Sotatercept, a first-in-class activin signaling inhibitor, improved 6-minute walk distance by 40.8 meters at 24 weeks and reduced the risk of clinical worsening or death by 84% in adults with pulmonary arterial hypertension (PAH) already receiving background therapy, according to the phase 3 STELLAR trial published in The New England Journal of Medicine. The findings, from 323 patients with WHO functional class II or III PAH, provided the pivotal evidence for the FDA’s March 2024 approval of sotatercept (Winrevair), the first therapy for PAH that acts on the underlying pulmonary vascular remodeling rather than on vessel tone.
Why PAH has needed a different approach
Pulmonary arterial hypertension is a rare, progressive disease of the small pulmonary arteries. Uncontrolled cellular proliferation and remodeling narrow the vessels, raising pressure on the right side of the heart. All approved PAH drugs before sotatercept worked by vasodilation, relaxing the narrowed vessels through one of three signaling pathways (endothelin, nitric oxide/cyclic guanosine monophosphate, or prostacyclin). Despite combination therapy across these three pathways, five-year survival for group 1 PAH remains around 60%, and the disease continues to progress in most patients. Nothing in the existing arsenal directly targets the vascular remodeling itself.
How sotatercept works
Sotatercept is an activin receptor type IIA-Fc fusion protein. It acts as a ligand trap, binding activin A, activin B, and related growth differentiation factors that normally signal through the ActRIIA/BMP receptor axis. In PAH, this signaling is dysregulated, tipping the balance toward vascular smooth muscle proliferation and away from cell death, which thickens the pulmonary artery walls. By mopping up these ligands, sotatercept restores balance in the signaling pathway, and preclinical work and phase 2 data showed that this reduces vascular proliferation and, over time, remodeling. It is administered by subcutaneous injection every three weeks. Its mechanism is distinct from every existing PAH drug and is characterized by some investigators as potentially disease-modifying.
How the trial was designed
STELLAR was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Investigators enrolled 323 adults with symptomatic WHO group 1 PAH classified as WHO functional class II or III, all on stable background therapy consisting of two or three approved PAH drugs. Participants were randomized 1:1 to receive sotatercept 0.7 mg/kg or placebo every three weeks by subcutaneous injection, added to their existing regimen. The trial was conducted at multiple centers across North America, Europe, and Asia.
The primary endpoint was change from baseline in 6-minute walk distance at week 24. Nine key secondary endpoints included multicomponent improvement (a composite of walk distance, N-terminal pro-B-type natriuretic peptide, and functional class), pulmonary vascular resistance, WHO functional class, and time to clinical worsening or death.
What the trial found
The primary endpoint was met. At 24 weeks, sotatercept improved 6-minute walk distance by 40.8 meters compared with placebo (95% CI, 27.5 to 54.1; P<0.001). Eight of the nine key secondary endpoints also reached statistical significance, including improvements in multicomponent response, pulmonary vascular resistance, N-terminal pro-B-type natriuretic peptide, and WHO functional class. Sotatercept reduced the composite risk of clinical worsening or death by 84% compared with placebo, with a hazard ratio of 0.16 (95% CI, 0.08 to 0.35; P<0.001) over a median follow-up of 32.7 weeks.
The most common adverse events more frequent with sotatercept than placebo were bleeding events, telangiectasia (small dilated blood vessels visible on the skin), increased hemoglobin, thrombocytopenia, increased blood pressure, and dizziness. Treatment-emergent adverse events occurred in 90.8% of the sotatercept group compared with 91.9% on placebo, and severe adverse events were actually less common on sotatercept (12.9% versus 18.1%). No unexpected safety signals emerged.
How the effect size should be read
A 40.8-meter improvement in 6-minute walk distance is clinically meaningful in PAH, where the minimum clinically important difference is estimated at roughly 33 meters. An 84% relative reduction in the composite of clinical worsening or death is a large effect, and it was consistent across pre-specified subgroups. However, STELLAR was neither designed nor powered to test mortality alone, and the median treatment period of roughly 7.5 months is too short to establish the long-term durability of benefit. The trial’s size is also modest relative to trials in more common cardiovascular conditions, reflecting the rarity of PAH.
What the evidence cannot yet answer
STELLAR’s median follow-up of 32.7 weeks is not long enough to demonstrate that sotatercept slows or reverses the underlying vascular remodeling in humans, though preclinical models support this mechanism and imaging substudies are ongoing. Whether the benefit persists over years, whether resistance emerges, and whether sotatercept improves overall survival are questions being addressed in the open-label SOTERIA extension trial and other long-term studies. Trials in earlier disease stages (WHO functional class I patients) and in other pulmonary hypertension groups (WHO groups 2, 3, and 4) are ongoing and may extend the indication, though the current approval is limited to group 1 PAH. Potential unblinding related to visible side effects such as telangiectasia is acknowledged by the trial authors as a limitation of the double-blind design.
What the approval settled
Sotatercept establishes that targeting BMP/activin signaling is a viable therapeutic strategy in PAH. Since STELLAR, some investigators have described the drug as a “fourth pillar” of PAH therapy, alongside the three existing vasodilator classes. Its arrival has renewed interest in other agents that target vascular proliferation and remodeling rather than vessel tone, and multiple such candidates are in earlier stages of development. Sotatercept does not replace current therapies. It is added on top of them, and the STELLAR data show that this combined approach produces improvements across measures that established PAH drugs, used at maximum recommended doses, could not achieve.
The trial authors concluded that “treatment with sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk distance) than placebo” and that sotatercept “had a favorable benefit-risk ratio.” For a disease with limited existing options and persistent progression despite triple therapy, the arrival of a mechanistically distinct addition represents a meaningful expansion of what can be offered to patients.
References
- Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. New England Journal of Medicine, 2023; 388: 1478-1490. DOI: 10.1056/NEJMoa2213558