Professor Marc Humbert: The Future of PAH Treatment Lies in Disease Modification

Pulmonary arterial hypertension (PAH) remains a serious and life-threatening disease despite significant advances in treatment over the past decades. As the field increasingly shifts its focus from symptom management toward disease modification, new therapeutic approaches targeting the underlying mechanisms of disease are gaining attention. In this interview, Professor Marc Humbert, one of the world's leading PAH experts and Chair of the Clinical Steering Committee for Cereno Scientific's CS1 program, shares his perspective on the current treatment landscape, key considerations in clinical development, and what may define the next generation of therapies for PAH.

You have worked with PAH patients and research for many years and contributed to international treatment guidelines. From your perspective, what remains the greatest challenge in treating PAH today?

- Despite the progress made in PAH treatment over the past three decades, PAH remains a serious and life-threatening disease. In clinical practice, we still see many patients who continue to deteriorate over time despite receiving combination therapies. One of the major challenges today is therefore to move beyond symptom control and toward therapies that can more fundamentally alter disease progression. Increasingly, the field is discussing whether the long-term goal in PAH should be remission, similar to concepts used in oncology. This is why there is growing interest in therapeutic approaches targeting the underlying biology of the disease, including pulmonary vascular remodeling, inflammation, and fibrosis.

As Principal Investigator of the studies that supported the approval of Winrevair (sotatercept) in 2024 as the first new PAH therapy in many years, how do you view the current evolution of PAH treatment?

- We have seen major progress in PAH over the last decades, with several approved treatment pathways and increasingly effective combination therapies. The approval of sotatercept marked an important step because it introduced the first PAH therapy specifically designed to target signaling pathways implicated in pulmonary vascular remodeling and disease progression. At the same time, many patients still face substantial morbidity, mortality and quality of life loss, highlighting the continued need for new therapeutic approaches. The future of PAH treatment is increasingly focused on reverse pulmonary vascular remodeling resulting in disease modification rather than only symptom control.

Which factors are most critical when designing clinical studies in PAH? What are the key considerations in designing a Phase IIb study in PAH?

- Clinical studies in PAH require rigorous patient selection, robust risk assessment, and meaningful endpoints reflecting both symptoms and disease progression. In addition to functional status, it is important to evaluate measures related to right heart function, clinical worsening, and hospitalization risk. For a Phase IIb study, safety, tolerability, dose optimization, and early signals of disease modification are all key considerations. Studies should also be conducted in expert PAH centers with extensive clinical experience, which is how the Phase IIb trial of CS1 is designed.

How do you view the therapeutic approach behind CS1?

- CS1 is particularly interesting because it aims to target the underlying mechanisms driving PAH progression rather than only providing symptomatic relief. Through epigenetic modulation and HDAC inhibition, it has the potential to influence pulmonary vascular remodeling, fibrosis, inflammation, and thrombosis simultaneously. This multifaceted approach is important in a complex disease like PAH where several biological pathways are involved. If successful, CS1 will establish a completely new treatment pillar in the treatment of PAH. The broad biological effects observed with CS1 make it an interesting and potentially important therapeutic approach in PAH.

Looking ahead, what do you believe will define the next generation of PAH therapies?

- The next generation of PAH therapies will likely focus increasingly on disease modification and targeting the biological mechanisms driving pulmonary vascular remodeling and right heart dysfunction. We are also moving toward more individualized treatment strategies and earlier intervention in the disease course. Continued innovation and well-designed clinical studies will be essential to improving and extending the lives of patients.

This interview was previously published in Cereno Scientific’s Annual Report 2025.