Novel PAH Drug Shows Promise in Mid-Stage Trial

WASHINGTON — The novel investigational therapy seralutinib effectively reduced pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) on standard background therapies in the TORREY study.

At 24 weeks, PVR significantly decreased with seralutinib — an inhaled drug that targets key pathways in PAH vascular remodeling — with a mean reduction of 14.3% versus placebo (P=0.031), reported Robert Frantz, MD, of the Mayo Clinic in Rochester, Minnesota.

The phase II trial met its primary endpoint of PVR, and subgroup analysis showed the greatest effect in the sickest patients with the highest mortality risk, he said at the annual meeting of the American Thoracic Society.

Franz explained that platelet-derived growth factor receptors (PDGFR), colony stimulating factor 1 receptor (CSF1R), and the c-KIT kinase pathways are key drivers of PAH-related PVR.

Seralutinib was designed as a dry powder inhalation compound therapy to target these dysfunctional pathways.

“When you think about what this compound is doing, and how it really does seem to be targeting activity that is important in the real world of pulmonary vascular disease — and that it is showing a signal of efficacy in a heavily pretreated, heavily prevalent population with a median duration of disease of 8 years — it is actually pretty mind blowing,” Frantz said.

The phase II, placebo-controlled, multicenter TORREY study was designed to examine the safety and efficacy of inhaled seralutinib in heavily treated patients with PAH over 24 weeks. Researchers enrolled 86 patients with World Health Organization (WHO) Functional Class II or III PAH, with 42 patients randomized to the placebo arm and 44 to the seralutinib arm of the study.

All patients remained on standard-of-care PAH background therapies during the trial. At baseline, 57% of patients were on background triple therapy, consisting of three classes of vasodilator treatments.

The primary endpoint was change from baseline to week 24 in PVR by right heart catheterization. For the key secondary endpoint of change in 6-minute walking distance (6MWD) from baseline to week 24, the observed mean difference of 6.5 m “numerically favored the seralutinib arm,” Frantz said.

Enhanced effects for both PVR and 6MWD were observed in patients with more severe baseline disease, as defined by WHO Functional Class and REVEAL 2.0 risk scores.

In WHO Functional Class III patients, a 21% reduction in PVR (P=0.0427) and 37 m improvement in 6MWD (P=0.0476) were observed for the seralutinib-treated group versus the placebo group.

In patients with baseline REVEAL 2.0 risk scores of 6 or greater, a 23% reduction in PVR (P=0.0134) and 22-m improvement in 6MWD (P=0.2482) were observed for the investigational arm.

Seralutinib treatment also resulted in a statistically significant reduction in the right heart stress biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 12 weeks on treatment, increasing to a 408.3 ng/L mean difference versus placebo at week 24 (P=0.0012).

Frantz said this biomarker change was accompanied by clinically relevant and statistically significant changes for seralutinib- versus placebo-treated patients in key assessments of right heart structure and function, including right atrium area and right ventricular free wall strain.

He added that the reduction in PVR combined with a reduction in NT-proBNP and improvement in other markers “indicates that seralutinib is effectively reducing right ventricular afterload and having a beneficial effect on the right heart.”

Mild to moderate cough was the most common adverse event in the seralutinib group.

Based on these results, a phase III trial of seralutinib for PAH is currently in the planning stages, Frantz said.

During a Q&A session following his presentation, he speculated on the treatment of PAH moving forward. “I think the whole [landscape] is going to change, and we are finally going to have drugs that have effects on inflammation and proliferation,” he said.