Inhaled seralutinib lowers pulmonary vascular resistance in adults with PAH over 24 weeks

Key takeaways:

• Among adults with pulmonary arterial hypertension, seralutinib showed more improvement in WHO functional class III and REVEAL 2.0 risk scores of 6 or more.
• The treatment also lowered right ventricular afterload.

WASHINGTON — In adults with pulmonary arterial hypertension, seralutinib reduced pulmonary vascular resistance over 24 weeks, according to a presentation at the American Thoracic Society International Conference.

“Seralutinib, a platelet-derived growth factor, colony-stimulating factor 1R and c-KIT tyrosine kinase inhibitor administered by a dry powder inhaler for deep lung delivery, demonstrated clinical activity and safety in the phase 2 TORREY trial,” Robert P. Frantz, MD, cardiologist and internist at Mayo Clinic, said during the presentation.

In a randomized, double-blind, placebo-controlled multicenter phase 2 study (TORREY), Frantz and colleagues analyzed 86 adults (median age, 48.8 years; 90.7% women; 86% white) with pulmonary arterial hypertension to see if inhaled seralutinib (Gossamer Bio) was safe and effective over 24 weeks.

Compared with their baseline measurements, researchers sought to assess patients’ change in pulmonary vascular resistance (PVR) and change in 6-minute walk distance (6MWD) over the study period. They also looked at NT-proBNP, RH structure and function by echocardiography as exploratory endpoints, as well as pulmonary arterial compliance (PAC) and cardiopulmonary hemodynamic parameters in right heart catheter (RHC) analyses.

For 2 weeks, patients received twice-daily 60 mg, and this dose increased to twice-daily 90 mg based on the patient’s tolerance, according to Frantz.

While most baseline characteristics were similar between those receiving seralutinib (n = 44) and those receiving placebo (n = 42), Frantz pointed out that more patients receiving the drug belonged to WHO functional class II than patients receiving placebo (n = 30; 68.2% vs. n = 20; 47.6%). Idiopathic PAH was the most common PAH classification in both groups, seen in 20 patients in the seralutinib group and 22 patients in the placebo group.

Of the total cohort, baseline PVR was 668.7 dyne*s/cm⁵ and 6MWD was 407.9 m. Additionally, average NT-proBNP of the total patient population was 628.3 ng/L, which Frantz said was elevated.

Frantz also said this cohort of patients was “well treated,” with 57% (n = 49) on three pulmonary hypertension therapies and 44.2% (n = 38) using a parental prostacyclin/prostacyclin receptor agonist as opposed to oral use.

When compared with patients receiving placebo, researchers found that patients receiving seralutinib had lower PVR from baseline to week 24 (14.3%; P = .031). Further, patients receiving seralutinib belonging to WHO functional class III showed a 20.8% decrease in PVR from baseline to week 24 (P = .0427). Lower PVR at week 24 with seralutinib was also found across several subgroups, including PAH background medications, baseline prostacyclin use, age groups younger and older than the median age and 65-year marker, race, region, PVR strata, connective tissue disease and REVEAL 2.0 risk scores, according to the presentation.

When assessing patients based on their REVEAL 2.0 risk score, Frantz pointed out during the presentation that patients with a score of 6 or higher demonstrated greater responses to seralutinib than patients with scores less than 6, “indicating the more sick patients actually had greater response than the less ill,” he said.

In terms of 6MWD, seralutinib did not demonstrate a significant improvement at week 24, but when researchers divided patients according to WHO functional class, they saw that those belonging to functional class III receiving seralutinib had a 37.3 m increase in 6MWD (P = .0476).

“It’s important to mention that this study was not powered for a difference of 6-minute walk, and the 6-minute walk was a little bit longer in this study than some other trials,” Frantz said during the presentation.

Compared with placebo, patients receiving seralutinib had lower NT-proBNP at week 12 (–309.6 ng/L; P = .0116) and at the end of the study period (–408.3 ng/L; P = .0012).

“During the latter 12 weeks of the study, there was worsening in the placebo group with uptrend in NT-proBNP, suggesting seralutinib was doing something to protect those patients from progressing and indeed improving their biomarker for right heart failure,” Frantz said.

With regard to changes in cardiopulmonary hemodynamics, seralutinib showed reduced mean pulmonary arterial pressure (least square mean difference, –4.7 mmHG; P = .0094) and higher pulmonary arterial compliance (least square mean difference, 0.22 mL/mmHg; P = .041) compared with placebo, according to the presentation.

Notably, seralutinib’s PVR and PAC improvements indicate the treatment may be lowering fixed and pulsatile components of right ventricular (RV) afterload, according to the presentation.

Lastly, researchers observed more drug discontinuation due to a treatment-emergent adverse event with seralutinib than with placebo (6 patients vs. 1 patient). The placebo patient discontinued treatment due to an abnormal liver function test, whereas each seralutinib patient discontinued treatment for a different reason, including cough, increased AST/ALT, hemoptysis, dry mouth, lower abdominal pain and increased transaminases, Frantz said during the presentation.

Further, cough occurred the most in both those receiving seralutinib (43.2%) and those receiving placebo (38.1%), and Frantz said this was expected because of the inhaled nature of the therapy.

“The TORREY study met its primary endpoint of reduction of pulmonary vascular resistance in a heavily treated prevalent study population on standard of care background medications,” Frantz said. “In a prespecified subgroup analysis, there was greater benefit in function class III patients and those at higher risk with a REVEAL 2.0 score greater than or equal to 6. Reduction in pulmonary vascular resistance combined with improvement in pulmonary capacities in conjunction with reduction in NT-pro-BNP indicates that seralutinib is effective in reducing RV afterload and having a beneficial effect on the right heart. Accordingly, proof of concept has been well demonstrated in this study and a global registrational phase 3 program in PAH is planned.”

According to Frantz, echocardiographic data from this study will be presented at a future meeting.