Seralutinib for the Treatment of Pulmonary Arterial Hypertension in Adults: TORREY Open-Label Extension Study

Seralutinib is an inhaled tyrosine kinase inhibitor targeting platelet-derived growth factor receptor (PDGFR) α/β, colony stimulating factor 1 receptor (CSF1R), and mast/stem cell growth factor receptor kit (c-KIT) kinases. TORREY, a phase 2, double-blind, randomized, placebo-controlled study of seralutinib in pulmonary arterial hypertension (PAH), met its primary endpoint, demonstrating a significant reduction in pulmonary vascular resistance (PVR) over placebo after 24 weeks (NCT04456998; EudraCT 2019-002669-37). We present results (as of December 5, 2024) from an open-label extension (OLE) study evaluating long-term safety, tolerability, and efficacy of seralutinib in adults with PAH (NCT04816604). Seventy-three of 80 patients who completed TORREY (WHO Group 1 PH on stable PAH medications) and 1/8 patients from a phase 1b study (NCT03926793) enrolled in the OLE. The study design called for dosing of inhaled seralutinib 90 mg twice daily. Treatment-emergent adverse events (TEAEs) were monitored. PVR was measured after 48 weeks (week 72 from TORREY baseline). Analyses are descriptive. At OLE entry, 34 patients continued on seralutinib (Seralutinib Continued); 40 switched from placebo to seralutinib (Placebo Crossover). Common TEAEs were headache (28.4%), coronavirus disease (COVID-19) (27.0%), and cough (23.0%). TEAEs led to seralutinib discontinuation in 20 (27.0%) patients; cough was the reason in 9/74 (12.2%). In the Seralutinib Continued group, median change in PVR from TORREY baseline to weeks 24 and 72 was − 94 dyne·s/cm5 and − 143 dyne·s/cm5, respectively (n = 28). In the Placebo Crossover group, corresponding values were − 32 dyne·s/cm5 and − 56 dyne·s/cm5, respectively (n = 27). Continued improvement in 6-min walk distance was observed. N-terminal pro-brain natriuretic peptide (NT-proBNP) significantly decreased with seralutinib during TORREY and remained stable throughout the OLE. After an increase in TORREY, NT-proBNP levels in the Placebo Crossover group nearly returned to TORREY baseline at week 72. These OLE data are consistent with TORREY results and support long-term safety and efficacy of inhaled seralutinib in patients with PAH. A phase 3 study of seralutinib in PAH is underway (PROSERA, NCT05934526). ClinicalTrials.gov identifier NCT04816604. A Graphical Abstract is available for this article. Pulmonary arterial hypertension is a progressive disease that causes small blood vessels in the lungs to get thicker and stiffer, making it harder for the heart to pump blood to the lungs. The phase 2 TORREY study compared inhaled seralutinib to placebo in 86 participants, showing that seralutinib reduced the pressure in blood vessels in the lungs better than placebo. This result was enhanced in participants with more severe symptoms. Seralutinib also made it easier to perform everyday activities, like walking, in patients with more symptoms. Mild-to-moderate cough was a common side effect, occurring with similar frequency in seralutinib and placebo treatment groups. In this article, we report results of an ongoing open-label extension study in which 74 patients (who participated in the TORREY study or an earlier study, collectively called the “parent studies”) received seralutinib for an extended period of time. The open-label extension looked at side effects as well as measures of improvement such as pressure in blood vessels in the lung and exercise capacity (using the 6-min walk test). Seralutinib was well tolerated. Ongoing improvements in lung blood vessel pressure and exercise capacity were observed. Because of these findings, a larger phase 3 study (PROSERA, NCT05934526) is currently underway.