Sotatercept to Wean Off Prostacyclin Infusion Therapy for Pulmonary Arterial Hypertension: A Case Report

ABSTRACT

The activin signaling inhibitor sotatercept was approved for Group 1 pulmonary arterial hypertension (PAH) based on Phase 2 and 3 clinical trials showing significant improvements in primary outcomes; reduced pulmonary vascular resistance (PVR) and increased 6‐min walk distance (6MWD), respectively. However, the efficacy and safety of transitioning off background therapies, including infusion prostacyclins, in patients receiving sotatercept are currently unknown. We report here a patient who was enrolled in sotatercept clinical trials (STELLAR/SOTERIA); during this period, he gradually transitioned from intravenous treprostinil. Subjective, physiologic, echocardiographic, and hemodynamic data after 2.5 years without intravenous therapy are presented. These results suggest that weaning off intravenous PGI2 may be feasible in some patients, but questions remain about the durability of the response and possible long‐term adverse side effects.

1.

Sotatercept is a novel fusion molecule that serves as an activin signaling inhibitor and is thought to “rebalance” pro‐proliferative signals in pulmonary arteries, reversing remodeling changes in Group 1 pulmonary arterial hypertension (PAH). Clinical trials of sotatercept have demonstrated significant improvements in pulmonary hemodynamics and functional capacity in patients with functional class II or III PAH taking 2–3 background therapies [1, 2]_. Whether background therapies, especially infusion prostacyclins, can be weaned after initiation of sotatercept is of great interest to patients and their caregivers, but little information is available on this topic. We report here a patient with Group 1 PAH who weaned off high‐dose intravenous (IV) treprostinil (tre) 14 months after initiation of sotatercept and has remained clinically stable for an additional 30 months.

This 56‐year‐old male patient was diagnosed with severe idiopathic PAH in 1997, in the setting of autoimmune hepatitis diagnosed by liver biopsy at age 14. The most recent liver biopsy in 2022 showed Grade 1, Stage 4 cirrhosis, and he does not have portal hypertension. He also has Crohn's disease, treated with Ustekinumab, and moderately severe obstructive sleep apnea (AHI 28.6 from 2023 sleep study). He has been intolerant of CPAP and is not interested in pursuing other therapies. Upon diagnosis of his PAH, he started IV epoprostenol, with an initial dramatic improvement. In 2001, he transitioned to subcutaneous (sq) tre because of the greater convenience (smaller pump, avoidance of central access, easier showers). However, he encountered intolerable site pain requiring narcotic medication for control and after it became commercially available, he gradually transitioned to oral sildenafil monotherapy (50 mg TID), weaning off sq tre entirely in 2006.

He did well subsequently, requiring only twice yearly follow‐up, maintaining functional class (FC) I and 6‐min walk distances (6MWD) in the 600 m range until December 2013, when he developed worsening dyspnea on exertion (DOE), leg edema and exertional syncope over a period of a few weeks and was found to be in right heart failure (Table 1). He resumed tre, this time IV, and right heart failure quickly resolved. He was unable to perform a 6MWD at the time of his right heart catheterization (RHC), but within 3 weeks, he had improved dramatically from FC IV to FC II with a 6MWD back to 610 m^a (Table 1). In March 2014, at his request, he transitioned to oral treprostinil, starting at 7 mg orally TID; this was accompanied by GI side effects and headache. After 9 months, despite aggressive dose titration up to 11 mg TID, the limit of his tolerance, he once again developed right heart failure (Table 1, December 2015). PO tre was transitioned to IV and once again had a dramatic recovery of his 6MWD within several weeks. Over the subsequent years, the treprostinil dose was gradually uptitrated to a dose of 280 ng/kg/min. This unusually high dose was necessitated by repeated worsening of his DOE every few months and prompt improvement with dose increases. He also lost weight from 73 kg in 2015 to 62 kg in 2022. Side effects included bilateral lower leg pain that was not dose‐related, fatigue, and diarrhea (which could also have been related to his underlying Crohn's disease).

Table 1.

Pulmonary hemodynamics from serial right heart catheterizations, functional capacity, and echocardiographic findings.

