug was approved by the US Food and Drug Administration and the European Medicines Agency in 2024, becoming the first disease-modifying biologic therapy for PAH​.^3,16

Despite growing clinical interest in sotatercept, a comprehensive synthesis of randomized evidence evaluating its efficacy and safety is lacking. Previous studies have varied in primary outcomes, patient populations, and follow-up durations, leaving clinicians without a consolidated understanding of its benefit-risk profile. This systematic review and meta-analysis aimed to fill this gap by synthesizing evidence from all randomized controlled trials (RCTs) of sotatercept in adults with PAH receiving background therapy. Specifically, we assessed its effects on hemodynamic markers (e.g., PVR), exercise capacity (6-minute walk distance, 6MWD), World Health Organization (WHO) functional class, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Secondary aims included evaluating all-cause mortality and adverse event (AE) profiles. To our knowledge, this is the first meta-analysis dedicated exclusively to evaluating sotatercept in this patient population.

METHODS

This systematic review and meta-analysis were conducted according to the PRISMA guidelines¹⁷ and the Cochrane Handbook for Systematic Reviews of Interventions.¹⁸ The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under ID CRD420251027187.

Search strategy

A comprehensive electronic search was conducted in PubMed, Scopus, Web of Science, Cochrane CENTRAL, and EMBASE from inception until April 15, 2025, with no restrictions on language or publication date. The search strategy used Boolean combinations of keywords, such as: ((“Pulmonary Arterial Hypertension” OR “PAH”) AND (“Sotatercept” OR “ActRIIA-Fc fusion protein”) AND (“Placebo”) AND (“Pulmonary Vascular Resistance” OR “PVR” OR “6-minute walk distance” OR “6MWD” OR “Functional Class” OR “WHO Functional Class” OR “Mortality” OR “Adverse Events”) AND (“Randomized Controlled Trial” OR “RCT” OR “Randomized Trial” OR “Placebo-Controlled Trial”)). The complete search strategy is provided in Supplementary Table 1.

Eligibility criteria and study selection

We included studies that met the following PICOS criteria: Population, adults diagnosed with PAH receiving stable background therapy; Intervention, sotatercept; Comparator, placebo; and Outcomes, change in PVR, 6MWD, NT-proBNP levels, and WHO functional class, with secondary outcomes of AEs, serious adverse events (SAEs), and treatment discontinuation due to AEs. The studies included were RCTs.

The following exclusion criteria were used: (1) sample size <10 participants per group; (2) studies not evaluating sotatercept; (3) non-RCT designs (e.g., reviews, case reports, editorials); (4) duplicate publications; and (5) studies not reporting any primary outcomes.

All retrieved records were imported into Covidence for deduplication and systematic screening. Two independent reviewer pairs screened titles and abstracts, followed by full-text assessment of potentially eligible articles. Discrepancies were resolved through discussion or adjudication by a senior author.

Data extraction

To ensure standardized and comprehensive data collection, a pilot-tested Excel extraction form was developed and refined. Two sets of reviewers independently extracted data from each included study. Extracted variables included study characteristics (first author, year of publication, country, journal name, study design, funding source, and sample size) and population data (mean age, gender distribution, baseline WHO functional class, and eligibility criteria). For outcomes, the form captured both primary outcomes, PVR, 6MWD, NT-proBNP levels, and WHO functional class improvement, and secondary outcomes, including all-cause mortality, overall AEs, SAEs, treatment-related AEs, bleeding events (such as epistaxis and telangiectasia), hemoglobin-related events (e.g., erythrocytosis, thrombocytopenia), treatment discontinuation, and RV failure.

Risk of bias and certainty of evidence

The Cochrane Risk of Bias 2 tool¹⁹ was employed to assess the methodological quality of the included RCTs. This process was performed by two sets of two reviewers, with discrepancies resolved by discussion or consultation with a senior author. Five domains were taken into consideration: the risk of bias associated with the randomization process, deviation from the intended intervention, missing outcome data, measuring the outcome, and choosing the reported results.

