Phase 2 CADENCE Trial Shows Positive Results, Establishing WINREVAIR™ as a Proof-of-Concept Therapy in CpcPH and HFpEF
Merck & Co.—known as MSD outside the United States and Canada—has unveiled comprehensive results from its Phase 2 CADENCE clinical trial, providing compelling new insights into the potential of WINREVAIR™ (sotatercept-csrk) as a treatment for a highly underserved cardiovascular condition: combined post- and precapillary pulmonary hypertension associated with heart failure with preserved ejection fraction (CpcPH-HFpEF). The findings, presented as late-breaking data at the American College of Cardiology Annual Scientific Session and Expo 2026 and simultaneously published in Circulation, underscore the drug’s ability to significantly improve key hemodynamic parameters in this complex and high-risk patient population.
Addressing a Critical Unmet Need
CpcPH-HFpEF represents a distinct and clinically challenging subtype of pulmonary hypertension that arises in the context of advanced heart failure. Unlike more commonly recognized forms of pulmonary hypertension, this condition involves both post-capillary and pre-capillary components, reflecting abnormalities in both left heart function and pulmonary vascular remodeling. Patients are often older and frequently present with multiple comorbidities, including hypertension, diabetes, and obesity.
Despite its serious clinical implications—including elevated morbidity and mortality—there are currently no therapies specifically approved to treat CpcPH-HFpEF. As a result, management strategies are largely supportive and extrapolated from treatments used in related conditions, often with limited effectiveness.
Against this backdrop, the CADENCE study was designed to explore whether WINREVAIR, a novel activin signaling inhibitor, could address the underlying pathophysiology of the disease and deliver meaningful clinical benefits.
CADENCE Study Design and Objectives
The Phase 2 CADENCE trial was a randomized, placebo-controlled study evaluating two dosing regimens of WINREVAIR—0.3 mg/kg and 0.7 mg/kg—in adult patients diagnosed with CpcPH-HFpEF. The study aimed to assess the drug’s efficacy, safety, and tolerability over a 24-week treatment period.
A total of approximately 164 participants were enrolled and distributed across the two treatment arms and a placebo group. The primary endpoint of the study was the change from baseline in pulmonary vascular resistance (PVR), a critical measure of the workload placed on the right side of the heart and a key determinant of disease severity and progression.
Secondary endpoints included functional capacity, as measured by six-minute walk distance (6MWD), as well as a range of hemodynamic and biomarker assessments, such as mean pulmonary arterial pressure (mPAP), pulmonary arterial wedge pressure (PAWP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and time to clinical worsening (TTCW).
Significant Improvements in Pulmonary Hemodynamics
The CADENCE trial met its primary endpoint, demonstrating statistically significant and clinically meaningful reductions in PVR for both doses of WINREVAIR compared with placebo at week 24.
Patients receiving the 0.3 mg/kg dose experienced a reduction of 1.02 Wood units in PVR (95% CI: -1.81 to -0.23; p=0.004), while those receiving the 0.7 mg/kg dose achieved a reduction of 0.75 Wood units (95% CI: -1.52 to 0.03; p=0.024). These results indicate a robust improvement in pulmonary vascular function, suggesting that WINREVAIR may directly target the vascular remodeling processes that drive disease progression.
Importantly, reductions in PVR are associated with decreased strain on the right ventricle, which may translate into improved cardiac performance and better long-term outcomes for patients.
Encouraging Trends Across Secondary Endpoints
While the study employed a hierarchical testing strategy that limited formal statistical testing of secondary endpoints, the observed trends across multiple measures further reinforce the therapeutic potential of WINREVAIR.
Exercise Capacity
Functional capacity, as assessed by the six-minute walk distance, showed encouraging improvements. Patients treated with the 0.3 mg/kg dose demonstrated a mean increase of 20.3 meters from baseline (95% CI: 1.5 to 39.1), suggesting a CADENCE clinically meaningful enhancement in exercise tolerance. Although the 0.7 mg/kg group showed a smaller increase of 5.8 meters (95% CI: -17.3 to 28.9), this did not reach statistical significance.
These findings suggest a potential dose-response relationship in which the lower dose may provide optimal functional benefits.
Hemodynamic Measures
Additional hemodynamic parameters showed consistent improvements across both dosing groups:
- Mean pulmonary arterial pressure (mPAP) decreased by approximately 9 mmHg in both treatment arms, indicating reduced pressure within the pulmonary arteries.
