Sotatercept for Pulmonary Arterial Hypertension within the First Year after Diagnosis (HYPERION)

Authors, Journal, Affiliations, Type, DOI

• McLaughlin VV, Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JSR, et al. for the HYPERION Trial Investigators
• N Engl J Med 2025;393:1599-611
• 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 loss of clinical equipoise
• DOI: 10.1056/NEJMoa2508170; NCT04811092

Overview

HYPERION enrolled 320 adults (FC II/III) with PAH diagnosed less than 1 year earlier, at intermediate or high risk (REVEAL Lite 2 ≥6 or COMPERA 2.0 ≥2), on stable double or triple background therapy ≥90 days, to receive add-on sotatercept (0.3→0.7 mg/kg SC Q21d) or placebo. The trial was stopped early before its planned interim analysis because ZENITH results led to declared loss of clinical equipoise. The primary composite (clinical worsening: death/PAH hospitalization/atrial septostomy/lung transplant/exercise testing deterioration) occurred in 10.6% vs 36.9% (HR 0.24, 95% CI 0.14–0.41, P<0.001; NNT=5 at 12 months). Exercise testing deterioration was the dominant composite driver (5% vs 29%); deaths were balanced (4.4% vs 3.8%). Safety was consistent with prior sotatercept trials; serious bleeding was slightly higher (3.8% vs 1.9%).

Keywords

Pulmonary arterial hypertension, sotatercept, early initiation, clinical worsening, REVEAL Lite 2, COMPERA 2.0, exercise testing, functional class, first year after diagnosis

Key Takeaways

Background

• STELLAR (FC II/III, mean 8 years since diagnosis) and ZENITH (FC III/IV, high-risk, mean 8 years) demonstrated sotatercept efficacy in long-standing PAH on stable background therapy
• Unanswered question: Can early add-on sotatercept within the first year after diagnosis prevent disease progression in intermediate/high-risk patients?
• Nonfatal clinical worsening events (exercise deterioration, hospitalization) in PAH are associated with markedly increased subsequent mortality — preventing these events has prognostic significance beyond symptom relief
• HYPERION population: older and with more comorbidities than STELLAR/ZENITH, aligning more closely with contemporary PAH registries

Methods

• Design: Phase 3 multicenter DBRCT; sponsor/steering committee stopped trial before planned interim analysis (loss of equipoise after ZENITH results); final database lock April 2025; April 2022 – January 2025
• Eligibility: Adults ≥18 years; WHO group 1 PAH (IPAH, HPAH, drug/toxin-induced, CTD-associated, or repaired CHD ≥1 year); WHO FC II or III; diagnosis <1 year before enrollment (defined as date of diagnostic RHC); intermediate or high risk defined as REVEAL Lite 2 ≥6 OR COMPERA 2.0 ≥2; PVR ≥320 dyn·s·cm⁻⁵ (≥4 WU); PAWP/LVEDP ≤15 mmHg; stable double or triple PAH therapy ≥90 days
• Key exclusion criteria: PAH associated with portal hypertension, HIV, PVOD, PCH; PH other than Group 1; LVEF <50%; significant valve disease
• COMPERA 2.0 risk score: Based on WHO-FC, 6MWD, NT-proBNP; scores 1–4 (low/intermediate-low/intermediate-high/high 1-year transplantation-free death risk); score ≥2 = intermediate-low or higher
• REVEAL Lite 2 threshold: ≥6 = intermediate or higher (cf. ZENITH used ≥9 = high risk only)
• Intervention: Sotatercept SC Q21d; starting 0.3 mg/kg → target 0.7 mg/kg
• Randomization: 1:1; stratified by WHO-FC (II vs III) and background therapy (double vs triple)
• Primary endpoint (clinical worsening composite): Death from any cause, unplanned hospitalization ≥24h for worsening PAH, atrial septostomy, lung transplantation, or deterioration in exercise testing (any 6MWD decrease on two consecutive tests ≥4h apart + ≥1 of: WHO-FC worsening, RV failure signs, new background therapy, or change to parenteral delivery); time-to-first-event; independent adjudication
• Secondary endpoints (hierarchical): Multicomponent improvement at week 24 (6MWD ↑≥30m + NT-proBNP ↓≥30% or <300 pg/mL + WHO-FC I/II); low REVEAL Lite 2 ≤5 at week 24; low simplified French risk score at week 24; NT-proBNP change; WHO-FC improvement/maintenance at week 24; 6MWD change; overall survival; PAH-SYMPACT domain scores
• Stopping rationale: Sponsor + steering committee (not DMC) declared loss of equipoise after ZENITH interim analysis; blinding maintained until database lock; no interim efficacy analysis of HYPERION performed
• n=320 (160 per group); median follow-up 13.2 months (sotatercept 14.6, placebo 11.5)

Results

Population

• Majority WHO FC II (67%); COMPERA 2.0 intermediate-low (64%); REVEAL Lite 2 intermediate (51%); most on double background therapy; only 17% on IV prostacyclin
• More comorbidities and older vs STELLAR/ZENITH; more representative of real-world contemporary PAH registries