Statistical analysis

The study employed R version 4.3, utilizing the meta, metafor, and dmetar packages for statistical analysis. The analysis combined results from multiple studies using either risk ratios (RR, for dichotomous outcomes) or mean differences (MD, for continuous outcomes), both with 95% confidence intervals (CI). A random-effects model was applied when significant heterogeneity (I² > 50%) was detected using the chi-square and I-square tests; otherwise, a common-effect model was used. Heterogeneity was interpreted according to the Cochrane Handbook (Chapter 9),¹⁸ with an I² value of 0% to 40% indicating low heterogeneity, 30% to 60% signifying moderate heterogeneity, 50% to 90% representing substantial heterogeneity, and 75% to 100% signifying considerable heterogeneity A chi-square test P value < 0.1 was considered statistically significant for heterogeneity.

RESULTS

The initial database search yielded 238 records: 194 from Scopus, 25 from Embase, 15 from Cochrane CENTRAL, and 4 from PubMed. After removing 25 duplicates via Covidence, 213 unique records were screened. Of these, 208 were excluded based on title and abstract. The full texts of five articles were reviewed, with two excluded for inappropriate study design. Ultimately, three RCTs were included in the final analysis (Figure 1).

Figure 1.

PRISMA flow diagram showing the study selection process and exclusion criteria.

Characteristics of included studies and patients

Three RCTs, encompassing 601 patients, were included in the analysis.^20–22 All were international, double-blind RCTs designed to assess the efficacy of sotatercept compared to placebo in individuals with PAH. Eligible participants were adults diagnosed with WHO functional class II to IV PAH, with exclusions applied for PAH etiologies related to portopulmonary hypertension, schistosomiasis, or HIV infection. Each study implemented a 24-week treatment period.

Across the three included RCTs, baseline patient characteristics were generally well balanced between the sotatercept and placebo arms. The mean age ranged from 47.6 to 55.3 years in the sotatercept group and 45.6 to 53.5 years in the placebo group. Female participants comprised the majority in all trials (70.9% to 89%). The mean body mass index (BMI) ranged from 26.1 to 27.3 kg/m², with obesity (BMI ≥30) observed in approximately 16.3% to 23.8% of participants. Most patients were White, and the predominant WHO functional classes at baseline were II and III, reflecting moderate disease severity. Patients had a median duration of PAH ranging from 6.5 to 8.8 years. All participants were receiving stable background therapy with approved PAH medications, including monotherapy, dual therapy, or triple therapy (e.g., endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclins). Although sample sizes ranged from 106 to 323 participants and primary endpoints varied slightly, including 6MWD, PVR, and composite clinical outcomes, all trials consistently evaluated the clinical efficacy and safety of sotatercept in rigorously defined PAH populations, utilizing standardized diagnostic and functional assessment criteria. The included studies’ summary and detailed patient baseline characteristics are described in Tables 1 and 2, respectively.

Table 1.

Study design, sample size, interventions, and primary outcomes of included randomized controlled trials

Variable	Hoeper et al21	Humbert et al22	Humbert et al20
Year	2023	2021	2025
Design	RCT, phase III	RCT, phase II	RCT, phase III
Country	International	International	International
No. of centers	NA	43	57
Blinding	Double-blind	Double-blind	Double-blind
Sample size	323	106	172
Intervention	Sotatercept	Sotatercept, with a subcomparison between two dosages	Sotatercept
Control	Placebo	Placebo	Placebo
Duration (wk)	24	24	24
Primary outcome	Change from baseline at week 24 in 6-minute walk distance	Change from baseline to week 24 in pulmonary vascular resistance	Composite of death from any cause, lung transplantation, or hospitalization (≥24 hours) for worsening pulmonary arterial hypertension

RCT indicates randomized controlled trial.

Table 2.

