Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death (ZENITH)

Authors, Journal, Affiliations, Type, DOI

• Humbert M, McLaughlin VV, Badesch DB, Ghofrani HA, Gibbs JSR, et al. for the ZENITH Trial Investigators
• N Engl J Med 2025;392:1987-2000
• Multicenter international trial; sponsor: Merck Sharp and Dohme (subsidiary of Merck, Rahway, NJ)
• Phase 3 multicenter double-blind randomized placebo-controlled trial; stopped early for efficacy
• DOI: 10.1056/NEJMoa2415160; NCT04896008

Overview

ZENITH was a phase 3 DBRCT evaluating add-on sotatercept (starting 0.3 mg/kg SC Q21d, escalated to 0.7 mg/kg) vs. placebo in 172 adults with WHO group 1 PAH (FC III/IV, REVEAL Lite 2 risk score ≥9) already receiving maximum tolerated double or triple background therapy. The trial was stopped early at interim analysis after overwhelming efficacy: the primary composite of all-cause death, lung transplantation, or hospitalization ≥24h for worsening PAH occurred in 17.4% vs. 54.7% (HR 0.24, 95% CI 0.13–0.43, P<0.001). The most striking individual component was PAH hospitalization (9.3% vs 50.0%). All-cause mortality was lower (8.1% vs 15.1%, HR 0.42) but did not reach the pre-specified alpha boundary due to early stopping. Adverse effects included epistaxis, telangiectasia, elevated hemoglobin, and thrombocytopenia; serious adverse events were paradoxically lower in the sotatercept group despite longer follow-up.

Keywords

Pulmonary arterial hypertension, sotatercept, activin signaling, ACTRIIA-Fc, TGF-β superfamily, REVEAL Lite 2, pulmonary vascular remodeling, right ventricular failure, high-risk PAH

Key Takeaways

Background

• PAH is a progressive, potentially fatal disease characterized by pulmonary vascular remodeling, rising PVR, and eventual right ventricular failure and death
• Established therapies (ERAs, PDE5i, sGC stimulators, prostacyclin-pathway agents) delay time to clinical worsening but primarily affect functional deterioration rather than hard outcomes (death, lung transplantation, hospitalization)
• Prior PAH RCTs (selexipag, macitentan, ambrisentan+tadalafil) showed delays in clinical worsening but their composite endpoints included less severe events
• Sotatercept, a first-in-class activin signaling inhibitor, addresses pulmonary vascular remodeling directly rather than via vasodilation — a mechanistically distinct approach
• The STELLAR trial (FC II/III) showed sotatercept improved 6MWD, PVR, and NT-proBNP and reduced clinical worsening by 84% in less advanced PAH
• ZENITH addresses the unmet need in high-risk advanced PAH: WHO FC III/IV patients with REVEAL Lite 2 ≥9 on maximum background therapy

Methods

• Design: Phase 3 multicenter DBRCT; sponsor-initiated with academic steering committee; independent data monitoring committee (stopped trial early for efficacy); December 2021 – July 2024 (cutoff)
• Eligibility: Adults 18–75 years; WHO group 1 PAH (IPAH, HPAH, drug/toxin-induced, CTD-associated, or repaired CHD ≥1 year); WHO FC III or IV; REVEAL Lite 2 score ≥9; PVR ≥400 dyn·s·cm⁻⁵ (≥5 WU) on screening RHC; PAWP/LVEDP ≤15 mmHg; stable maximum tolerated double or triple PAH therapy ≥30 days before screening
• Key exclusion criteria: PAH associated with portal hypertension, HIV, PVOD, or PCH; PAH other than Group 1; LVEF <45%; significant mitral/aortic valve disease; hemoglobin above sex-specific ULN; platelets <50,000/mm³
• REVEAL Lite 2 risk score: 6-variable noninvasive tool assessing 1-year mortality risk; variables include WHO functional class, systolic BP, heart rate, 6MWD, NT-proBNP, and renal function; scores 1–14 (higher = greater risk); score ≥9 = high risk
• Intervention: Sotatercept SC Q21 days; starting dose 0.3 mg/kg, escalated to target 0.7 mg/kg; dose adjustments for hemoglobin levels, platelet counts, telangiectasia, and serious bleeding
• Control: Placebo SC Q21 days; all patients continued maximum tolerated background PAH therapy
• Randomization: 1:1; stratified by REVEAL Lite 2 score (9–10 vs ≥11) and PAH subtype (CTD-associated vs not)
• Primary endpoint: Composite of all-cause death, lung transplantation, or hospitalization ≥24h for worsening PAH (time-to-first-event); adjudicated by independent committee
• Secondary endpoints (hierarchical): Overall survival; transplantation-free survival; REVEAL Lite 2 change at week 24; proportion achieving REVEAL Lite 2 ≤7 at week 24; NT-proBNP change; mPAP change; PVR change; WHO functional class improvement; 6MWD change; cardiac output change; EQ-5D-5L change
• Interim analysis: Planned after ~59 events; Lan-Demets O'Brien-Fleming spending function; one-sided P-value boundary 0.0021; hierarchical testing strategy (secondary endpoints eligible only if primary significant)
• Analysis population: Intention-to-treat (all randomized patients); safety population (received ≥1 dose)
• n=172 (86 sotatercept, 86 placebo); median follow-up 10.6 months (sotatercept) vs 7.1 months (placebo)

Results

Population

• Baseline: WHO FC III 82%, FC IV 13%; REVEAL Lite 2 score 9–10: 49%; ≥11: 51%; background triple therapy: most patients; CTD-associated PAH: ~30%