Parameter	Jan 1998 (diagnosis)	Dec 2013 (follow‐up)	Dec 2015 (follow‐up)	Feb 2022 (STELLAR baseline)	Aug 2022 (STELLAR follow‐up)	Jan 2024 (SOTERIA follow‐up)	Jun–Aug 2024 (SOTERIA follow‐up)	Nov 2024 (SOTERIA follow‐up)
PAH treatment	Naive	Sildenafil	Sildenafil + oral treprostinil	Sildenafil + IV treprostinil	Sildenafil + IV treprostinil + sotatercept	Sildenafil + sotatercept + ambrisentan	Sildenafil + sotatercept + ambrisentan	Sildenafil + sotatercept + ambrisentan
mRAP (mmHg)	8	11	19	3	2	5	NA	7
mPAP (mmHg)	69	72	70	47	31	38	NA	38
PAWP (mmHg)	8	11	15	9	9	13	NA	13
CI (L/min/m²)	2.3	2.54	2.05	3.23	3.37	2.61	NA	4.0
PVR (WU)	14.2	12.7	14.8	6.85	4.91	6.43	NA	3.74
SvO2	NA	NA	45%	67%	70%	69%	NA	72%
NYHA functional class	NA	IVa	IVa	II	II	II	II	II
6MWD (meters)	NA	610a	564a	399b	418b	524	548	NA
RV sizea	NA	Severely dilated	Severely dilated	Severely dilated	Mod. to severely dilated	Moderately dilated	Moderately dilated	NA
RV functiona	NA	Severely reduced	Severely reduced	Severely reduced	Moderately reduced	Mod. to severely reduced	Moderately reduced	NA

Abbreviations: 6MWD (meters) = 6‐min walk distance, BNP (pg/mL) = brain natriuretic peptide, CO (L/min) = cardiac output – measured by thermodilution, CI (L/min/m²) = cardiac index, mRAP (mm Hg) = mean right atrial pressure, mPAP (mm Hg) = mean pulmonary artery pressure, NYHA Functional Class = New York Heart Association Functional Class, PCWP (mm Hg) = pulmonary capillary wedge pressure, PVR (WU) = pulmonary vascular resistance (wood units), RV size = right ventricular size, RV function = right ventricular function, SvO2 = mixed venous O2 saturation obtained from pulmonary artery during right heat catheterization.

^aWhen the subject underwent both of his RHCs while in Right Heart Failure, he was unable to perform 6MWTs. The 6MWD associated with these RHCs occurred several weeks later, when the subject was much improved. Functional Class was II at the time of the 6MWDs. Similarly, echocardiograms were performed up to several weeks apart from their corresponding RHCs, meaning the subject's hemodynamic status may have changed significantly between the echocardiogram and the RHC.

^b6MWD during the Stellar study was limited partly by fatigue and leg pain.

In February 2022, he was enrolled in the STELLAR clinical trial [2]; his baseline right heart catheterization (RHC) revealed that his hemodynamics were much improved since resuming IV treprostinil (Table 1). At the end of the STELLAR study (24 weeks), hemodynamics had further improved (Table 1, August 2022); it was later determined that he had been randomized to the sotatercept arm. He transitioned to the SOTERIA open‐label extension study in August 2022 on a dose of 280 ng/kg/min of treprostinil that had remained stable throughout the STELLAR trial. Because of the marked clinical improvement on sotatercept and the patient's desire to transition off IV treprostinil, in October 2022, he began decreasing the treprostinil dose 8 ng/kg/min each week until stopping it entirely in April 2023. The patient noted that his dyspnea was slightly worse while climbing inclines, but overall, he felt much better, with less fatigue and leg pain, and was able to resume an active lifestyle, including swimming and biking. Concerns about using ambrisentan in a cirrhotic patient and exclusions of clinical trials had delayed our initiation previously, but because of our prior work on ambrisentan in cirrhotics [3], we added it (5 mg daily) in December 2023 to maximize background oral therapy and titrated to 10 mg daily in February 2024. In January 2024, RHC showed a slight increase in mean pulmonary artery pressure (MPAP) and PVR compared to the previous one, but functional class (FC) was stable at II, and 6‐min walk distance improved (Table 1). His most recent right heart catheterization in November 2024 showed an improved cardiac index and PVR (Table 1). As of July 2025, he remains off infusion therapy with a 6MWD of 588 m and FC II. He has also developed new telangiectasias on his trunk and forearms and has had minor epistaxis intermittently.