Baseline characteristics of patients enrolled in the three included randomized controlled trials

Variable		Group	Hoeper et al21	Humbert et al22	Humbert et al20
Characteristics	Age (y), m (SD)	Sotatercept	47.6 (14.1)	49.5 (14.7)	55.3 (14.3)
		Placebo	48.3 (15.5)	45.6 (13.4)	53.5 (14.3)
	Female, n (%)	Sotatercept	129 (79.1)	66 (89)	61 (70.9)
		Placebo	127 (79.4)	26 (81)	71 (82.6)
	BMI (kg/m2), m (SD)	Sotatercept	26.1 (5.7)	27.0 (5.9)	NA
		Placebo	26.6 (6.1)	27.3 (5.9)	NA
	BMI > 30 kg/m2, n (%)	Sotatercept	36 (22.1)	NA	14 (16.3)
		Placebo	38 (23.8)	NA	19 (22.1)
Race, n (%)	White	Sotatercept	147 (90.2)	68 (92)	73 (84.9)
		Placebo	141 (88.1)	30 (94)	76 (88.4)
	Black	Sotatercept	2 (1.2)	4 (5)	NA
		Placebo	5 (3.1)	0	NA
	Asian	Sotatercept	1 (0.6)	NA	NA
		Placebo	6 (3.8)	NA	NA
	Other	Sotatercept	7 (4.3)	2 (3)	12 (14.0)
		Placebo	6 (3.8)	2 (6)	10 (11.6)
	Missing	Sotatercept	6 (3.7)	NA	1 (1.2)
		Placebo	2 (1.2)	NA	0
Years since diagnosis of pulmonary arterial hypertension, m (SD)		Sotatercept	9.2 (7.3)	7.7 (5.6)	7.2 (5.6)
		Placebo	8.3 (6.7)	7.7 (5.5)	8.2 (6.7)
Classification of pulmonary arterial hypertension, n (%)	Idiopathic	Sotatercept	83 (50.9)	61 (58)	42 (48.8)
		Placebo	106 (66.2)	19 (59)	44 (51.2)
	Heritable	Sotatercept	35 (21.5)	61 (58)	11 (12.8)
		Placebo	24 (15.0)	7 (22)	7 (8.1)
	Associated with connective-tissue disease	Sotatercept	29 (17.8)	18 (17)	22 (25.6)
		Placebo	19 (11.9)	3 (9)	26 (30.2)
	Drug- or toxin-induced	Sotatercept	7 (4.3)	7 (7)	6 (7.0)
		Placebo	4 (2.5)	1 (3)	5 (5.8)
	Associated with corrected congenital shunts	Sotatercept	9 (5.5)	3 (3)	5 (5.8)
		Placebo	7 (4.4)	2 (6)	4 (4.7)
WHO functional class, n (%)	II	Sotatercept	79 (48.5)	39 (53)	NA
		Placebo	78 (48.8)	17 (53)	NA
	III	Sotatercept	84 (51.5)	35 (47)	66 (76.7)
		Placebo	82 (51.2)	15 (47)	62 (72.1)
	IV	Sotatercept	NA	NA	20 (23.3)
		Placebo	NA	NA	24 (27.9)
Background therapy for pulmonary arterial hypertension	Prostacyclin infusion therapy	Sotatercept	65 (39.9)	39 (39)	53 (61.6)
		Placebo	64 (40.0)	10 (31)	49 (57.0)
	Monotherapy	Sotatercept	9 (5.5) 4 (2.5)	7 (9)	NA
		Placebo	4 (2.5)	3 (9)	NA
	Double therapy	Sotatercept	56 (34.4)	25 (34)	21 (24.4)
		Placebo	56 (35.0)	12 (38)	27 (31.4)
	Triple therapy	Sotatercept	98 (60.1)	42 (57)	65 (75.6)
		Placebo	100 (62.5)	17 (53)	59 (68.6)
Hemoglobin (g/dL), m (SD)		Sotatercept	13.9 (1.7)	13.3 (1.6)	12.9 (1.9)
		Placebo	13.7 (1.6)	13.7 (1.8)	12.9 (1.9)
Estimated glomerular filtration rate (mL/min/1.73 m2), m (SD)		Sotatercept	91.2 (34.6)	NA	65.1 (24.6)
		Placebo	88.3 (35.8)	NA	73.5 (29.7)
6-minute walk distance (meter), m (SD)		Sotatercept	397.6 (84.3)	392.5 (89.9)	270.3 (104.8)
		Placebo	404.7 (80.6)	409.1 (63.9)	270.7 (99.9)
NT-proBNP (pg/mL), m (SD)		Sotatercept	1037.5 (2498.6)	924.9 (1465.2)	3603.1 (4101.2)
		Placebo	1207.8 (2694.4)	870.2 (1213.3)	2687.3 (2771.2)
Mean pulmonary artery pressure (mm Hg), m (SD)		Sotatercept	53.0 (14.6)	51.6 (12.5)	57.0 (13.4)
		Placebo	52.2 (13.0)	54.1 (13.4)	55.2 (12.1)
Pulmonary vascular resistance (dyn·sec·cm−5), m (SD)		Sotatercept	781.3 (398.5)	770.4 (361.0)	883.2 (410.9)
		Placebo	745.8 (313.5)	797.4 (322.6)	874.7 (344.2)
Cardiac index (L/min/m2), m (SD)		Sotatercept	2.7 (0.6)	2.6 (0.58)	2.6 (0.6)
		Placebo	2.7 (0.6)	2.5 (0.54)	2.6 (0.8)
Pulmonary artery wedge pressure (mm Hg), m (SD)		Sotatercept	9.7 (3.2)	10.3 (3.1)	10.0 (3.3)
		Placebo	9.8 (3.1)	10.4 (3.0)	9.8 (3.1)
Cardiac output (L/min), m (SD)		Sotatercept	4.9 (1.3)	4.6 (1.1)	NA
		Placebo	4.8 (1.2)	4.6 (0.83)	NA
Right atrial pressure (mm Hg), m (SD)		Sotatercept	8.0 (4.3)	7.5 (3.6)	NA
		Placebo	8.5 (4.5)	9.4 (5.6)	NA