Primary Efficacy

• Primary composite (death/transplant/PAH hospitalization ≥24h): 17.4% vs 54.7% (HR 0.24, 95% CI 0.13–0.43, P<0.001); 76% risk reduction
• Trial stopped early at interim analysis — 62 first events accrued
• Consistent benefit across all prespecified subgroups

Individual Components of Primary Composite

• All-cause death: 8.1% vs 15.1% (HR 0.42, 95% CI 0.17–1.07; did not reach P<0.0021 alpha threshold — first secondary endpoint, testing stopped)
• Lung transplantation: 1.2% vs 7.0%
• Hospitalization ≥24h for worsening PAH: 9.3% vs 50.0% (dominant driver of composite)
• Transplantation-free survival: HR 0.34 (95% CI 0.15–0.78) — provided but not formally tested

Secondary Endpoints (not statistically tested after overall survival failed alpha threshold)

• REVEAL Lite 2 score decreased (improved) with sotatercept at week 24
• Proportion achieving low/intermediate REVEAL Lite 2 ≤7 at week 24: greater with sotatercept
• NT-proBNP: decreased with sotatercept
• mPAP: decreased with sotatercept
• PVR: decreased with sotatercept
• WHO functional class: improved with sotatercept
• 6MWD: improved with sotatercept
• EQ-5D-5L: improved with sotatercept
• Cardiac output: did not change substantially (consistent with prior sotatercept trials)

Safety

• Adverse events reported in 98.8% (sotatercept) vs 96.5% (placebo)
• Higher with sotatercept (≥5pp difference): Epistaxis (44.2% vs 9.3%), telangiectasia (25.6% vs 3.5%), gingival bleeding (10.5% vs 2.3%), vomiting (12.8% vs 5.8%), back pain (10.5% vs 4.7%)
• Adverse events of interest higher with sotatercept: Telangiectasia (25.6% vs 3.5%); increased hemoglobin (12.8% vs 1.2%); thrombocytopenia (14.0% vs 8.1%)
• Bleeding: 62.8% vs 34.9% — driven by epistaxis/gingival bleeding; serious bleeding similar (5.8% vs 4.7%)
• Serious adverse events: 53.5% vs 64.0% — lower in sotatercept group despite longer follow-up
• Severe adverse events: 37.2% vs 50.0%
• AEs leading to death: 5.8% vs 14.0%
• Drug discontinuation due to AEs: 0% (sotatercept) vs 4.7% (placebo)
• No patients in sotatercept group discontinued for serious AEs
• Off-target effects: erythropoiesis (↑Hb), hemostasis (bleeding), microvascular structure (telangiectasia)

Discussion

• The ZENITH trial used a primary composite of only major outcomes (death, transplant, major hospitalization), distinguishing it from prior PAH trials that used softer endpoints (exercise capacity deterioration, WHO-FC worsening, rescue therapy initiation)
• The 76% risk reduction in major outcomes in patients on maximum background therapy reflects sotatercept's unique mechanism — targeting pulmonary vascular remodeling via activin/BMP pathway rebalancing rather than vasodilation alone
• The magnitude of benefit (HR 0.24) and early stopping are highly unusual for a PAH randomized trial
• Despite longer follow-up in the sotatercept group, serious adverse events and deaths were lower — strengthening the safety interpretation
• Cardiac output did not substantially change despite improvements in PVR and mPAP — a consistent finding across sotatercept trials possibly reflecting complex vascular remodeling vs. pure vasodilation effects
• The early stopping reduced power for secondary endpoints; overall survival HR 0.42 is clinically important but technically unproven

Limitations of the Document

• Small sample size (n=172): partly offset by large treatment effect and number of events, but limits precision of subgroup analyses
• Trial stopped early for efficacy: curtailed follow-up (median 8.9 months), reduced power to test secondary endpoints including overall survival
• PAH hospitalization was the dominant composite component (50% of placebo patients); if hospitalization thresholds or practice vary between centres, this could affect generalizability
• Enriched for high-risk PAH (REVEAL Lite 2 ≥9): findings may not apply to lower-risk or earlier-disease patients
• Asymmetric follow-up: earlier discontinuations in placebo group → more missing data in placebo arm
• Some continuous endpoint changes sensitive to missing data handling due to deaths and hospitalizations
• Sponsor-funded and sponsor-conducted analyses; academic authors had full data access and vouched for fidelity

Key Concepts Mentioned

• concepts/PAH-Risk-Stratification — REVEAL Lite 2 ≥9 used as high-risk threshold for enrollment; sotatercept as escalation therapy for high-risk patients
• concepts/RV-PA-Coupling — RV function improvement with sotatercept; cardiac output unchanged despite PVR/mPAP reduction

Key Entities Mentioned

• entities/Pulmonary-Hypertension — WHO group 1 PAH treatment; sotatercept expands beyond vasodilator-based approach
• entities/Sotatercept — clinical trial program development; PULSAR → SPECTRA → STELLAR → ZENITH

Wiki Pages Updated

• wiki/sources/sotatercept-zenith-nejm-2025.md — created
• wiki/entities/Sotatercept.md — created
• wiki/entities/Pulmonary-Hypertension.md — sotatercept/ZENITH section expanded; new contradiction; source_count 7→8
• wiki/concepts/PAH-Risk-Stratification.md — ZENITH/REVEAL Lite 2 ≥9 high-risk threshold; treatment escalation implication; new contradiction; source_count 1→2
• wiki/wikiindex.md — Sotatercept entity added
• wiki/sourceindex.md — sotatercept-zenith-nejm-2025 added
• log.md — updated