PAH Expert Forum: Sotatercept, De-escalation, and the Limits of Upfront Therapy

Pulmonary arterial hypertension (PAH) management now spans 4 distinct mechanistic pathways — endothelin receptor antagonism, nitric oxide/cyclic GMP augmentation, prostacyclin agonism, and activin signaling inhibition — and the introduction of sotatercept (Winrevair; Merck) as the first agent in the fourth pathway has reshaped clinical thinking around escalation, de-escalation, and what combination therapy can realistically achieve.¹

Pivotal data from the STELLAR trial demonstrated a 34.4-meter improvement in 6-minute walk distance (95% CI, 33.0–35.5 m) and an 84% reduction in time to death or nonfatal clinical worsening in 323 patients with WHO functional class II/III PAH on background dual or triple therapy — 39.9% of whom were receiving parenteral prostacyclin.² The ZENITH trial, published in the New England Journal of Medicine in 2025, extended this evidence to high-risk functional class III/IV patients on maximal background therapy — 59.3% on prostacyclin infusion — and demonstrated a 76% relative risk reduction in a composite of all-cause death, lung transplant, and PAH-related hospitalization (hazard ratio [HR], 0.24; 95% CI, 0.13–0.43; P <.0001); the trial was stopped early for efficacy.³

Despite these advances, important questions about where sotatercept fits in the upfront treatment algorithm, which patients are true hemodynamic responders, and how emerging real-world signals should modify clinical practice remain largely unanswered in the literature.

Against this backdrop, HCPLive convened a panel of pulmonologists and advanced lung disease specialists representing UCLA, Cedars-Sinai Medical Center, and community pulmonology practices in the San Diego Valley for an in-depth roundtable discussion on optimizing PAH management in the current therapeutic era. The forum was moderated by Rajan Saggar, MD, a pulmonologist at UCLA, and included clinicians from nationally recognized PAH centers of excellence, large academic referral programs, and resource-limited community practices to provide a layered view of how clinical evidence is interpreted and implemented across divergent institutional settings. The discussion was structured around 4 areas: initial combination therapy and risk stratification, sotatercept's real-world profile and emerging safety signals, de-escalation philosophy and monitoring, and the systemic barriers to drug access.

The discussion opened with broad agreement that upfront dual oral combination therapy with an ERA and a PDE5 inhibitor remains the standard of care for non-high-risk PAH — a framework that sotatercept has not yet formally displaced despite growing clinical intuition that it may warrant reconsideration. Saggar, MD, referenced a published Italian multicenter analysis of 181 treatment-naive PAH patients in which approximately one-third failed to achieve a PVR reduction greater than 25% at 6-month follow-up right heart catheterization after initiating ERA plus PDE5i — raising the question of whether the current upfront paradigm is adequate for a meaningful proportion of patients.⁴ Risk stratification tools — including REVEAL 2.0, COMPERA, and the ESC/ERS 3- and 4-strata models — were discussed as valuable but imperfect, particularly given the absence of echocardiographic RV parameters from most validated scoring systems.¹ One panelist noted that patients can score as low-risk by REVEAL yet present with markedly compromised RV morphology on echo — a discordance that can lead to undertriage. The panel broadly agreed that any validated risk tool applied consistently has value, and that the decision between dual and triple upfront therapy in intermediate-to-high risk patients ultimately comes down to available resources, severity of presentation, and patient tolerance — not the specific risk instrument used.

The panel's discussion of sotatercept's real-world profile surfaced several clinically important observations that have not yet been fully described in published trial data. Erythrocytosis was the most commonly discussed hematologic effect: the average hemoglobin increase of 2 to 3 g/dL was acknowledged as modest, though the UCLA program has set a cutoff of 20 g/dL and Cedars-Sinai at 22 g/dL, with hyperviscosity symptoms described as subtle and infrequent in practice at these thresholds. A more notable emerging signal was iron depletion following sotatercept initiation. Multiple panelists had independently observed patients developing iron deficiency — with or without anemia — after starting the drug, in the absence of other apparent causes. The hypothesized mechanism involves erythropoiesis-driven iron consumption, possibly at the level of hepatocyte-based iron absorption, though this remains under investigation. The UCLA team has incorporated prospective iron monitoring — at baseline and every 3 months — into their sotatercept workflow, and while the signal has appeared in a handful of poster presentations, it has not yet been well characterized in the peer-reviewed literature.

One panelist observed during the discussion: "I've had a few patients who start with normal iron stores and then they drop after starting sotatercept. And I actually don't think that's been reported in the literature." The panel also described a striking subset of hyper-responders — patients who, after sotatercept initiation, demonstrate near-normalization of RV appearance on echocardiography — an outcome that the moderator characterized as "crazy" relative to what he expected from prior PAH therapies.

Insurance prior authorization emerged as the single most consequential systemic barrier to optimal care, with the experience of near-reflexive denial for macitentan/tadalafil fixed-dose combination (Opsynvi) by most insurers on first submission — Blue Shield specifically named — described as practice-destabilizing. Another panelist, whose community practice operates without a dedicated pharmacist or coordinator, described the burden of filling prior authorization paperwork, educating staff who must do it, and managing appeals as disproportionate to an internist-pulmonologist functioning as sole PAH provider in a resource-limited setting.

The panel endorsed AI-generated prior authorization appeal letters incorporating RHC data and step-therapy failure history as an effective and time-saving workaround, with generic tadalafil via GoodRx or Mark Cuban's Cost Plus Drugs (~$20–30 for 60 tablets) cited as a practical bridge while appeals are processed. At least one panelist recounted a case in which a patient died while tadalafil approval was pending because the insurer required right heart catheterization data the patient was physically unable to undergo — a case that drew immediate concern from the group and that underscored the clinical stakes of administrative delay. For sotatercept specifically, Merck's patient assistance program was noted as activatable after 2 insurance denials, though at least one case was described in which both insurance and manufacturer assistance were simultaneously denied, leaving a patient without access to a drug to which she had been responding well.

References

1. Humbert M, Kovacs G, Hoeper MM, et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618–3731. doi:10.1093/eurheartj/ehac237

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. Ghio S, Pazzano AS, Klersy C, et al; iPHNET Investigators. Risk reduction and hemodynamics with initial combination therapy in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2021;203(4):484–492. doi:10.1164/rccm.202004-1006OC