BMI indicates body mass index; m, mean; NA, data not available; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SD, standard deviation; WHO, World Health Organization.

Risk of bias and certainty of evidence

All included studies were assessed as having a low overall risk of bias across all five domains of the Cochrane Risk of Bias 2.0 tool. The quality evaluation can be seen in Figure 2.

Figure 2.

Risk of bias summary for included randomized controlled trials. (a) Domain-level risk of bias summary for all studies using the cochrane RoB 2.0 tool. (b) Risk of bias judgments by domain for each study.

Based on the GRADE assessment (Table 3), the certainty of evidence varied across the evaluated outcomes. The certainty was rated as high for improvement in WHO functional class, indicating strong confidence that the observed effect is close to the true effect. Moderate certainty was observed for both 6MWD and PVR, with downgrading primarily due to high statistical heterogeneity (I² > 75%) among the included trials. The certainty for NT-proBNP levels was rated as low, reflecting serious concerns regarding inconsistency and imprecision, the latter attributed to wide confidence intervals exceeding 1000 pg/mL and substantial between-study variance (τ²). No downgrading was applied for risk of bias, indirectness, or publication bias for any of the assessed outcomes. These findings suggest that while the evidence supporting functional improvement and hemodynamic changes is robust, additional high-quality trials are warranted to strengthen the certainty regarding biomarker-related outcomes.

Table 3.

GRADE evidence profile summarizing the certainty of evidence for primary and secondary outcomes in randomized controlled trials evaluating sotatercept for pulmonary arterial hypertension

Certainty assessment							Summary of findings
Participants (studies) Follow-up	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Overall certainty of evidence	Study event rates (%)		Relative effect (95% CI)	Anticipated absolute effects
							With Placebo	With Sotatercept		Risk with placebo	Risk difference with sotatercept
6-minute walk distance (m)
601 (3 RCTs)	Not serious	Serious a	Not serious	Not serious	None	⨁⨁⨁◯ Moderate	–	–	MD 38.40 (23.69 to 53.11)	–	MD 38 m higher (24 higher to 53 higher)
NT-proBNP (pg mL⁻¹)
559 (3 RCTs)	Not serious	Serious a	Not serious	Serious b	None	⨁⨁◯◯ Low	–	–	MD −852.85 (−1561.59 to −144.10)	–	MD −853 pg mL⁻¹ (144 to lower 1562 lower)
Pulmonary vascular resistance (dyn·s·cm⁻5)
601 (3 RCTs)	Not serious	Serious a	Not serious	Not serious	None	⨁⨁⨁◯ Moderate	–	–	MD −200.25 (−205.37 to −195.13)	–	MD −200 dyn·s·cm⁻5 (195 lower to 205 lower)
WHO functional class
601 (3 RCTs)	Not serious	Not serious	Not serious	Not serious	None	⨁⨁⨁⨁ High	50/277 (18.1 %)	113/323 (35.0 %)	RR 2.04 (1.53 to 2.70)	181 per 1000	187 more per 1,000 (from 95 more to 306 more)