- Pulmonary arterial wedge pressure (PAWP), a marker of left heart filling pressures, declined by 3.04 mmHg in the 0.3 mg/kg group and 2.53 mmHg in the 0.7 mg/kg group.
These reductions highlight the dual impact of WINREVAIR on both pulmonary vascular resistance and left-sided cardiac pressures, a particularly important feature in a condition characterized by combined pathophysiology.
Biomarker Response
Levels of NT-proBNP, a widely used biomarker of cardiac stress and heart failure severity, also decreased meaningfully:
- A reduction of 344 pg/mL was observed in the 0.3 mg/kg group (95% CI: -656 to -31).
- A reduction of 402 pg/mL was seen in the 0.7 mg/kg group (95% CI: -846 to 42).
Lower NT-proBNP levels are generally associated with improved cardiac function and reduced risk of adverse outcomes, further supporting the clinical relevance of these findings.
Time to Clinical Worsening
The study also evaluated time to first clinical worsening event, a composite endpoint that includes hospitalization, disease progression, or death. Patients receiving WINREVAIR experienced a delay in clinical worsening compared to placebo:
- The hazard ratio was 0.18 (95% CI: 0.05 to 0.62) for the 0.3 mg/kg dose.
- The hazard ratio was 0.59 (95% CI: 0.25 to 1.36) for the 0.7 mg/kg dose.
These results suggest a substantial reduction in the risk of disease progression, particularly with the lower dose.
Safety and Tolerability Profile
The safety profile of WINREVAIR in the CADENCE study was generally consistent with previous findings observed in patients with pulmonary arterial hypertension (PAH). No new or unexpected safety signals were identified.
Adverse events were manageable and aligned with the known pharmacological effects of the drug, supporting its continued development in this new indication. The overall tolerability profile reinforces the feasibility of long-term treatment, an important consideration for chronic conditions such as CpcPH-HFpEF.
Expert Perspectives
Clinical experts have emphasized the importance of these findings in addressing a long-standing gap in cardiovascular medicine. CpcPH-HFpEF has historically been underdiagnosed and poorly understood, in part due to its complex pathophysiology and overlap with other forms of heart failure and pulmonary hypertension.
The CADENCE results provide strong proof-of-concept evidence that targeting the activin signaling pathway can yield meaningful improvements in both pulmonary vascular and cardiac function. This dual mechanism of action distinguishes WINREVAIR from existing therapies and positions it as a potentially transformative treatment option.
Path Forward: Phase 3 Development
Based on the totality of evidence from the CADENCE study, Merck & Co. is advancing WINREVAIR into a Phase 3 registrational program for CpcPH-HFpEF. The company is actively engaging with regulatory authorities to design a study that prioritizes clinically meaningful outcomes, including functional capacity, quality of life, and long-term morbidity and mortality.
Notably, the data suggest that the 0.3 mg/kg dose may offer the most favorable benefit-risk profile, combining robust efficacy with a strong safety and tolerability profile. This dose is expected to play a central role in the design of future trials.
Broader Implications for Cardiovascular Innovation
The success of WINREVAIR in the CADENCE trial reflects a broader shift toward precision medicine in cardiovascular disease, where therapies are increasingly tailored to specific pathophysiological mechanisms and patient subgroups.
By targeting a previously unaddressed pathway in a well-defined but underserved population, WINREVAIR exemplifies how innovative drug development can unlock new treatment paradigms and improve outcomes for patients with complex conditions.
The Phase 2 CADENCE study marks a significant milestone in the development of WINREVAIR for CpcPH-HFpEF. With statistically significant improvements in pulmonary vascular resistance and consistent positive trends across multiple secondary endpoints, the CADENCE therapy has demonstrated strong potential to address a critical unmet need.
As Merck & Co. moves forward with Phase 3 development, the medical community will be watching closely to see whether these promising results translate into a first-in-class treatment for this challenging and often overlooked condition.
About the CADENCE study and additional results
CADENCE is a double-blind, randomized, placebo-controlled Phase 2 proof-of-concept study (NCT04945460) evaluating the efficacy, safety and tolerability of WINREVAIR versus placebo in adults with CpcPH-HFpEF. Adult patients in the trial had a diagnosis of CpcPH-HFpEF with New York Heart Association (NYHA) FC II or III. The study enrolled 164 participants, and the demographics and clinical characteristics at baseline were generally balanced. The median age was 75 years old (69-79) and 69.5% of the patients were female (n=114). 65.9% of patients had a NYHA FC III diagnosis and 34.1% had a NYHA FC II diagnosis. At baseline, 34.8% had atrial fibrillation and 46.3% had diabetes.
