Safety, pharmacokinetics, and preliminary efficacy of VS-01, an intraperitoneal liposomal infusion, in patients with decompensated liver cirrhosis, ascites, and covert hepatic encephalopathy: a phase 1b, first-in-human, open-label, non-randomised, single ascending and multiple dose study

BACKGROUND: Acute-on-chronic liver failure (ACLF) is characterised by systemic inflammation and organ failures in patients with decompensated liver cirrhosis. In the absence of specific approved treatments, ACLF is associated with a high short-term mortality. In this study, we aimed to evaluate the investigational drug VS-01, a liposomal formulation for intraperitoneal infusion, in patients with decompensated liver cirrhosis, ascites, and covert hepatic encephalopathy, to inform further studies in patients with more advanced disease (eg, overt hepatic encephalopathy and ACLF). METHODS: This phase 1b, first-in-human, open-label, non-randomised, single ascending and multiple dose study was conducted at the Hospital of the Goethe University Frankfurt in Germany. Eligible patients had decompensated liver cirrhosis, ascites requiring paracentesis, and covert hepatic encephalopathy (ie, minimal or grade 1 according to West Haven criteria) and were aged 18-60 years in part A of the study and 18-64 years in part B. The main exclusion criterion was organ failures meeting the definition of ACLF. Patients received single ascending doses of VS-01 (15 mL/kg, 30 mL/kg, and 45 mL/kg) in part A and multiple doses (34-42 mL/kg per day on 4 consecutive days) in part B, in addition to standard care. VS-01 was administered intraperitoneally over 60 min using a standard paracentesis catheter, with a dwell time of 2 h in part A and on days 2 and 3 of part B and a dwell time of 3 h on days 1 and 4 of part B. At the end of the dwell time, VS-01 was passively drained and the peritoneal cavity was washed. Patients were followed up in hospital for 7 days after the last dose. The primary endpoint was the safety and tolerability of VS-01, including the incidence and severity of treatment-related adverse events (TEAEs) and serious adverse events, vital signs, electrocardiograms (ECGs), and laboratory abnormalities. Safety was analysed in the safety analysis set, defined as all patients who received at least one dose of VS-01. This study was registered with EudraCT, 2018-004606-25, and is complete. FINDINGS: Patients were recruited between Sept 23, 2019, and Dec 18, 2020. Of 15 patients screened, nine were assigned to part A (n=3 per dose level; male:female=7:2) and three were assigned to part B (male:female=1:2). No serious adverse events were reported. 20 TEAEs were reported in seven (58%) of 12 patients (four events in part A; 16 in part B). Most TEAEs were mild (14) and short in duration (19 resolved during follow-up). One TEAE-an overdose of VS-01 (26·4 mL/kg instead of 15 mL/kg; CTCAE grade 1) in part A-was considered to be definitely related to VS-01. Two (10%) of 20 TEAEs were judged to be possibly related to VS-01: one episode of grade 1 extravasation at the infusion site (part A, 45 mL/kg), which resolved within 3 days, and one episode of grade 2 pleural effusion on day 11 (part B, 41·8 mL/kg), which required no therapeutic procedure. Six (30%) of 20 TEAEs (reported in three [25%] patients) were of grade 3 but none were deemed to be treatment-related. No patients discontinued the study or VS-01 due to adverse events. The most common TEAEs were gastrointestinal disorders (seven [35%] of 20 events, reported in four [33%] of 12 patients). No clinically significant changes in vital signs, ECGs, or laboratory values were noted in any patient. INTERPRETATION: VS-01 was generally well tolerated with a favourable safety profile in patients with decompensated liver cirrhosis, ascites, and covert hepatic encephalopathy. The results of this study supported the initiation of proof-of-concept studies in larger cohorts of patients with decompensated cirrhosis and ACLF. FUNDING: Versantis AG.