CI indicates confidence interval; MD, mean difference; NT-proBNP, N-terminal pro-B-type natriuretic peptide; RCT, randomized controlled trial; RR, risk ratio; WHO, World Health Organization.

^aHigh statistical heterogeneity (I² > 75%) across the three trials.

^bWide confidence interval spanning >1000 pg mL⁻¹ and very large τ² indicate serious imprecision.

Primary outcomes

Six-minute walk distance

Sotatercept significantly improved 6MWD compared to placebo (MD: 38.40 m, 95% CI: 23.69 to 53.11, P < 0.001, I² = 100%) (Figure 3a). Leave-one-out sensitivity analysis revealed that exclusion of Humbert 2025 resolved heterogeneity (I² = 0%, P = 0.429) (Supplemental Figure S1a).

Figure 3.

Forest plots of primary outcomes: (a) 6-minute walk distance; (b) N-terminal pro-B-type natriuretic peptide; (c) pulmonary vascular resistance; and (d) World Health Organization functional class improvement.

NT-proBNP levels

NT-proBNP levels were significantly reduced with sotatercept compared to placebo (MD: −852.85 pg/mL, 95% CI: −1561.59 to −144.10, P = 0.0184, I² = 100%) (Figure 3b). Sensitivity analysis indicated that no single study disproportionately influenced the overall effect. Hence, heterogeneity could not be resolved (Supplemental Figure S1b).

Pulmonary vascular resistance

Sotatercept significantly reduced PVR (MD: −200.25 dyn·s·cm⁻⁵, 95% CI: −205.37 to −195.13, P < 0.001, I² = 73.6%) (Figure 3c). Heterogeneity was eliminated when either Hoeper 2023 or Humbert 2025 was excluded (Supplemental Figure S1c).

WHO functional class

WHO functional class improved significantly with sotatercept versus placebo (RR: 2.04, 95% CI: 1.53 to 2.70, P < 0.001, I² = 0%) (Figure 3d).

Secondary outcomes

Adverse events

Any AEs occurred at similar rates between sotatercept and placebo (RR: 1.01, 95% CI: 0.97–1.05, P = 0.652, I² = 0%) (Figure 4a). Related AEs were significantly more frequent with sotatercept (RR: 1.78, 95% CI: 1.41–2.25, P < 0.001, I² = 0%) (Figure 4b), indicating a higher likelihood of treatment-related AEs. Discontinuation due to AEs showed a nonsignificant trend that decreased with sotatercept (RR: 0.42, 95% CI: 0.15–1.15, P = 0.09, I² = 41.6%) (Figure 4c). Withdrawals from the study occurred at similar rates between the sotatercept and placebo groups (RR: 0.69, 95% CI: 0.24–2.03, P = 0.50, I² = 0%) (Figure 4d). However, death from any cause was significantly less frequent in the sotatercept group compared to placebo (RR: 0.39, 95% CI: 0.16–0.95, P = 0.04, I² = 0%) (Figure 4e).

Figure 4.

Forest plots of safety outcomes: (a) overall adverse events (AEs); (b) related AEs; (c) discontinuations; (d) withdrawals; (e) mortality; (f) serious AEs; (g) discontinuation due to serious AEs; (h) related serious AEs; and (i) bleeding events.

