Sotatercept for Combined Post- and Pre-capillary Pulmonary Hypertension Associated With Heart Failure: Results from the Phase 2, Randomized, Placebo-Controlled CADENCE Study
Sotatercept reduces pulmonary vascular resistance by ~1 Wood unit vs placebo in CpcPH-HFpEF.
Hodges-Lehmann shift -1.02 Wood units
95% CI -1.81 to -0.23
P=0.004
n=164
Key points
Context & question:To evaluate the efficacy and safety of sotatercept in reducing pulmonary vascular resistance in adults with combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction.
Methods & population:Multicenter, randomized, placebo-controlled, phase 2 trial (CADENCE); 164 patients were randomized 54:55:55 to receive sotatercept 0.3 mg/kg, sotatercept 0.7 mg/kg, or placebo subcutaneously every 3 weeks; The primary endpoint was the change from baseline in pulmonary vascular resistance at week 24, assessed via Hodges–Lehmann shift estimates.
Finding & limits:Median change in pulmonary vascular resistance at week 24 was –0.67 Wood units with sotatercept /kg, –0.33 Wood units with /kg, and 0.26 Wood units with placebo, resulting in Hodges–Lehmann shifts of –1.02 Wood units and –0.75 Wood units, respectively. Whether the gains in blood flow measures and heart function lead to clinically meaningful outcomes still needs a phase 3 study, which Gomberg-Maitland calls for. Sarma notes that the fall in resting PVR was relatively modest.
“This is really exciting because we see improvements in heart failure clinical markers as well as biomarkers of heart function in both the right side and the left side. The left atrial volume and left atrial pressure (measured as wedge pressure) improved, features that can put you at risk for a variety of bad outcomes with HFpEF. Seeing these improvements in addition to improvements in the pulmonary vasculature makes this a big deal.”
Mardi Gomberg-MaitlandPresenting authorGeorge Washington University School of Medicine and Health Sciences
“Patients and the scientific community have been waiting a long time for a treatment that shows benefit in CpcPH associated with HFpEF, as previous trials have failed and there are no approved therapies. We have seen recent improvements in HFpEF therapies but none that are specific to the distinct clinical condition of CpcPH-HFpEF. These patients continue to have severe heart failure symptoms.”
“The totality of evidence and consistency in trends across multiple endpoints from the CADENCE study support advancement of WINREVAIR into a registrational Phase 3 program in CpcPH-HFpEF. While both doses suggest efficacy, CADENCE results support that the 0.3 mg/kg dose may optimize the benefit-risk profile of WINREVAIR in the distinct population of CpcPH-HFpEF. We are working with regulatory agencies to design a Phase 3 registrational study with endpoints that focus on clinical outcomes most relevant to the needs of this population, with the ultimate goal of providing the first treatment option for CpcPH-HFpEF.”
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Full evidence
Why the trial, tables, limitations, PICO, abstract, media & sources
Why the trial?
The CADENCE trial was conducted to address the lack of proven therapies for combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH–HFpEF), a condition involving remodeling of both the heart and pulmonary vasculature and associated with significant mortality.
Does sotatercept improve pulmonary vascular resistance in adults with combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction?
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Study Design
Type
RCT (n=164)
Randomization
54:55:55
Multicenter
Yes
Structured PICO
Does sotatercept improve pulmonary vascular resistance in adults with combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction?
P
Population
164 adults with combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH-HFpEF)
I
Intervention
Sotatercept (0.3 or 0.7 mg/kg) every 3 weeks
C
Comparator
Placebo every 3 weeks
O
Outcome
Change in pulmonary vascular resistance at week 24surrogate
Main Result
Effect estimate: Hodges-Lehmann shift -1.02 Wood units (95% CI -1.81 to -0.23)
Absolute Event Rate: -0.67% vs 0.26%
p-value: p=0.004
Sotatercept significantly reduced pulmonary vascular resistance at 24 weeks in patients with combined post- and pre-capillary pulmonary hypertension associated with HFpEF, providing proof of concept for activin signaling inhibition in this population.
