Sotatercept, De-escalation, and Systemic Barriers: A PAH Expert Forum

The treatment of pulmonary arterial hypertension (PAH) has undergone a fundamental transformation over the past 4 decades, from a condition with median survival of approximately 2.8 years from diagnosis — established by the landmark 1984 NIH registry — to 1 managed with multi-pathway combination regimens capable of substantially improving hemodynamics and functional outcomes.¹

The approval of sotatercept (Winrevair; Merck) by the US Food and Drug Administration in March 2024 marked the introduction of the first activin signaling inhibitor in PAH, representing a mechanistically distinct fourth pathway beyond the prostacyclin, endothelin receptor antagonist, and nitric oxide/cyclic GMP axes that have defined therapy for decades. Pivotal data from the STELLAR trial, published in the New England Journal of Medicine in 2023, demonstrated statistically significant improvements in 6-minute walk distance, functional class, and a composite of worsening events — including an 84% risk reduction versus placebo — in 323 patients on background dual or triple therapy.² The subsequent phase 3 ZENITH trial, also published in the New England Journal of Medicine in 2025, evaluated sotatercept in WHO functional class III/IV patients on maximal background therapy and showed a 76% reduction in the composite of all-cause death, transplant, and PAH-related hospitalization; the trial was stopped early for efficacy.³ The HYPERION trial, published later in 2025, further demonstrated significant reductions in clinical worsening events in patients with PAH diagnosed within the first year, extending the evidence base to earlier disease.⁴

Against this backdrop, HCPLive convened a panel of pulmonologists and advanced lung disease specialists from Inova Fairfax Hospital and Howard University Hospital for an in-depth roundtable discussion on overcoming barriers to optimal PAH care. The forum was moderated by Vik Khangoora, MD, a pulmonologist and critical care physician at Inova Fairfax, and included advanced lung disease specialists alongside general pulmonologists and critical care clinicians from both institutions. The composition of the panel — spanning a referral center of excellence, community-connected pulmonology, and inpatient critical care — allowed for a wide-ranging discussion bridging clinical trial data with the administrative and logistical realities of prescribing PAH therapy in an insurance-constrained environment. The discussion was structured around 4 primary domains: initial therapy selection and risk stratification, prostacyclin escalation and de-escalation in the sotatercept era, monitoring and composite endpoints, and systemic barriers to optimal care.

"I tend to like to be aggressive up front and rather step down then have to step up... get them on parenteral prostacyclin, reassess risk, get them on maybe convert to the Orenitram or Uptravi other than being stuck on the parenteral prostacyclin,” one panelist said.

The forum reached broad consensus that sotatercept has meaningfully shifted prescribing behavior for escalation therapy. Most panelists indicated they now reach for Winrevair ahead of inhaled or oral prostacyclins in intermediate-high-risk patients on dual therapy, driven primarily by STELLAR and ZENITH efficacy data and the practical appeal of a bimonthly subcutaneous injection over four-times-daily inhaled treprostinil.²,³ Several panelists described an aggressive upfront approach in high-risk patients — initiating parenteral prostacyclins followed by sotatercept addition — with an explicit goal of subsequent de-escalation once hemodynamics improve, a strategy that remains without prospective validation. Risk stratification was described as a multimodal, every-visit exercise, with most panelists relying on whichever validated tool — REVEAL 2.0, REVEAL Lite, COMPERA, or the ESC/ERS 3- or 4-Strata model — showed the worse risk, and maintaining a low threshold for repeat right heart catheterization when clinical and objective data were discordant. Khangoora raised real-world safety signals not yet reflected in trial publications — specifically pericardial effusions and non-reversing pulmonary shunting associated with sotatercept in routine practice — and the panel debated whether the availability of Winrevair is inadvertently delaying transplant evaluation in patients who should be referred sooner, an unintended consequence no trial has yet examined.

Insurance coverage was identified as the most significant systemic barrier to optimal PAH care, with prior authorization denials for sotatercept and inhaled treprostinil (Yutrepia) described as increasingly common; peer-to-peer physician review was cited as the most reliable mechanism for overturning them. Medication adherence was flagged as a greater challenge than clinical intuition might suggest: a meta-analysis of 14 studies encompassing more than 14,000 patients found approximately 60.9% (95% CI, 52.3%–69.1%) of patients with PAH met adherence criteria, with a discontinuation rate of 42.3%.⁵ Non-persistence carries measurable consequences — a retrospective cohort study found nonadherence to PDE5 inhibitors was associated with more than double the risk of mortality (hazard ratio [HR], 2.33; 95% CI, 1.79–3.03; P <.001), with an even greater risk for ERA nonadherence (HR, 5.43; 95% CI, 3.33–8.85; P <.001).⁶ The panel proposed pharmacist-led check-in models and industry nursing support programs as underutilized mechanisms for improving persistence. A well-documented diagnostic delay adds further urgency to these concerns: nationwide US data have shown a median time from symptom onset to PAH diagnosis exceeding 2 years, with symptoms frequently attributed to asthma or deconditioning in primary care settings.⁷ Evidence gaps highlighted for future research included de-escalation outcomes after prostacyclin-to-oral therapy transition, endothelin receptor antagonist use in mixed-group PAH with concurrent interstitial lung disease or sarcoidosis, dose equivalency formulas for same-class prostacyclin switches, and the role of four-strata versus three-strata risk assessment at treatment initiation.

References

1. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991;115(5):343–349. doi:10.7326/0003-4819-115-5-343

2. Hoeper MM, Badesch DB, Ghofrani HA, et al; STELLAR Trial Investigators. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478–1490. doi:10.1056/NEJMoa2213558

3. Humbert M, McLaughlin VV, Badesch DB, et al; ZENITH Trial Investigators. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med. 2025;392(20):1987–2000. doi:10.1056/NEJMoa2415160

4. McLaughlin VV, Hoeper MM, Badesch DB, et al; HYPERION Trial Investigators. Sotatercept for pulmonary arterial hypertension within the first year after diagnosis. N Engl J Med. 2025;393(16):1599–1611. doi:10.1056/NEJMoa2508170

5. Raina A, DeTurk WE, Walpole SC, et al. Real-world adherence and persistence of upfront therapy in patients with pulmonary arterial hypertension in the United States. Pulm Ther. 2025. doi:10.1007/s41030-025-00311-4

6. [Author TK]. PAH medication nonadherence linked to worse outcomes, higher mortality. Respir Med. 2026 [full citation pending final PubMed indexing; findings reported by Pulmonology Advisor, February 2026; Komodo Research Database claims cohort, 2017–2022].

7. Nair A, Sherif M, Bhagat A, Duggal A. Time to diagnosis of pulmonary hypertension and diagnostic burden: a retrospective analysis of nationwide US healthcare data. Pulm Circ. Published online January 6, 2023. doi:10.1002/pul2.12188