Serious adverse events

SAEs occurred less frequently with sotatercept, though the difference did not reach statistical significance (RR: 0.81, 95% CI: 0.65–1.00, P = 0.054, I² = 26.5%) (Figure 4f). Discontinuation due to SEAs was significantly lower with sotatercept compared to placebo (RR: 0.16, 95% CI: 0.03–0.93, P = 0.0417, I² = 0%) (Figure 4g). Rates of drug-related SAEs were similar between groups (RR: 1.24, 95% CI: 0.34–4.58, P = 0.75, I² = 0%) (Figure 4h).

Bleeding events

Bleeding events were significantly more frequent in the sotatercept group compared to placebo (RR: 1.77, 95% CI: 1.35–2.34, P < 0.001, I² = 0%) (Figure 5a). Epistaxis, a specific bleeding event, was also markedly higher with sotatercept (RR: 4.92, 95% CI: 2.71–8.90, P < 0.001, I² = 0%) (Figure 5b). Similarly, telangiectasia events were significantly more common with sotatercept (RR: 4.61, 95% CI: 2.18–9.73, P < 0.001, I² = 2.9%) (Figure 5c).

Figure 5.

Forest plots of bleeding and hematologic adverse events: (a) any bleeding events; (b) epistaxis; (c) telangiectasia; (d) hemoglobin-related events; (e) neutropenia; and (f) thrombocytopenia.

Increases in hemoglobin-related events

Increases in hemoglobin-related events were significantly more frequent with sotatercept compared to placebo (RR: 11.37, 95% CI: 2.74–47.17, P < 0.001, I² = 0%) (Figure 5d), indicating a notable class effect of erythropoiesis. In contrast, neutropenia occurred at similar rates between groups without statistical significance (RR: 0.66, 95% CI: 0.07–6.24, P = 0.72, I² = 0%) (Figure 5e). However, thrombocytopenia was significantly more frequent with sotatercept (RR: 2.01, 95% CI: 1.01–3.98, P = 0.046, I² = 0%) (Figure 5f).

Cardiac failure and peripheral edema

Cardiac failure and peripheral edema occurred at similar rates in the sotatercept and placebo groups. Cardiac failure was not significantly different (RR: 0.57, 95% CI: 0.23–1.44, P = 0.23, I² = 0%) (Figure 6a), and peripheral edema also did not differ significantly (RR: 0.70, 95% CI: 0.40–1.24, P = 0.22, I² = 0%) (Figure 6b). Hypokalemia showed no significant change with sotatercept (RR: 1.03, 95% CI: 0.58–1.82, P = 0.92, I² = 0%) (Figure 6c). In contrast, RV failure was significantly less frequent with sotatercept (RR: 0.26, 95% CI: 0.09–0.75, P = 0.01, I² = 0%) (Figure 6d).

Figure 6.

Forest plots of cardiometabolic adverse events: (a) cardiac failure; (b) peripheral edema; (c) hypokalemia; and (d) right ventricular failure.

Gastrointestinal and neurologic symptoms

The incidence of gastrointestinal and neurologic symptoms was generally comparable between sotatercept and placebo. Diarrhea occurred more frequently in the sotatercept group but did not reach statistical significance (RR: 1.42, 95% CI: 0.93–2.15, P = 0.10, I² = 0%) (Figure 7a). Fatigue (RR: 0.92, 95% CI: 0.59–1.45, P = 0.72, I² = 39.9%) (Figure 7b), headache (RR: 1.19, 95% CI: 0.85–1.66, P = 0.32, I² = 0%) (Figure 7c), and nausea (RR: 1.00, 95% CI: 0.65–1.54, P = 0.99, I² = 0%) (Figure 7d) were also similar between groups. Dizziness tended to occur more frequently with sotatercept compared to placebo, but the difference did not reach statistical significance (RR: 1.79, 95% CI: 0.96–3.34, P = 0.07, I² = 57.1%) (Figure 7e). Leave-one-out sensitivity analysis revealed that heterogeneity was primarily driven by Hoeper 2023, as its exclusion reduced I² to 0% (P = 0.86) (Supplemental Figure S1d).

Figure 7.

Forest plots of gastrointestinal, neurologic, and infectious adverse events: (a) diarrhea; (b) fatigue; (c) headache; (d) nausea; (e) dizziness; and (f) COVID-19 infection.

