Sotatercept Demonstrates Its Potential in the Phase 3 ZENITH Trial

At the ACC 2025 Scientific Session, Marc Humbert, MD, professor of respiratory medicine at the South Paris University, discussed the role of sotatercept, a novel biologic therapy, in treating pulmonary arterial hypertension (PAH), particularly for patients at high risk of death. In an interview with Pharmacy Times®, Humbert highlighted the mechanism of action of sotatercept as a ligand trap for activin, which plays a key role in the proliferation of small pulmonary arteries and the subsequent obstruction leading to PAH. He also shared insights from the ZENITH trial (NCT04896008), which focused on patients with a major unmet need, showing significant improvements in key clinical outcomes.

Pharmacy Times: What makes sotatercept a promising therapy for high-risk PAH patients, and how does it differ mechanistically from current treatments?

Marc Humbert, MD, PhD: Sotatercept is an interesting therapy because it is a ligand trap that captures activin. Activin is very important in promoting the proliferation of the small pulmonary arteries, and this is one of the causes of the obstruction of these arteries, which leads to pulmonary hypertension. What is really important with sotatercept is that it is a biologic—so it is a new class of drug—and it works as an anti-proliferative agent, addressing the basic mechanisms of pulmonary remodeling.

Pharmacy Times: Can you summarize the findings of the ZENITH phase 3 trial regarding the efficacy and safety of sotatercept in high-risk patients with PAH?

Humbert: For patients with a high risk of death, there are very few studies ongoing because it’s a very challenging situation. The ZENITH trial focused exclusively on patients with a high risk of death, and in that study, patients were randomized to receive either placebo or sotatercept on top of maximum tolerated therapy. This is a very important study because it focuses on people with a major unmet need.

With this therapy, the results of the study were very clear. There was a significant improvement in time to death, lung transplantation, or hospitalization for pulmonary hypertension. So, it's a very robust composite end point made up of very significant measures.

REFERENCES

A study of sotatercept in participants with PAH WHO FC III or FC IV at high risk of mortality (MK-7962-006/​ZENITH) (ZENITH). Updated March 25, 2025. Accessed March 30, 2025. https://clinicaltrials.gov/study/NCT04896008