Sotatercept Shows Right Heart Gains in PAH: Anjali Vaidya, MD

At this year’s European Society of Cardiology (ESC) Congress, held in Madrid, Spain, August 29 to September 1, new data were presented on sotatercept, an activin signaling inhibitor. In a session that explored novel treatments and therapeutic strategies for pulmonary arterial hypertension as measured by improvement to right ventricular function, Anjali Vaidya, MD, FACC, FASE, FACP, presented “Clinical Data Into Context: Effect of Sotatercept on Right Ventricular Function and Structure.”

Overall, these data show the prognostic potential for 24 weeks of sotatercept therapy to improve the heart’s right ventricular size and function, maximal oxygen uptake (VO₂), tricuspid regurgitation, atrial pressure, pulmonary vascular resistance, NT-proBNP level, and overall efficiency.

Vaidya, who is a professor of medicine and director of the Advanced Pulmonary Hypertension, Right Heart Failure, and Chronic Thromboembolic Pulmonary Hypertension Program at Temple University, spoke with The American Journal of Managed Care^® about the data and how sotatercept’s mechanism of action differs from traditional vasodilator therapies for pulmonary arterial hypertension.

This transcript has been lightly edited for clarity.

AJMC: According to your presentation at ESC, what part of the heart is the primary focus when assessing how a patient with pulmonary arterial hypertension is responding to therapy? Can you summarize sotatercept's effects on the right side of the heart?

Anjali Vaidya, MD, FACC, FASE, FACP | Image Credit: Temple University Hospital

VAIDYA: The right heart is the primary focus when it comes to assessing patients with pulmonary arterial hypertension. We have data to support prognostic value as it relates to multiple aspects of the right heart, including right ventricular size, right ventricular function, tricuspid regurgitation, pericardial effusion, and inferior vena cava size. Sotatercept’s effects have been studied on right ventricular size, right ventricular function, and tricuspid regurgitation, and have been shown to significantly improve all of the above.

AJMC: The studies you included in your analysis measured several key hemodynamic and structural parameters. Can you discuss the specific and statistically significant changes observed at week 24 for systolic pulmonary artery pressure (sPAP), pulmonary vascular resistance, and the size of the right ventricle, both end-diastolic volume and end-systolic volume?

VAIDYA: Systolic pulmonary artery pressure, pulmonary vascular resistance, and right ventricle size as measured by end-diastolic area, end-systolic area, and volumes all improved significantly. These were statistically significant changes, and they additionally have great clinical significance based on the magnitude and known correlation with prognosis and survival over time in pulmonary arterial hypertension.

AJMC: Your findings presented a nuanced picture of tricuspid annular plane systolic excursion (TAPSE). How do you explain the finding that TAPSE alone did not show a statistically significant improvement at week 24, while the TAPSE/sPAP ratio improved significantly?

VAIDYA: TAPSE was normal at baseline. As such, there are physiologic limitations in the ability to augment this further, even with a dramatic change on sPAP, which was achieved via the direct effect on sotatercept. The ratio of TAPSE/sPAP improved on this basis. Despite TAPSE not having a significant improvement, which is a marker of longitudinal shortening of the right ventricle, there was significant change in right ventricular fractional area change, which takes into account longitudinal and transverse contraction of the right ventricle.

AJMC: What did longer-term data from the PULSAR study (NCT03496207) show about TAPSE?

VAIDYA: The longer-term data from the open-label extension analysis of the PULSAR study showed that among those on sotatercept for 18 to 24 months, there was an improvement in TAPSE.

AJMC: How did sotatercept impact tricuspid regurgitation?

VAIDYA: There were dramatic improvements in tricuspid regurgitation. At the 24-week follow-up, 92% of patients had insignificant tricuspid regurgitation—none, trace, or only mild—compared with 78% of those on placebo. These results are not only statistically significant but also very clinically significant.

AJMC: Why is the combination of improved tricuspid regurgitation (to mild or less) and TAPSE (≥1.8 cm or 1.9 cm) considered so prognostically important for long-term, transplant-free survival in patients who have pulmonary arterial hypertension?

VAIDYA: The severity of tricuspid regurgitation has been shown to correlate with overall survival and prognosis in pulmonary arterial hypertension. This is no surprise, as it mechanistically represents abnormalities in the overall structure and function of the right side of the heart. Multiple studies have shown this prognostic importance, particularly when taken in conjunction with TAPSE as a measure of right ventricular function, including one global study published in 2020 that looked at nearly 700 patients with pulmonary arterial hypertension across multiple centers; patients who had normal TAPSE without significant tricuspid regurgitation had much greater survival benefits compared with those who had normal TAPSE with significant tricuspid regurgitation.

Additionally, when tricuspid regurgitation has been added to noninvasive risk assessment tools such as COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, which includes 6-minute walk distance, functional class, and NT-ProBNP/BNP), tricuspid regurgitation is able to discriminate between those with intermediate-low vs intermediate-high risk, with a separation in prognosis that is both early (months) and sustained (over 5 years).

AJMC: Overall, sotatercept had a muted, or blunted, effect on cardiac output and cardiac index. What is the physiological reason given for this? How does sotatercept’s mechanism of action differ from traditional vasodilator therapies for pulmonary arterial hypertension that do increase cardiac output?

VAIDYA: This is complex, with multiple underlying physiologic explanations. The mechanism of action of sotatercept is different from other pulmonary arterial hypertension medical therapies in that it is not a vasodilator. Our other therapies, due to having vasodilatory properties, have the effect of dropping both systemic and pulmonary vascular resistance. When systemic vascular resistance is affected, independent of pulmonary vascular resistance effect, there is a reflexive response in arterial baroreceptors, which lead to an augmentation of sympathetic tone and increased cardiac contractility and cardiac output. Sotatercept does not have this effect on systemic vascular resistance.

Additionally, in the STELLAR trial (NCT04576988), patients at baseline had preserved cardiac output and cardiac index, indicating baseline coupling of the right ventricle and pulmonary circulation. As such, there is limited ability to augment cardiac output or cardiac index, even with a decrease in pulmonary vascular resistance from sotatercept therapy.

Finally, impacts on radius of the vessel, viscosity of the blood, and pressure, when taken all together, based on Poiseuille’s law, can lead to this expected result.

AJMC: Considering the broad improvements across right ventricular size and function, hemodynamics (pulmonary vascular resistance), and biomarkers (NT-proBNP), what is the ultimate clinical implication of these findings? How might they help patients achieve key prognostic goals that can override traditional risk stratification models?

VAIDYA: These composite findings represent groundbreaking clinical implications of this medication and its impact on patients achieving key prognostic goals. These end points and parameters are largely represented in traditional risk stratification models and represent consistency within the evolution of our knowledge in the field that patients who can improve and normalize performance of the right side of their heart have an excellent prognosis relative to those who do not.