Seralutinib did improve 6-minute walk times and biomarkers, especially in patients with higher-risk disease.
Topline data from the phase 3 PROSERA trial indicate that seralutinib, an investigational inhaled tyrosine kinase inhibitor, did not meet its prespecified primary efficacy threshold in
“While we are disappointed to have narrowly missed the stringent prespecified statistical threshold for our primary endpoint, the result still clears the traditional 0.05 p-value, and we believe these data clearly demonstrate seralutinib is an active drug in patients with PAH,” Faheem Hasnain, Chairman, Co-Founder, and CEO of Gossamer Bio, said in a statement.1
According to Gossamer Bio, the randomized, double-blind, placebo-controlled PROSERA study enrolled 390 patients with World Health Organization (WHO) functional class II or III PAH receiving background therapy.¹ Patients were randomized to seralutinib (n = 197) or placebo (n = 193) for up to 48 weeks. At week 24, the placebo-adjusted Hodges-Lehmann median difference in 6MWD was +13.3 meters (P = .0320), which did not meet the prespecified alpha threshold of 0.025 for the primary endpoint.¹ Because the primary endpoint was not met at the adjusted alpha level, secondary endpoint p values are considered nominal.
Median change from baseline in 6MWD was +28.2 meters in the seralutinib group and +13.5 meters in the placebo group at week 24.¹ In prespecified patients with intermediate- and high-risk PAH (REVEAL Lite 2 score ≥6; n = 234), the placebo-adjusted improvement was +20.0 meters (P = .0207), an efficacy signal that was consistent with data seen from the phase 2 TORREY trial.1,2 Changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) at week 24 favored seralutinib (estimated location shift −120.4 ng/L; P = .0002), and other secondary measures—including clinical improvement and ≥1-point REVEAL Lite 2 score reduction—also numerically favored active treatment.¹ Time-to-clinical worsening hazard ratio was 0.744 (P = .4360).¹
“We are also pleased by the clinically meaningful improvements observed in intermediate- and high-risk patients who are at an increased risk of significant morbidity and mortality events and represent a population with a high unmet need. From a clinical development perspective, this is not a narrow or exploratory finding. Seralutinib has once again demonstrated a statistically robust and clinically meaningful signal in higher‑risk patients, consistent with the TORREY Study, which is a clearly defined and readily identifiable population. This finding is compelling on its own,” Hasnain said.1
Seralutinib is an inhaled inhibitor of platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R), and c-KIT, pathways implicated in vascular proliferation and remodeling.2 Unlike established PAH therapies, which primarily target vasodilation, seralutinib is designed to address proliferative and inflammatory mechanisms. Phase 2 data from the TORREY study previously demonstrated improvements in pulmonary vascular resistance and exploratory clinical endpoints which supported advancement to phase 3 evaluation.
Drug: Seralutinib
Class: Inhaled tyrosine kinase inhibitor (PDGFR, CSF1R, c-KIT)
Indication studied: Pulmonary arterial hypertension
Trial: PROSERA, phase 3, randomized, placebo-controlled (n = 390)¹
Primary endpoint: Placebo-adjusted 6MWD +13.3 m at Week 24 (P = .0320; prespecified α = 0.025)¹
Key safety finding: Transaminase elevations ≥3× ULN in 13% vs 1% with placebo¹
Regulatory status: Investigational; sponsor plans FDA discussion¹
Seralutinib was generally well tolerated. Treatment-emergent adverse events (TEAEs) occurred in 86.5% of patients receiving seralutinib and 80.5% receiving placebo.¹ Serious adverse events occurred in 16.0% and 18.9%, respectively. Transaminase elevations ≥3 times the upper limit of normal were reported in 13% of seralutinib-treated patients versus 1% with placebo.¹ Cough was the most frequent AE (37.0%).
PAH remains a progressive and life-threatening condition characterized by pulmonary vascular remodeling and right ventricular failure.3 Contemporary treatment algorithms emphasize risk stratification and early combination therapy with endothelin receptor antagonists, phosphodiesterase-5 inhibitors or soluble guanylate cyclase stimulators, and prostacyclin pathway agents. Despite therapeutic advances, morbidity and mortality remain substantial, particularly among intermediate- and high-risk patients. Hasnain stressed that the PROSERA population reflects the difficult-to-treat reality in contemporary practice: 55% were receiving triple or quadruple background therapy and 61% were on prostacyclin treatment.¹
Although the primary endpoint narrowly missed the prespecified statistical threshold, the nominally positive 6MWD result and consistent signal in higher-risk subgroups suggest biological activity. Gossamer Bio has indicated plans to meet with the United States Food and Drug Administration (FDA) to discuss a potential path forward.¹
