A Phase 1 Single and Multiple Ascending Dose Study to Assess the Safety and Pharmacokinetics of SZN-043, a Novel Bispecific Fusion Protein Targeting ASGR1 and ZNRF3/RNF43, in Healthy Volunteers and Subjects with Liver Cirrhosis

INTERVENTION: Part 1: Single doses of SZN‐043 will be administered via intravenous injection (doses equal to or less than 3mg/kg) or infusion (doses greater than 3mg/kg). Each dose level will be tested within one cohort. Each patient will only be assigned one dose level. Dose cohorts will increase through 3mg/kg IV Injection, 10mg/kg, and 30mg/kg. Progression between cohorts will commence based upon recommendation of the SRC based on its review of safety data after all patients in the preceding cohort have been observed for at least 14 days after dose. All dosing is performed while patients are confined in the clinical trial unit for a period prior and after dosing. Part 2: Multiple doses (6) of SZN‐043 will be administered via intravenous injection (doses of 3mg/kg) or infusion (doses greater than 3mg/kg). Dosing will occur on Days 0, 14, 17, 21, 24 and 28. Part 2 may commence upon recommendation of the SRC based on its review of all safety data after the highest cohort in Part 1 has completed dosing, and the last participant has been observed for 14 days. Each patient will only be assigned one dose level. Dose cohorts will increase through 10mg/kg, and 30mg/kg (lower doses may be considered depending on outcome in Part 1). Progression between cohorts will commence based upon recommendation of the SRC based on its review of safety data after all patients in the preceding cohort have been observed for at least 14 days after their last dose. All dosing is performed while patients are confined in the clinical trial unit for a period prior and after dosing. CONDITION: Inflammatory and Immune System ‐ Other inflammatory or immune system disorders Alcoholic Hepatitis;Liver Cirrhosis; ; Alcoholic Hepatitis ; Liver Cirrhosis PRIMARY OUTCOME: Parts 1 and 2: Safety and tolerability of SZN‐043 in HVs, based on the frequency and severity of treatment‐emergent adverse events (TEAEs), treatment‐emergent serious adverse events (TESAEs), electrocardiograms (ECGs), and treatment‐emergent laboratory and physical examination findings. Adverse events may include reactions to study drug, injection or infusion site reactions, etc. Events will be assessed based on investigator observation and patient self report. AEs will be graded in accordance with CTCAE criteria.[Part 1: The safety observations of all types that are assessed by the investigator or reported by the site will be assessed at least every other week, with TEAEs and TESAEs assessed at every contact with the subject until 4 weeks post dose.; Part 2: The safety observations of all types that are assessed by the investigator or reported by the site will be assessed at least every other week, with TEAEs and TESAEs assessed at every contact with the subject until 4 weeks post last dose.] Parts 1 and 2: The maximum tolerated dose (MTD) of SZN‐43 in HV; [Part 1 and 2: The maximum tolerated dose (MTD) of SZN‐043 in HVs will be defined as the dose below which 2 or greater subjects experience a treatment‐related TEAE (NCI CTCAE equals grade 3 or higher) occurring within 14 days of administration of SZN 043, except for isolated alkaline phosphatase (ALP) elevations.] SECONDARY OUTCOME: Pharmacokinetic parameters (measured from blood serum) in HVs following a single IV dose (Part 1) and in participants with liver cirrhosis following single and multiple doses (Part 2) of SZN‐043, as data allow. PK Parameters assessed will include but are not limited to Cmax, Clast, Tmax, AUC0‐last, AUC0‐inf, CL, CLss, t1/2,, etc. as available data allow. ; ; ; ; Part 2: ADA will be measured on Day 0 (day of dosing) once pre‐dose, and at Day 14, 28, 35 and 56. ; ] INCLUSION CRITERIA: Part 1: 1. Healthy male or female volunteers. Part 2: 1. Males or female with documented history of liver cirrhosis and a Child‐Pugh score between 5 and 7, inclusive, at screening. ; [Part 1 (IV): PK will be measured on Day 0 (day of dosing) once pre‐dose, and post‐dose (end of administration): 5 min (± 5 minutes), 30 mins (±5 minutes), 2 hours (±5 minutes), 4 hours (± 10 minutes), 8 hours (± 10 minutes), 12 hours (± 10 minutes), and then on Days 1, 2, 3, 5, 7, 14, 21, and 28. ; Part 2: PK will be measured on Day 0 (day of dosing), once pre‐dose and post‐dose (end of administration): 5 min (± 5 minutes), 30 mins (±5 minutes), 2 hours (±5 minutes), 4 hours (±10 minutes), 8 hours (± 10 minutes), 12 hours (± 10 minutes), then on Days 1, 2, 3, 5, 7, 14, 21, 28, 29, 31, 33, 35, and 56.] Prevalence of Anti‐Drug Antibodies (measured in blood serum) for SZN‐043 in HVs (Part 1) and subjects with liver cirrhosis (Part 2) at baseline and incidence of ADA during the study.[Part 1 (IV and SC): ADA will be measured on Day 0 (day of dosing) once predose, and at Day 14 and 28. 2. A fibroscan of equal to or greater than 9kPa. 3. MELD Score of equal to or less than 12 at Screening based on local lab results.