MILAN — Sotatercept, a first-in-class activin signaling inhibitor, is currently under scrutiny as a potential game-changer in the treatment of pulmonary arterial hypertension (PAH). Data unveiled at the European Respiratory Society (ERS) International Congress 2023, held in Milan, Italy, suggest that sotatercept treatment has the capacity to deliver significant clinical benefits and could reshape the trajectory of this challenging disease. Experts are cautiously optimistic that this drug may soon find a place within the PAH treatment algorithm.
The STELLAR Trial: A Milestone in PAH Research
PAH is intricately linked to the dysregulation of members within the TGF-beta superfamily, including activin receptor type IIA (ActRIIA) and its ligands activin A and activin B. This signaling pathway is believed to be a driving force behind the pulmonary vascular remodeling observed in PAH patients. Sotatercept, a fusion protein acting as a ligand trap for selected TGF-beta superfamily members, has been proposed to recalibrate pulmonary vascular homeostasis by promoting growth-inhibiting and pro-apoptotic signaling.
Sotatercept was tested first in a phase 2 trial (PULSAR) and later in a phase 3 trial (STELLAR). The STELLAR clinical trial, funded by Acceleron Pharma (now a subsidiary of Merck), was the subject of two presentations given by Marius M. Hoeper, MD, director of the Department of Respiratory Medicine at Hannover Medical School, Hannover, Germany.
Hoeper commented on results published in April in the New England Journal of Medicine during a session entitled, “Disease modification in pulmonary arterial hypertension.” Later, during the “From the Editor’s Desk” session, he presented new results recently published in the European Respiratory Journal about the effects of sotatercept on hemodynamics and right heart function.
Disease Modification in PAH
In his initial address, Hoeper expounded on the concept of reverse remodeling as a therapeutic avenue for PAH. “PAH is not a disease of pulmonary vasoconstriction,” he clarified, “but a disease of proliferation. Endothelial cells and pulmonary vascular muscle cells proliferate and obliterate the lumen. It has been hypothesized that when we target this system successfully, we may not only stop disease progression, but we may have a chance to have at least some reverse remodeling, because, if these cells go into apoptosis, there may be a partial reopening of the vessels.”
“Sotatercept is probably going to be a game changer in our field,” Hoeper continued. “Is sotatercept a disease-modifying agent? It certainly induces disease improvement; in a few patients, although not in the majority, we see a normalization of hemodynamics. We target the underlying pathophysiology; this is clearly distinct from symptomatic treatment.” Hoeper went through the list of characteristics that a disease-modifying agent should have.
“To be able to say that a drug endures sustained clinical benefit, according to the FDA, you need to withdraw the drug, and this is something we do not know. We know that we can interrupt the treatment once or twice, but long-term I do not believe that,” he said, while acknowledging the need for more extended-term safety and efficacy data.
Unmasking Hemodynamic Impact
Hoeper’s second presentation focused on a post-hoc analysis of the STELLAR trial never presented before. He analyzed right heart catheterization (RHC) and echocardiography (ECHO) data. With sotatercept treatment at week 24, the researchers observed:
a small increase in systemic blood pressure and systemic vascular resistance
no changes in systolic and diastolic volumes of the left ventricle (LV)
a small but significant reduction in LV ejection fraction
a great reduction in the mean pulmonary artery pressure (mPAP)
no change in cardiac output
an improvement in pulmonary artery compliance
a reduction in the right ventricle work and in right atrial pressure
an improvement of echocardiographic parameters, including a significant decrease in tricuspid regurgitation
“A drop of roughly 14 mm Hg in mPAP is something that we have never seen in PAH with any other add-on medication. This was entirely driven by improvement in the sotatercept group, not by deterioration in the placebo group,” Hoeper pointed out. Of note, change in mPAP correlated with changes in NT-proNBP and with changes in 6-minute walk distance (6MWD), the primary endpoint of the STELLAR trial. “We effectively unload the right ventricle by lowing the artery pressure. What we observe is exactly what we want to achieve in patients with PAH, because the heart is what really matters,” he concluded.
A New Course in PAH Treatment?
