Phase I trial of the single-chain urokinase intrapleural LTI-01 in complicated parapneumonic effusions or empyema

BACKGROUND. Current dosing of intrapleural fibrinolytic therapy (IPFT) in adults with complicated parapneumonic effusion (CPE)/empyema is empiric, as dose-escalation trials have not previously been conducted. We hypothesized that LTI-01 (a single-chain urokinase [scuPA]), which is relatively resistant to plasminogen activator inhibitor–1 (PAI-1), would be well tolerated. METHODS. This was an open-label, dose-escalation trial of LTI-01 IPFT at 50,000-800,000 IU daily for up to 3 days in adults with loculated CPE/empyema and failed pleural drainage. The primary objective was to evaluate safety and tolerability, and secondary objectives included assessments of processing and bioactivity of scuPA in blood and pleural fluid (PF), and early efficacy. RESULTS. LTI-01 was well tolerated, with no bleeding, treatment-emergent adverse events, or surgical referrals ( n = 14 subjects). Urokinase PA (uPA) antigen increased in PFs at 3 hours after LTI-01 ( P < 0.01) but not in plasma. PF saturated active PAI-1, generated PAI-1–resistant bioactive complexes, and increased PA and fibrinolytic activities and D-dimers. There was no systemic fibrinogenolysis or increments in plasma D-dimers. Decreased pleural opacities occurred in all but 1 subject. Both subjects receiving 800,000 IU required 2 doses to relieve pleural sepsis, with 2 other subjects similarly responding at lower doses. CONCLUSION. LTI-01 IPFT was well tolerated at these doses, with no safety concerns. Bioactivity of LTI-01 IPFT was confirmed, limited to PFs, where its processing simulated that previously reported in preclinical studies. Preliminary efficacy signals including reduction of pleural opacity were observed. TRIAL REGISTRATION. ANZCT ID: ACTRN12616001442493. FUNDING. Lung Therapeutics Inc. (LTI), NIH SMARTT HHSN268201100014C (SI), UO-1 HL121841-01A1 (SI). 1R01HL130402-01A1 (AAK, GF, SI), UTHSCT AG18-09 (AAK).