Merck Reports Positive Phase 2 CADENCE Results for WINREVAIR in CpcPH-HFpEF, Supporting Advancement to Phase 3
Merck has announced encouraging results from its Phase 2 CADENCE clinical trial evaluating WINREVAIR™ (sotatercept-csrk) in adults diagnosed with combined post- and precapillary pulmonary hypertension associated with heart failure with preserved ejection fraction (CpcPH-HFpEF). The findings demonstrate that the investigational therapy met its primary endpoint and showed clinically meaningful improvements across several key measures, reinforcing its potential as a novel treatment option for this underserved patient population.
The CADENCE study was designed to assess the efficacy, safety, and tolerability of WINREVAIR at two dose levels—0.3 mg/kg and 0.7 mg/kg—compared with placebo. The primary endpoint focused on the change in pulmonary vascular resistance (PVR), a critical indicator of how effectively blood flows through the lungs and into the heart. At 24 weeks, both dosing groups achieved statistically significant reductions in PVR compared with placebo, indicating improved pulmonary hemodynamics.
Patients receiving the 0.3 mg/kg dose experienced a reduction of 1.02 Wood units in PVR, while those in the 0.7 mg/kg group saw a reduction of 0.75 Wood units. These results highlight WINREVAIR’s ability to enhance blood flow through the pulmonary circulation, a key therapeutic goal in patients with pulmonary hypertension and heart failure.
Beyond the primary endpoint, the study also evaluated a range of secondary outcomes, including exercise capacity, cardiac function, biomarkers, and clinical progression. While not all secondary endpoints reached statistical significance due to the study’s hierarchical testing design, consistent trends across multiple measures further supported the drug’s therapeutic potential.
One such measure, the six-minute walk distance (6MWD), is commonly used to assess functional capacity in patients with cardiopulmonary conditions. Patients receiving the 0.3 mg/kg dose demonstrated a mean increase of 20.3 meters from baseline, suggesting improved exercise tolerance. Although the higher dose group showed a smaller improvement of 5.8 meters that did not reach statistical significance, the overall trend indicates potential functional benefits.
Additional hemodynamic improvements were observed in both treatment groups. Mean pulmonary arterial pressure (mPAP) decreased significantly, with reductions of approximately 9 mmHg in both dose arms. Similarly, pulmonary arterial wedge pressure (PAWP), a measure of left heart pressure, declined in both groups, reflecting improvements in cardiac function and reduced strain on the heart.
Biomarker analysis also revealed favorable outcomes. Levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), a marker of heart failure severity, were reduced in patients treated with WINREVAIR. This reduction suggests improved cardiac stress and overall heart function.
Importantly, the study also examined time to clinical worsening (TTCW), a composite endpoint that includes events such as hospitalization, worsening symptoms, or death. Patients treated with WINREVAIR experienced a delay in clinical worsening compared with those receiving placebo, further supporting the therapy’s potential to improve long-term outcomes.
The safety profile observed in the CADENCE trial was generally consistent with previous studies of WINREVAIR in pulmonary arterial hypertension (PAH). Rates of serious adverse events were comparable across treatment groups, with no unexpected safety signals identified. Common adverse events included diarrhea, fatigue, peripheral edema, and respiratory infections. Bleeding events were reported at similar rates across all groups, including placebo.
While the higher dose group experienced slightly more discontinuations due to adverse events, the lower dose of 0.3 mg/kg appeared to offer a more favorable balance between efficacy and safety. These findings suggest that the lower dose may be optimal for further development in this patient population.
The CADENCE trial enrolled 164 participants with confirmed CpcPH-HFpEF, a condition characterized by the coexistence of pulmonary vascular disease and cardiac dysfunction. Patients were randomized equally to receive placebo or one of the two dosing regimens of WINREVAIR, administered once every three weeks. The study population was reflective of real-world patients, with a median age of 75 years and a high prevalence of comorbidities such as atrial fibrillation and diabetes.
CpcPH-HFpEF represents a distinct and challenging clinical condition. Unlike pulmonary arterial hypertension, which primarily affects the pulmonary vasculature, this syndrome involves both pulmonary and cardiac components. It is often underdiagnosed and is associated with poor prognosis and high mortality rates. Currently, there are no approved therapies specifically targeting this condition, highlighting a significant unmet medical need.
The positive findings from the CADENCE trial provide strong evidence supporting the advancement of WINREVAIR into a Phase 3 registrational program. Merck has indicated that it is actively engaging with regulatory authorities to design a study that will focus on clinically meaningful outcomes, with the ultimate goal of bringing the first approved treatment option to patients with CpcPH-HFpEF.
WINREVAIR is already approved for the treatment of pulmonary arterial hypertension, where it has demonstrated the ability to improve exercise capacity and reduce the risk of clinical worsening events. The drug works by targeting the activin signaling pathway, helping to restore balance between pro-proliferative and anti-proliferative signals in the vasculature. This mechanism leads to structural and functional improvements in blood vessels, including reduced vessel wall thickness and improved hemodynamics.
Preclinical studies have also shown that WINREVAIR may contribute to partial reversal of right ventricular remodeling, a key factor in heart failure progression. These combined effects make it a promising candidate for treating complex cardiopulmonary conditions such as CpcPH-HFpEF.
Despite its potential, WINREVAIR is associated with certain risks that require careful monitoring. The therapy may increase hemoglobin levels, which could elevate the risk of thromboembolic events, and may also reduce platelet counts, increasing the risk of bleeding. As such, regular monitoring of blood parameters is recommended during treatment.
In conclusion, the Phase 2 CADENCE trial provides compelling evidence that WINREVAIR has meaningful clinical activity in patients with CpcPH-HFpEF. The consistent improvements observed across multiple endpoints, combined with a manageable safety profile, support continued development of this therapy. If confirmed in Phase 3 studies, WINREVAIR could represent a significant breakthrough for patients with this complex and currently untreatable condition.
About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities
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