Olivier Sitbon, MD, PhD, professor of respiratory medicine at Université Paris-Saclay and consultant at the French Referral Center for Pulmonary Hypertension, echoed Hoeper’s enthusiasm. “What is important about sotatercept studies is that for the first time it has been demonstrated that to add a fourth drug improves hemodynamics in PAH patients on background triple-combination therapy. Today, triple therapy is the maximum treatment before lung transplantation,” he told Medscape.
Sitbon highlighted ongoing studies with sotatercept, including the ZENITH trial, focused on high-risk PAH patients, and the HYPERION trial, aimed at patients diagnosed within the first year of their PAH journey. He acknowledged that experts currently lack consensus on the ideal position for sotatercept within the PAH treatment algorithm. However, he anticipates a lively debate and expects sotatercept to find its place as a second-line treatment for intermediate low-risk or intermediate high-risk patients, with potential consideration for high-risk patients.
“There are two more studies ongoing with sotatercept: the ZENITH trial, dedicated to PAH patients at high risk, whose primary endpoint is mortality/need for lung transplant, and the HYPERION trial, dedicated to patients diagnosed less than 1 year (not really newly diagnosed but quite incident, while patients included in previous trial were very prevalent), whose primary endpoint is time to clinical worsening,” Sitbon noted, pointing out that there is currently no consensus among the experts about where to place sotatercept in the PAH treatment algorithm.
Further Insights Into Sotatercept
The ERS Congress also unveiled two additional studies that provided fresh perspectives on sotatercept’s potential. Ioana R. Preston, MD, from Tufts Medical Center in Boston, presented the first interim analysis of SOTERIA, a long-term follow-up study involving 409 patients with a median exposure duration of 462 days to sotatercept. Treatment-emergent adverse events were reported by 80% of patients, with 20% reporting a serious TEAE. Overall, 4 serious TEAEs (1% of patients) led to death, but only 5 patients (1.2%) discontinued sotatercept because of TEAE.
Notably, improvements in clinical efficacy measures persisted after 1 year. During SOTERIA, roughly 3% of patients on any prostacyclin discontinued it. “Results of SOTERIA support the long-term durable clinical benefit and safety of sotatercept for the treatment of PAH. Of note, patients were offered home self-administration therapy, so they do not need to come back to the office” Preston said.
A second late-breaking abstract presented by Vallerie McLaughlin, MD, University of Michigan, Ann Harbor, described the possible long-term impact of sotatercept on morbidity and mortality. STELLAR trial data were analyzed to see how the risk profile of patients changed in the 24 weeks of study. Real-world registry data from the COMPERA registry were then used to extrapolate mortality and transplant need over 30 years based on risk transition. According to the simulation model, adding sotatercept to background therapy is expected to increase life expectancy by threefold, while avoiding nearly 700 hospitalizations and 4 lung/heart-lung transplantations per 1000 patients. “Real-world data are needed to confirm these findings,” cautioned McLaughlin.
Hoeper disclosed speaking and consulting fees from Acceleron, Actelion, Altavant, AOP Health, Bayer, Ferrer, Janssen, Keros, and MSD. Sitbon disclosed speaking and consulting fees from Acceleron Pharmaceuticals, Altavant Sciences, AOP Orphan, Bayer, Ferrer, Gossamer Bio, Janssen, MSD, and United Therapeutics, and grant/research support from Acceleron Pharmaceuticals, AOP Orphan, Bayer, Janssen, and MSD.
Preston disclosed speaking and consulting fees from Janssen, LLC, United Therapeutics, and grant/research support from Janssen, LLC, Respira Therapeutics. She has participated in scientific advisory boards for Aereovate, Altavant, and Gossamer Bio, and was in the Steering Committee of Acceleron, Liquidia, and United Therapeutics.
McLaughlin has received speaking and consulting fees from Aerami, Aereovate, Caremark, Corvista, Enzyvant, Gossamer Bio, Janssen, LLC, Merck, United Therapeutics, and Vertex, and grant/research support from Aerovate, Enzyvant, Gossamer Bio, Janssen, Merck, and Sonovia. She is a member of the Board of Directors of Clene.
European Respiratory Society (ERS) International Congress 2023. Presented September 9-13, 2023.
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Publish date : 2023-09-15 16:34:14
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