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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 pulmonary arterial hypertension (PAH), despite achieving nominal statistical significance on 6-minute walk distance (6MWD) at 24 weeks and higher efficacy in patients with intermediate and high-risk PAH.¹
“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