Where experts stand
Heart failure evidence still forming
Experts read CADENCE as an encouraging proof of concept for sotatercept in a hard-to-treat form of heart failure with pulmonary hypertension, but not yet practice-changing until a larger outcomes trial reports.
Clinicians who commented were positive. They stressed that the benefit seemed to reach past the lung blood vessels to the right and left heart and to how patients function. No one disputed the result, but one commentator called the drop in vascular resistance itself modest, and the field is waiting on a phase 3 trial to show whether these signals mean better clinical outcomes.
Agreement
All three clinicians who commented argue that the benefit of sotatercept goes beyond lowering pulmonary vascular resistance. They point to improvements in heart function, biomarkers or functional capacity.
3 clinicians say this directly
Still unclear
Whether the gains in blood flow measures and heart function lead to clinically meaningful outcomes still needs a phase 3 study, which Gomberg-Maitland calls for. Sarma notes that the fall in resting PVR was relatively modest.
Implication
Opens new treatment axis for CpcPH-HFpEF with none approved; extends sotatercept efficacy from PAH to this phenotype.
Abstract
Background: Combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH–HFpEF) involves remodeling in both the heart and pulmonary vasculature. Despite significant mortality, there are no proven therapies. Methods: In this multicenter, randomized, placebo-controlled, phase 2 trial, adults received sotatercept (0.3 or 0.7 mg/kg) or placebo every 3 weeks. The primary end point was change in pulmonary vascular resistance at week 24. Hodges–Lehmann shift estimates described placebo-adjusted changes. Results: 164 patients were randomized 54:55:55 to sotatercept 0.3 mg/kg, 0.7 mg/kg, and placebo, and baseline median pulmonary vascular resistance was 5.2 (interquartile range [IQR] 4.0–6.9) Wood units. The median change from baseline in pulmonary vascular resistance at week 24 was –0.67 Wood units in the sotatercept 0.3 mg/kg group, –0.33 Wood units in the sotatercept 0.7 mg/kg group, and 0.26 Wood units in the placebo group. The Hodges–Lehmann shift estimates in pulmonary vascular resistance were –1.02 Wood units (95% CI, –1.81 to –0.23; P =0.004) for 0.3 mg/kg and –0.75 Wood units (95% CI, –1.52 to 0.03; P =0.024) for 0.7 mg/kg sotatercept. Reductions were observed in mean pulmonary arterial pressure (0.3 and 0.7 mg/kg: –9.19 mm Hg [95% CI, –13.00 to –5.38] and –9.22 [95% CI, –12.97 to –5.46]) and pulmonary arterial wedge pressure (0.3 and 0.7 mg/kg: –3.04 mm Hg [95% CI, –5.77 to –0.32] and –2.53 [95% CI, –5.33 to 0.28]). Changes in 6-minute walk distance were 20.3 meters (95% CI, 1.5–39.1) for 0.3 mg/kg and 5.8 meters (95% CI, –17.3 to 28.9) for 0.7 mg/kg sotatercept. The most common adverse events with sotatercept (both groups) were increased hemoglobin and diarrhea. Conclusions: These findings provide proof of concept for improved pulmonary vascular and cardiac hemodynamics following activin signalling inhibition with sotatercept in patients with CpcPH–HFpEF.
Cite This Study
Gomberg-Maitland et al. (2026) conducted an RCT in Combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction (CpcPH-HFpEF) (n=164). Sotatercept vs. Placebo was evaluated on change in pulmonary vascular resistance at week 24 (Hodges-Lehmann shift -1.02 Wood units, 95% CI -1.81 to -0.23, p=0.004). Sotatercept at /kg and /kg reduced pulmonary vascular resistance compared to placebo in CpcPH-HFpEF.
