Vallerie McLaughlin, MD, is a professor of medicine and director of the Pulmonary Hypertension Program in the Division of Cardiovascular Medicine at the University of Michigan.

Vallerie McLaughlin, MD

Ralinepag Achieves 55% Risk Reduction in PAH, With Vallerie McLaughlin, MD

Data from the phase 3 ADVANCE OUTCOMES trial presented at the 

American Thoracic Society (ATS) 2026 International Conference

 in Orlando, Florida, suggest ralinepag, an investigational once-daily oral prostacyclin receptor agonist, significantly reduced the risk of clinical worsening in patients with 

, including a largely pretreated population already receiving background combination therapy.

The event-driven, randomized, double-blind study enrolled 687 patients with PAH and evaluated ralinepag versus placebo on top of standard of care. Ralinepag achieved a 55% reduction in risk of adjudicated clinical worsening events compared with placebo (hazard ratio [HR], 0.45; 95% CI, 0.33 to 0.62; P <.0001).

“Ralinepag is highly potent. It's probably more potent than the currently available agents, and it's a once-daily agent, as opposed to twice daily,” Vallerie V. McLaughlin, MD, professor of cardiovascular medicine and director of the pulmonary hypertension program at the University of Michigan, said in an interview at ATS 2026. “We’re hoping that it would get higher levels of prostacyclin agonism in a patient and be potentially more effective.”

McLaughlin noted that prostacyclin pathway therapies remain foundational in PAH management, but clinical use has long been limited by tolerability and the need for careful dose adjustment. She described ralinepag as a potentially more patient-friendly approach that may allow for more effective prostacyclin pathway activation while maintaining individualized dosing strategies similar to existing clinical practice.

In addition to the primary endpoint, ralinepag demonstrated statistically significant improvements in key secondary outcomes. Investigators reported reductions in NT-proBNP levels from baseline to week 28 (24.3% reduction over placebo; 

 =.0013) and improvements in 6-minute walk distance (6MWD) (+20.4 m placebo-corrected difference; 

 =.0033). Additionally, ralinepag increased the odds of achieving clinical improvement by 47% (

The trial population included a high proportion of patients on background therapy, with many already receiving dual oral agents (80%). Despite this, ralinepag demonstrated benefit across multiple measures of disease progression, including time to hospitalization and other components of clinical worsening, suggesting additive efficacy in contemporary combination regimens.

McLaughlin emphasized that these findings may have implications for treatment sequencing in PAH, particularly as clinicians increasingly escalate therapy earlier in the disease course. She suggested that once approved, a once-daily oral prostacyclin receptor agonist could be integrated as an additional option for patients already receiving endothelin receptor antagonists and phosphodiesterase type 5 inhibitors, potentially as a third- or later-line therapy depending on risk profile and disease trajectory.

The ADVANCE OUTCOMES study also included individualized dose titration without a ceiling, reflecting real-world prostacyclin management principles. McLaughlin indicated that this approach helps balance disease symptoms with medication adverse events.

From a safety standpoint, findings were consistent with the known prostacyclin class profile, with no new safety signals identified. Adverse events were generally consistent with vasodilatory effects, and discontinuation rates were in line with expectations for this therapeutic class.

United Therapeutics plans on submitting a new drug application for ralinepag to treat PAH to the US Food & Drug Administration by the second half of 2026.

McLaughlin V, Ataya A, Albert J, et al. (

) ADVANCE Outcomes: A Phase 3, Randomized Clinical Trial Evaluating Ralinepag for Pulmonary Arterial Hypertension. Poster presented at ATS 2026 in Orlando, Florida, on May 20.

United Therapeutics Corporation Announces ADVANCE OUTCOMES Study of Ralinepag Presented at ATS 2026. Unither.com. Published 2026. Accessed May 20, 2026. 

https://ir.unither.com/press-releases/2026/05-17-2026-191518923

Videos

At ATS 2026, Vallerie McLaughlin, MD discusses ADVANCE OUTCOMES showing ralinepag reduced PAH clinical worsening risk by 55% in pretreated patients.

Sotatercept Improves Composite Mortality Endpoint in Patients With PAH, With Vallerie McLaughlin, MD

Sotatercept has significantly improved a composite endpoint of mortality and major morbidity outcomes, transplant-free survival, and overall survival in patients with 

 WHO functional class (FC) II-IV, based on a pooled analysis of the PULSAR, STELLAR, and ZENITH trials.