COVID-19 infection incidence

The incidence of COVID-19 infection was comparable between the sotatercept and placebo groups (RR: 1.07, 95% CI: 0.70–1.64, P = 0.75, I² = 0%) (Figure 7f).

DISCUSSION

PAH is a devastating disease characterized by progressive pulmonary vascular remodeling, increased PVR, and eventual RV failure.⁸ Despite the development of several therapeutic classes targeting vasodilation, long-term outcomes in PAH remain suboptimal.^23,24 Traditional therapies alleviate symptoms and improve hemodynamics but have limited impact on the underlying proliferative vasculopathy and RV dysfunction that drive disease progression.^25,26 Against this, sotatercept, a novel activin signaling inhibitor, represents a new frontier in PAH treatment by directly targeting key pathogenic mechanisms.^21,27

Summary of key findings

This systematic review and meta-analysis of three RCTs involving 601 patients demonstrated that sotatercept improves several clinical outcomes in patients with PAH. Sotatercept was associated with improvements in 6MWD, reductions in NT-proBNP levels and PVR, and better WHO functional class compared to placebo. In addition, sotatercept reduced all-cause mortality, RV failure, and treatment discontinuations due to AEs and SAEs.

The mean improvement of 38.4 m in 6MWD exceeds the recognized threshold for clinical importance for patients with PAH, reinforcing the clinical relevance of the observed treatment effect and suggesting a meaningful impact on patients’ functional status​​.²⁸ PVR reductions of approximately 200 dyn·s·cm⁻⁵ reflect substantial alleviation of pulmonary vascular load, a critical determinant of RV afterload and function.²⁹​ This degree of reduction is indicative of an effective vasodilatory and antiproliferative response to therapy, often correlating with improved RV-pulmonary arterial coupling, enhanced cardiac output, and better functional capacity.³⁰ NT-proBNP, a validated biomarker of RV dysfunction, is a key component of risk stratification tools in PAH and has been consistently associated with worse clinical outcomes.³¹ In our study, NT-proBNP levels declined significantly with treatment, suggesting a favorable myocardial response. Importantly, our analysis identified not only improvements in surrogate endpoints but also a meaningful reduction in clinical events, including mortality and RV failure. This marks a significant advance, as previous vasodilatory therapies have only modestly impacted survival, despite symptomatic benefits​.²⁵

The marked reduction in RV failure associated with sotatercept is of particular clinical importance. RV adaptation to increased afterload is the key determinant of prognosis in PAH.³² Chronic pressure overload, driven by increased pulmonary vascular resistance, leads to progressive RV hypertrophy and fibrosis, which eventually culminates in RV dilation, impaired contractility, and failure.³³ Conventional therapies have a limited impact on the structural progression of RV remodeling.³⁴ In contrast, sotatercept’s ability to lower RV afterload, combined with potential direct myocardial benefits​​, suggests a dual-action mechanism supporting RV function.³⁴ This capacity to preserve or restore right heart performance may explain the observed survival benefit and distinguish sotatercept from prior therapeutic strategies.

Sotatercept’s benefits are grounded in its unique action within the TGF-β superfamily signaling network.³⁵​ In PAH, dysregulation of TGF-β/activin pathways contributes to endothelial dysfunction, smooth muscle proliferation, and vascular fibrosis.^36,37​ Sotatercept functions as a ligand trap, binding to activins and growth differentiation factors, thereby rebalancing anti-proliferative and proliferative signals​​.³⁸ Preclinical studies have shown that activin inhibition not only halts vascular remodeling but also improves RV-pulmonary arterial coupling, reduces inflammatory signaling, and attenuates pulmonary arterial stiffness.^15,39

Safety remains a critical consideration when evaluating sotatercept’s role in PAH treatment. Overall, AE rates were comparable between sotatercept and placebo, though certain class-related AEs were observed. The erythropoietic activity of sotatercept leads to increases in hemoglobin levels.⁴⁰ These increases, however, also raise the risk of hemoglobin-related AEs, including potential complications from hyperviscosity and thrombosis. This highlights the importance of regular hematologic monitoring in patients receiving sotatercept, particularly to assess thrombotic risks.