Primary Efficacy

• Clinical worsening (primary composite): 10.6% vs 36.9% (HR 0.24, 95% CI 0.14–0.41, P<0.001); NNT=5 at 12 months; 22 percentage-point absolute risk reduction
• Kaplan–Meier curve separation evident after three doses of sotatercept — early and sustained separation, similar to ZENITH
• Consistent benefit across all prespecified subgroups (including CTD-associated, double therapy, intermediate REVEAL Lite 2 or intermediate-low COMPERA 2.0)

Primary Composite Components (standalone, not formally compared)

• Deterioration in exercise testing: 5.0% vs 28.8% ← dominant driver (~29% of 36.9% placebo events)
• PAH hospitalization ≥24h: 1.9% vs 8.8%
• Death from any cause: 4.4% vs 3.8% ← balanced; no mortality benefit
• Atrial septostomy: 0% vs 0%
• Lung transplantation: 0% vs 0%

Secondary Endpoints

• Multicomponent improvement at week 24: Significant (P=0.003) — more patients in sotatercept group achieved 6MWD ↑≥30m + NT-proBNP ↓≥30%/<300 + WHO-FC I/II
• Low REVEAL Lite 2 ≤5 at week 24: Significant (P=0.04)
• Low simplified French risk score at week 24: NOT significant → hierarchy stopped; subsequent endpoints not formally tested
• Suggestive (not formally tested): improvements in WHO-FC, 6MWD, NT-proBNP consistent with STELLAR
• 6MWD improvement smaller than STELLAR — attributed to older age, more comorbidities, and ongoing improvement from recently started background therapy

Safety

• Adverse events: 89.4% vs 90.0% (similar)
• Higher with sotatercept (≥5pp): Epistaxis (31.9% vs 6.9%); telangiectasia (26.2% vs 11.2%)
• Elevated hemoglobin: 11.2% vs 1.2%; mean increase at week 24: +1.2 g/dL vs 0.0 g/dL
• Bleeding events: 41.2% vs 16.2%; serious bleeding: 3.8% vs 1.9% (higher with sotatercept — differs from ZENITH where serious bleeding was balanced)
• Serious AEs: 24.4% vs 28.1% (similar)
• Severe AEs: 20.0% vs 19.4% (similar)
• Drug discontinuation due to AEs: 3.1% vs 0%
• AEs leading to death: 2.5% vs 3.1% (similar)

Discussion

• HYPERION establishes that sotatercept benefit extends to early-disease PAH (diagnosed <1 year), in a more diverse and older population than prior trials
• The HR 0.24 is numerically identical to ZENITH but represents qualitatively different event prevention: exercise deterioration and functional progression rather than death/transplantation
• Early curve separation (after 3 doses) across all sotatercept trials suggests a rapid biological effect on pulmonary vascular remodeling
• Failure of the simplified French risk score endpoint (despite significant multicomponent improvement and REVEAL Lite 2 ≤5) may reflect the inability of older/comorbid patients to reach the 6MWD >440m threshold, irrespective of drug efficacy
• The question of sotatercept as first-line therapy (without background therapy established first) remains unanswered
• SOTERIA open-label extension will provide longer-term safety and efficacy data

Limitations of the Document

• Early termination: reduced follow-up (median 13.2 months), limited longer-term efficacy and safety assessment; deaths and transplantation events are few
• 33 patients did not reach week 24 — excluded from secondary endpoint analyses
• PAH-SYMPACT quality-of-life measure: <50% patient participation → no valid QoL conclusions
• Secondary endpoints assessed at 24 weeks only — no longer-term functional data
• Elevated hemoglobin in sotatercept arm may unintentionally unmask blinding for subjective assessments (possible bias in exercise testing, WHO-FC rating, symptom reporting)
• "Diagnosis <1 year" does not guarantee lower disease severity — HYPERION patients were older with more comorbidities and may have had significant disease burden at enrollment
• Sotatercept as first-line monotherapy (without prior background therapy) not studied

Key Concepts Mentioned

• concepts/PAH-Risk-Stratification — REVEAL Lite 2 ≥6 and COMPERA 2.0 ≥2 used as intermediate/high-risk thresholds; sotatercept benefit extends to intermediate-low COMPERA risk tier
• concepts/RV-PA-Coupling — RV functional improvement and exercise capacity as endpoints

Key Entities Mentioned

• entities/Sotatercept — HYPERION as the fourth major trial in the clinical development program; early-disease evidence
• entities/Pulmonary-Hypertension — early treatment paradigm shift for group 1 PAH

Wiki Pages Updated

• wiki/sources/sotatercept-hyperion-nejm-2025.md — created
• wiki/entities/Sotatercept.md — HYPERION added to trial program; new contradictions; source_count 2→3
• wiki/entities/Pulmonary-Hypertension.md — sotatercept section updated with HYPERION; new contradiction; source_count 8→9 [done in prior ZENITH ingest; now →9]
• wiki/concepts/PAH-Risk-Stratification.md — HYPERION intermediate-risk threshold added; source_count 2→3 [done in prior ZENITH ingest; now →3]
• wiki/wikiindex.md — no new entity (Sotatercept entity already exists; updated)
• wiki/sourceindex.md — sotatercept-hyperion-nejm-2025 added
• log.md — updated