American Heart Association’s Scientific Sessions 2025

, in New Orleans, Louisiana, by lead study author Vallerie McLaughlin, MD, Kim A. Eagle MD Endowed Professor of Cardiovascular Medicine at the University of Michigan Medical School.

Sotatercept, a novel, first-in-class fusion protein, rebalances pulmonary vascular homeostasis towards growth-inhibiting and proapoptotic signaling by inhibiting ligands in the TGF-β superfamily. In PULSAR, STELLAR, and ZENITH, all of which were double-blind, placebo-controlled trials, sotatercept demonstrated its efficacy and a manageable safety profile in patients with PAH.

 spoke with McLaughlin to discuss the implications of these findings for PAH treatment on a larger scale.

“We pulled patients from 3 different trials to look at those 3 hard endpoints of death, lung transplantation, and PAH-related hospitalization, so that we have a larger number of patients and events to evaluate,” McLaughlin told 

. “And the results we found were very consistent.”

The phase 3 ZENITH trial investigated sotatercept when added to maximum tolerated background therapy, with primary endpoints of time to first event of all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours. It ultimately enrolled 173 participants, who were randomly assigned in a 1:1 ratio to either sotatercept at a starting dose of 0.3 mg/kg and a target dose of 0.7 mg/kg or placebo, both of which were administered subcutaneously every 21 days for 24 weeks.

The phase 3 STELLAR study investigated a similar population, with a primary outcome of exercise capacity as measured by the 6-minute walk distance. This measurement was taken at 24 weeks following treatment initiation. A total of 324 patients with PAH were included and were then randomized to either sotatercept 0.7 mg/kg subcutaneously once every 3 weeks or placebo.

Finally, the phase 2 PULSAR trial followed 106 patients with PAH of WHO FC II-III, who were randomly assigned in a 3:3:4 ratio to either placebo, sotatercept 0.3 mg/kg, or sotatercept 0.7 mg/kg subcutaneously every 21 days. Endpoints included changes in pulmonary vascular resistance, 6-minute walk distance, and echocardiographic parameters.

Following positive results from all 3 trials, McLaughlin and colleagues pooled data from patients receiving background therapy who were randomized to either sotatercept or placebo. The post-hoc analysis included the following endpoints: time to first morbidity event (including lung transplantation, PAH worsening-related hospitalization, and all-cause death), transplant-free survival, and overall survival.

A total of 323 patients who had received sotatercept and 278 patients who had received placebo were included in the analysis. Baseline characteristics were largely comparable, with investigators noting long-standing PAH as a significant commonality. When compared with placebo, the team found that sotatercept significantly reduced the risk of a first morbidity-mortality event (HR, 0.25; 95% CI, 0.16-0.4; 

 <.0001); a total of 25 patients experienced ≥1 event with sotatercept versus 68 patients with placebo.

Similarly, sotatercept improved transplant-free survival (HR, 0.44; 95% CI, 0.24-0.83; 

 = .005), wherein 16 patients with sotatercept and 27 patients with placebo experienced ≥1 event, and improved overall survival (HR, 0.49; 95% CI, 0.25-0.98; 

 = .0019), which saw 14 patients receiving sotatercept and 21 receiving placebo experience ≥1 event. Additionally, investigators highlighted all 3 Kaplan-Meier curves demonstrating clear separation between treatment arms by 3-6 months.

“The curves separating early and maintaining their separation really gives the sense that this drug is doing something to alter the course of the disease,” McLaughlin said. “Disease modification is a challenging term that means different things to different people, but I think what I feel comfortable saying is that it does alter the outcomes in patients with this very deadly disease.”

Editor's Note: McLaughlin reports disclosures with Janssen, Merck, Sonovie, Gossamer-Bio, Keros, Aerovate, and others.

McLaughlin V, Badesch D, Ghofrani AH, et al. Effect of Sotatercept on Mortality and Major Morbidity Outcomes in Patients with Pulmonary Arterial Hypertension: Pooled Analysis of the PULSAR, STELLAR, and ZENITH Trials. Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10, 2025.

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(16):1478-1490. 