A total of 164 participants were randomized in a 1:1:1 ratio to one of the three treatment groups: placebo once every three weeks (Q3W) (n=55), 0.3 mg/kg WINREVAIR Q3W (n=54) and 0.7 mg/kg WINREVAIR Q3W (n=55) during the placebo-controlled treatment period. CADENCE For those randomized to the 0.7 mg/kg dose of WINREVAIR, participants received a starting dose level of WINREVAIR 0.3 mg/kg for the initial three dosing visits, then escalated to the 0.7 mg/kg dose Q3W.
The CADENCE trial was designed as a proof-of-concept study with biomarkers, invasive hemodynamics, non-invasive imaging and exercise capacity. The primary endpoint is change from baseline in PVR. The study also evaluated exercise capacity, as well as echocardiographic, biomarker and clinical endpoints. Time to clinical worsening was defined by a composite endpoint of death, ≥1 hospitalization due to cardiopulmonary indication; ≥1 administration of intravenous diuretics or subcutaneous furosemide or ≥15 percent decrease from baseline in 6MWD confirmed by two tests.
At baseline, the median PVR was 5.2 Wood units (4.0, 6.9), mPAP was 43 mmHg (38.0, 50.0), PAWP was 21.0 mmHg (18.0, 25.0), the median 6MWD was 273.8 meters (199.5, 343.8), and the median NT-proBNP level was 1119 pg/mL (554-2383).
Serious adverse events (SAEs) were reported in 20% of participants receiving WINREVAIR 0.3 mg/kg, 33% of participants receiving WINREVAIR 0.7 mg/kg and 22% receiving placebo. Adverse events leading to treatment discontinuation were comparable between WINREVAIR 0.3 mg/kg and placebo, with no discontinuations in either group. There were three discontinuations due to an AE and one discontinuation due to a drug-related AE in the WINREVAIR 0.7 mg/kg group.
Bleeding events occurred in 26% of patients in the WINREVAIR 0.3 mg/kg group, 27% in the WINREVAIR 0.7 mg/kg group and 24% of patients in the placebo group. Adverse events leading to death occurred in one patient in the WINREVAIR 0.7 mg/kg group and two CADENCE patients in the placebo group. Adverse events with an incidence of ≥10% in any group included diarrhea, fatigue, peripheral edema, influenza, nasopharyngitis, urinary tract infection, dizziness, headache and dyspnea.
About the syndrome of combined post- and precapillary pulmonary hypertension and heart failure with preserved ejection fraction (CpcPH-HFpEF)
Combined post- and precapillary pulmonary hypertension and heart failure with preserved ejection fraction (CpcPH-HFpEF) is a distinct, identifiable and well-characterized condition that develops in people with long-term or advanced heart failure. Different from Group 1 pulmonary arterial hypertension (PAH), CpcPH-HFpEF is caused by two interrelated components: pulmonary vascular disease and cardiac disease. CpcPH-HFpEF is thought to be uncommon and underdiagnosed, typically impacting people who are older and have other comorbid conditions. CADENCE It is associated with a worse prognosis and higher mortality rate compared to HFpEF alone. There are no treatments specifically approved for CpcPH-HFpEF.
About WINREVAIR™ (sotatercept-csrk) for injection, for subcutaneous use, 45 mg, 60 mg
WINREVAIR is FDA-approved for the treatment of adults with pulmonary arterial hypertension (PAH, WHO Group 1 pulmonary hypertension) to improve exercise capacity and World Health Organization (WHO) functional class (FC), and reduce the risk of clinical worsening events, including hospitalization for PAH, lung transplantation and death. WINREVAIR is the first activin signaling inhibitor therapy approved to treat PAH.
WINREVAIR improves the balance between pro-proliferative and anti-proliferative signaling to modulate vascular proliferation. In preclinical models, CADENCE WINREVAIR induced cellular changes that were associated with thinner vessel walls, partial reversal of right ventricular remodeling and improved hemodynamics.
WINREVAIR is the subject of a licensing agreement with Bristol Myers Squibb.
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