Increased bleeding events, including epistaxis and telangiectasia, have been observed more frequently with sotatercept, highlighting the need for caution in individuals predisposed to bleeding. In such cases, particularly among those with a history of severe hemorrhage, thrombocytopenia, or who are on anticoagulation, a multidisciplinary assessment is recommended to carefully evaluate the risk-benefit profile before initiating treatment.⁴¹

The incidence of other major AEs, including cardiac failure, peripheral edema, and hypokalemia, did not differ significantly between sotatercept and placebo groups, further reinforcing its safety. Moreover, the incidence of gastrointestinal and neurologic symptoms was comparable between treatment groups, with no meaningful differences in fatigue, headache, or nausea.

Despite these AEs, serious complications and treatment discontinuations remained relatively low. These findings support the overall safety profile of sotatercept in the treatment of PAH, provided that regular monitoring for class-related adverse effects is implemented.

Study limitations

The number of eligible trials remains limited, and the aggregate sample size, though sufficient for primary endpoints, may constrain the statistical power to detect infrequent or delayed AEs. Moreover, heterogeneity in baseline patient characteristics and background therapies introduces potential variability that could affect the generalizability of the findings. The reliance on trial-level data, rather than individual patient-level data, further limits the ability to conduct nuanced subgroup analyses or adjust for potential confounders. Another notable limitation is the relatively short duration of follow-up in most included trials, which restricts the ability to draw conclusions regarding the long-term durability of sotatercept’s clinical benefits and safety profile.

Future directions

Despite the promising therapeutic profile of sotatercept in PAH, several critical gaps remain that warrant further investigation to optimize its clinical utility and establish its role in long-term disease management. First, longitudinal data are necessary to assess the sustainability of sotatercept’s clinical benefits. While short-term improvements in exercise capacity, pulmonary hemodynamics, and RV function are encouraging, the long-term impact on survival, hospitalization rates, and disease progression remains to be fully evaluated. Ongoing extension studies and future trials with extended follow-up will be essential in evaluating treatment durability and long-term safety.

Second, comparative efficacy studies are needed to determine sotatercept’s position relative to existing therapies. Direct head-to-head trials against established agents or its incorporation into multidrug regimens could clarify whether sotatercept offers additive or synergistic benefits when used in combination with endothelin receptor antagonists, phosphodiesterase-5 inhibitors, or prostacyclin analogs. Such data will inform evidence-based treatment sequencing and combination strategies.

Third, precision medicine approaches should be pursued to identify biomarkers predictive of response to sotatercept. Stratifying patients based on molecular, genetic, or hemodynamic profiles may enhance therapeutic targeting and improve clinical outcomes while minimizing unnecessary exposure in nonresponders. This is particularly relevant given the heterogeneity of PAH pathogenesis and the variable progression among patient subgroups.

Finally, pharmacovigilance and real-world effectiveness studies will be essential as sotatercept transitions into broader clinical use. Postmarketing surveillance should focus on the incidence and management of hematologic abnormalities, bleeding events, and other class-specific adverse effects. These insights will be critical to refining monitoring protocols and ensuring safe long-term administration.

CONCLUSION

This systematic review and meta-analysis provides robust evidence supporting the clinical efficacy of sotatercept as an adjunctive therapy in patients with PAH. Sotatercept significantly improves exercise capacity, hemodynamic parameters, and functional status while reducing NT-proBNP levels, mortality, RV failure, and discontinuation due to AEs. These benefits suggest that sotatercept may offer a disease-modifying effect, setting it apart from traditional vasodilator therapies.

The safety profile was comparable to placebo overall; however, a higher incidence of class-related AEs, such as bleeding and hematologic abnormalities, warrants close clinical monitoring. These increases may raise concern for complications such as blood hyperviscosity or thrombosis, emphasizing the importance of individualized risk assessment and hematologic surveillance during treatment. Given the limitations in long-term and real-world data, further studies are essential to evaluate the durability of benefit, optimal treatment combinations, and strategies for patient selection and monitoring.

Disclosure statement/Funding

The authors report no funding or conflict of interest.