Acceleron Pharma, Inc. A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) (ZENITH). ClinicalTrials.gov identifier: NCT04896008. Updated August 22, 2025. Accessed November 10, 2025. 

https://www.clinicaltrials.gov/study/NCT04896008

Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021;384(13):1204-1215.

Acceleron Pharma, Inc. A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/A011-11) (STELLAR). ClinicalTrials.gov identifier: NCT04576988. Updated September 19, 2024. Accessed November 10, 2025. 

https://clinicaltrials.gov/study/NCT04576988

McLaughlin discussed the previous ZENITH, PULSAR, and STELLAR trials, and how this pooled cohort analysis emphasizes sotatercept’s impressive efficacy.

Sotatercept could be a life-saving therapy for high-risk patients with pulmonary arterial hypertension (PAH), according to the ZENITH trial.

Approved in 2024 based on the STELLAR trial, which demonstrated its effects on exercise capacity, the ZENITH trial details statistically significant 76% reduction in relative risk for the primary outcome of all-cause mortality, lung transplantation, or hospitalization for worsening PAH.

“The ZENITH study represents the first PAH clinical trial with a primary endpoint comprised entirely of major outcome measures – all-cause death, lung transplantation and hospitalization for PAH,” said Marc Humbert, MD, PhD, Department of Respiratory and Intensive Care Medicine Hospital Bicêtre (AP-HP), University Paris-Saclay and Inserm Unit 999.

American College of Cardiology (ACC) 2025 Annual Scientific Sessions

, the phase 3 ZENITH trial evaluated the efficacy of sotatercept as an add-on therapy for patients with PAH at high risk of death. Per trial protocol, all 172 participants were receiving the maximum tolerated dose of background therapy and were randomly assigned to receive sotatercept at starting dose of 0.3 mg/kg that was escalated to 0.7 mg/kg or placebo every 3 weeks.

The primary outcome of interest was a composite of all-cause mortality, lung transplantation, or hospitalization for worsening PAH, assessed using a time-to-first-event analysis. The trial was terminated early due to the efficacy findings from a prespecified interim analysis.

Data from ACC.25 suggested at least 1 primary endpoint event occurred among 17.4% of patients in the sotatercept group compared to 54.7% among the placebo group (Hazard Ratio [HR], 0.24; 95% CI, 0.13 to 0.43; 

<.001). When examining individual components of the outcome, investigators found death from any cause was reported in 8.1% of the sotatercept group and 15.1% of the placebo group (HR, 0.42; 95% CI, 0.17 to 1.07). Investigators noted this did not meet the criterion for significance at the interim analysis, which had a required 

 value less than .0021, and was not tested in subsequent secondary outcomes.

Investigators also pointed out use of sotatercept was associated with a reduction in risk for lung transplantation (1.2% and 7.0%; HR, 0.34; 95% CI, 0.15 to 0.78) and hospitalization for worsening PAH (9.3% vs. 50.0%).

For more on these results and how they inform the potential of sotatercept, check out our interview from ACC.25 with study investigator Vallerie McLaughlin, MD, professor of medicine and director of the Pulmonary Hypertension Program in the Division of Cardiovascular Medicine at the University of Michigan.

ZENITH Shows Sotatercept Reduces Mortality, Risk of Transplant in PAH, with Vallerie Mclaughlin, MD

Relevant disclosures for McLaughlin include Bayer, Merck, Janssen Pharmaceuticals, Corvista, and others.

Humbert M, McLaughlin VL, Badesch DB. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. 

 (sotatercept-csrk) Reduced the Risk of a Composite of All-Cause Death, Lung Transplantation and Hospitalization for Pulmonary Arterial Hypertension (PAH) by 76% Compared to Placebo in the Phase 3 ZENITH Trial - Merck.com. Merck.com. Published March 31, 2025. Accessed April 1, 2025. 

https://www.merck.com/news/winrevair-sotatercept-csrk-reduced-the-risk-of-a-composite-of-all-cause-death-lung-transplantation-and-hospitalization-for-pulmonary-arterial-hypertension-pah-by-76-compared-to-placebo-i

Vallerie Mclaughlin, MD, discusses the ZENITH trial and its historic effects of sotatercept on mortality, transplant risk, and more in PAH.

Vallerie McLaughlin, MD

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