Right Ventricular Compensation With Sotatercept: A Prospective Single Arm Open Label Phase 4 Study to Evaluate the Effects of Sotatercept on Right Ventricular Function in Pulmonary Arterial Hypertension (RECOMPENSE)

Summary

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodelling resulting in elevated pressures in the pulmonary artery (PA). This elevated pressure ultimately leads to fulminant right heart failure. Current therapeutic options are limited and are centred around vasodilatory medications such as phosphodiesterase-5 inhibitors and prostacyclin. While these medications allow for the widening of blood vessels that are narrowed due to remodelling, they have no effect on the remodelling itself. Sotatercept is a novel medication which targets the BMPR2/TGF-β pathway and restore a pro- and anti- proliferative balance to ultimately counteract vascular remodelling. Recent phase 2 and 3 trials showed that treatment with sotatercept led to lower resistance and pressure in the pulmonary vasculature and improved exercise tolerance. However, these results were not coupled with an increase in cardiac output, a change that is seen with other PAH-medications with a primarily vasodilatory effect. These results suggest that cardiac work is reduced and cardiac efficiency is improved in patients being treated with sotatercept, in contrast with conventional PAH therapies. This is a potentially beneficial effect that may result in improved disease control in the long-term. Our study aims to explore the effect of sotatercept on cardiac work and function. We hypothesize that the effects of sotatercept are more beneficial for cardiac function than that of traditional PAH medications. All participants included in the trial will undergo a screening visit in which it will be checked that all inclusion criteria and no exclusion criteria are met. The screening visit involves a physical exam, blood draw, 6-minute walk test, right heart catheterization (RHC) and cardiac magnetic resonance imaging (cMRI) with contrast to assess fibrosis. Upon inclusion, all participants will receive a subcutaneous injection of sotatercept starting at a dose of 0.3 mg/kg. Participants will return to the hospital every three weeks for a blood draw, physical examination and an adverse event review. If the laboratory values (specifically haemoglobin and platelet counts) stay stable after the first dose, the dosage will be escalated to 0.7 mg/kg. The dose will not be escalated beyond 0.7 mg/kg. After 24 weeks of receiving sotatercept, there will be an end of treatment visit including a physical exam, 6-minute walk test, right heart catheterization (RHC) and cardiac magnetic resonance imaging (cMRI) with contrast material.

Timeline

Start

2025-05-14

Primary completion

2026-05-01

Completion

2026-05-01

Publications

• Background Vonk Noordegraaf A, Westerhof BE, Westerhof N. The Relationship Between the Right Ventricle and its Load in Pulmonary Hypertension. J Am Coll Cardiol. 2017 Jan 17;69(2):236-243. doi: 10.1016/j.jacc.2016.10.047.
• Background Sniderman AD, Fitchett DH. Vasodilators and pulmonary arterial hypertension: the paradox of therapeutic success and clinical failure. Int J Cardiol. 1988 Aug;20(2):173-81. doi: 10.1016/0167-5273(88)90261-6. No abstract available.
• Background Joshi SR, Liu J, Bloom T, Karaca Atabay E, Kuo TH, Lee M, Belcheva E, Spaits M, Grenha R, Maguire MC, Frost JL, Wang K, Briscoe SD, Alexander MJ, Herrin BR, Castonguay R, Pearsall RS, Andre P, Yu PB, Kumar R, Li G. Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension. Sci Rep. 2022 May 12;12(1):7803. doi: 10.1038/s41598-022-11435-x.
• Background Gomberg-Maitland M, McLaughlin VV, Badesch DB, Ghofrani HA, Hoeper MM, Humbert M, Preston IR, Souza R, Waxman AB, de Oliveira Pena J, Lu JT, Manimaran S, Gibbs JSR. Long-Term Effects of Sotatercept on Right Ventricular Function: Results From the PULSAR Study. JACC Heart Fail. 2023 Oct;11(10):1457-1459. doi: 10.1016/j.jchf.2023.05.030. Epub 2023 Jul 12. No abstract available.
• Background Souza R, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Waxman AB, Grunig E, Kopec G, Meyer G, Olsson KM, Rosenkranz S, Lin J, Johnson-Levonas AO, de Oliveira Pena J, Humbert M, Hoeper MM. Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial. Eur Respir J. 2023 Sep 21;62(3):2301107. doi: 10.1183/13993003.01107-2023. Print 2023 Sep.
• Background Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Souza R, Waxman AB, Grunig E, Kopec G, Meyer G, Olsson KM, Rosenkranz S, Xu Y, Miller B, Fowler M, Butler J, Koglin J, de Oliveira Pena J, Humbert M; STELLAR Trial Investigators. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023 Apr 20;388(16):1478-1490. doi: 10.1056/NEJMoa2213558. Epub 2023 Mar 6.
• Background Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman AB, Ghofrani HA, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, de Oliveira Pena J, Badesch DB. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur Respir J. 2023 Jan 6;61(1):2201347. doi: 10.1183/13993003.01347-2022. Print 2023 Jan.
• Background Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman A, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, Barnes J, Linde PG, de Oliveira Pena J, Badesch DB; PULSAR Trial Investigators. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021 Apr 1;384(13):1204-1215. doi: 10.1056/NEJMoa2024277.
• Background Handoko ML, de Man FS, Allaart CP, Paulus WJ, Westerhof N, Vonk-Noordegraaf A. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. Eur Respir Rev. 2010 Mar;19(115):72-82. doi: 10.1183/09059180.00007109.
• Background Messroghli DR, Radjenovic A, Kozerke S, Higgins DM, Sivananthan MU, Ridgway JP. Modified Look-Locker inversion recovery (MOLLI) for high-resolution T1 mapping of the heart. Magn Reson Med. 2004 Jul;52(1):141-6. doi: 10.1002/mrm.20110.
• Background Waxman AB, Systrom DM, Manimaran S, de Oliveira Pena J, Lu J, Rischard FP. SPECTRA Phase 2b Study: Impact of Sotatercept on Exercise Tolerance and Right Ventricular Function in Pulmonary Arterial Hypertension. Circ Heart Fail. 2024 May;17(5):e011227. doi: 10.1161/CIRCHEARTFAILURE.123.011227. Epub 2024 Apr 4.

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Indications