This case demonstrates that the addition of sotatercept allowed for weaning of IV tre followed by clinical stability for at least 30 months. All previous attempts in this patient at transition from infusion to oral treprostinil had led to the development of right heart failure. After weaning off the treprostinil, he did have a slight worsening of dyspnea on exertion, albeit with an improved 6MWD. He also had a slight increase in MPAP and PVR, the latter likely not important considering that the most recent RHC (Table 1, November 2024) showed that these were transitory. The most recent cardiac echo in August 2024 shows sustained improvement in RV size and function compared with that obtained for the STELLAR baseline (Table 1).

The question must be raised whether the addition of ambrisentan in December 2023 contributed to the patient's stability after weaning off tre. Although adding ambrisentan to sildenafil alone significantly improves pulmonary hemodynamics [4], its addition to sildenafil in combination with sotatercept has not been studied. We think it likely that sotatercept was the greater contributor to improvement, considering the magnitude of the patient's improvement during the STELLAR trial, the lesser improvement in hemodynamics after initiation of ambrisentan, and the fact that the patient deteriorated in the past when switched to oral tre with background sildenafil. Also, the recently reported Zenith trial on prevalent PAH patients with advanced disease (functional class III or IV) showed a very robust response to sotatercept when added to optimal background therapy, including parenteral prostacyclins in 59% and triple therapy (including endothelin receptor antagonists) in 72% [5].

Recently, Ollson et al. [6] reported their experience with 14 patients who were deemed candidates for weaning of tre. Four failed, all of whom recovered after resumption of tre. The 10 successfully weaned remained clinically stable for a median of 12 months. The highest tre dose before weaning was 49 ng/min/kg. Our case demonstrates that sotatercept can allow successful weaning from a prostacyclin infusion in a prevalent patient with a history of severe PAH starting at a much higher tre dose than in the Olsson trial and maintaining clinical stability for 2.5 years. However, the durability and safety of weaning parenteral prostacylins in patients on sotatercept remain unknown. Pending further investigation, weaning of infusion prostacyclins in patients on sotatercept should be undertaken with caution and close monitoring.

Author Contributions

Daniel Strick was the lead author and was responsible for collecting the data, drafting, editing, and submitting the manuscript. Meredith Kaplan assisted in writing, data collection, and manuscript revisions. Dr. Nicholas Hill was the patient's primary pulmonary hypertension physician, provided clinical expertise and served as senior author. Dr. Harrison Farber and Dr. Ioana Preston, who closely collaborated with Dr. Hill in both clinical care and research related to pulmonary hypertension, served as advisors and contributed to manuscript editing. Michael Bennett, the patient, contributed to data gathering and manuscript review for accuracy. All authors reviewed and approved the final version of the manuscript.

Ethics Statement

Institutional review board (IRB) approval was not required for this single‐patient case report.

Consent

Written consent was obtained from the patient for publication of this report.

Conflicts of Interest

Daniel J. Strick: consulting fee/travel reimbursement relationship with Actelion Pharmaceuticals US Inc.

Ioana R. Preston: receives research grants from United Therapeutics, Liquidia, Merck and Janssen, is a consultant for Respira, Merck, Gossamer, Liquidia, United Therapeutics, and Janssen.

Harrison W. Farber: advisory committee member relationship with Actelion; consulting fee/advisory committee member relationship with Atlavant, Acceleron, Aerovate, United Therapeutics, Aerami,; grant/research support/advisory committee member relationship with Acceleron.

Nicholas S. Hill: consulting fee/consultant relationship with 4D medical, Breas, Philips Respironics, Liberate Medical, Inogen and Fisher Paykel; consulting fee/advisory committee member relationship with Inogen, Altavant consulting fee/scientific medical advisor relationship with Liquidia and Aerovate.

The other authors, Meredith A. Kaplan and Michael Bennett, declare no conflicts of interest.

Strick D. J., Kaplan M. A., Bennett M., Preston I.R., Farber H. W., Hill N. S., “Sotatercept to Wean Off Prostacyclin Infusion Therapy for Pulmonary Arterial Hypertension: A Case Report,” Pulmonary Circulation 15 (2025): 1‐4. 10.1002/pul2.70160.