None listed
Conditions
Brief summary
Severe alcohol-associated hepatitis (SAH) is a huge unmet medical need, associated with high mortality. Corticosteroids have not been associated with improved long-term survival benefit and there has been no improvement in survival in SAH with medical management during the last 60 years. SAH is associated with impaired growth of new cells in your liver (known as hepatocyte proliferation). Elevated Wnt signaling and increased hepatocyte proliferation have been linked to greater survival, suggesting that therapies that can enhance hepatocyte proliferation can benefit patients. R-spondins (RSPOs) are known enhancers of Wnt signaling. SZN-043 is a bispecific fusion protein and hepatocyte-specific RSPO mimetic shown to bring on hepatocyte-targeted Wnt signaling and hepatocyte proliferation in research studies performed in laboratories. SZN-043 was evaluated for safety and how the drug behaves in the human body in a single center, first-in-human study in healthy volunteers and patients with mild cirrhosis of the liver. This second study will evaluate the same things in patients who have severe AH.
Interventions
SZN-043 is a is an antibody fusion protein that is an RSPO mimetic specifically targeted to hepatocytes through ASGR1 binding. SZN-043 will be administered via intravenous injection. Doses of 0.5mg/kg, 1.0mg/kg, and 1.5mg/kg are planned to be tested in 3 separate cohorts, twice within one week (Day 0, Day 4). The product is administered and observed by qualified staff in an in an inpatient setting. Optional cohorts are possible to test other doses and frequencies to be determined by review o
SZN-043 is a is an antibody fusion protein that is an RSPO mimetic specifically targeted to hepatocytes through ASGR1 binding. SZN-043 will be administered via intravenous injection. Doses of 0.5mg/kg, 1.0mg/kg, and 1.5mg/kg are planned to be tested in 3 separate cohorts, twice within one week (Day 0, Day 4). The product is administered and observed by qualified staff in an in an inpatient setting. Optional cohorts are possible to test other doses and frequencies to be determined by review of available data. The frequency may increase to as much as 3x (Day 0, 4, and 7) or decrease. The determination of the frequency and of the exact dose will be made based on emerging safety data, PK data, and/or other indicators with respect to patient outcomes from the preceding cohorts. The maximum exposure will not exceed a dose equivalant of 3,0mg/kg.
Sponsors
Surrozen Operating, Inc.
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female (sex assigned at birth), 18 years of age or older AND considered to be an adult in accordance with local law. 2. BMI between 18.0 and 36.0 kg/m2, inclusive, at Screening. 3. A clinical diagnosis of AH that is anticipated to require inpatient care for a period to encompass at a minimum the first dose of study drug based on typical serum chemistry (as determined by local laboratory) meeting all of the following parameters: a. Onset of jaundice within prior 8 weeks; b. History of heavy alcohol abuse: >40 (female) or 60 (male) g alcohol/day for greater than or equal to 6 months; c. Consumed alcohol within 8 weeks before study entry; d. AST >50, AST/ALT >1.5, and both values are: <400 IU/L, and e. Serum total bilirubin >3.0 mg/dL. 4. MELD score of 21 to 30, inclusive. 5. Willing to use acceptable methods of contraception or not physically able to conceive or impregnate others.
Exclusion criteria
1. Previous receipt of antibody or biologic therapy within the past 6 months 2. Treatment with any experimental drug within 30 days, or within 5 half-lives (whichever is longer), before Day 0 visit (Baseline). 3. Other causes of liver disease 4. Recent start of liver toxic medications 5. Have a portosystemic shunt or scheduled for transjugular intrahepatic portosystemic shunt placement or highly likely to receive a liver transplant during the study. 6. Dependent upon inotropic support (including selepressin or terlipressin) or ventilatory or vasopressor support. 7. Organ failure (as defined by hepatic encephalopathy >stage 3) or requires renal replacement therapy or creatinine >2.5 mg/dL (or 221 mmol/L). 8. Uncontrolled hyperthyroidism, history of Paget's disease, osteomalacia, or fracture within 4 weeks of Screening. 9. Uncontrolled bacterial infections, as determined by the investigator's judgment after a minimum of 2 days of antibiotic therapy. 10. History of a previous severe allergic reaction with generalised urticaria, angioedema, or anaphylaxis. 11. A QT duration corrected for heart rate by Fridericia's formula (QTcF) >450 msec for males and >470 msec for females based on either single or averaged QTcF values of triplicate ECGs before study drug administration. 12. A history of malignant neoplasm, evidence of recurrence of certain skin cancers, or under investigation for a malignancy. 13. Gastrointestinal (GI) bleeding within 2 days of Screening requiring transfusion of more than 3 units of blood. 14. Grade 3 or higher encephalopathy by West Haven Criteria. 15. Acute kidney injury defined as an increase in serum creatinine (sCr) greater than or equal to 0.3 mg/dL within 48 h or increase in sCr greater than or equal to 50% from baseline known or presumed 16. Presence of portal vein thrombosis. 17. Presence of acute pancreatitis. 18. Cerebral hemorrhage, extensive retinal hemorrhage, acute myocardial infarction (within the last 6 weeks) or severe cardiac arrhythmias (not including atrial fibrillation). 19. Evidence of GI bleeding or renal failure after 7 days of treatment within 8 weeks of screening. 20. Liver imaging at screening showing any lesions (except benign lesions, i.e., hemangiomas). 21. Known infection with HIV or HIV Ab positive at screening . 22. Organ transplantation (such as liver, kidney, lung, heart, bone marrow, or stem cell etc.), other than cornea transplant. 23. Positive urine screen for amphetamines, cocaine, or non-prescribed opiates. 24. Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study. 25. Planning to donate sperm (male) or ovum (female) within 90 days after the last dose of study drug. 26. Current use of anticoagulants that affect prothrombin time or international normalised ratio (INR). 27. Eligibility: All participants where HepQuant SHUNT test kit use is specified: a. Extensive resection of large segments of small intestine (short gut) or severe gastroparesis; On either a non-selective beta blocker or an angiotensin-converting enzyme inhibitor or angiotensin II receptor blockers who are unwilling or unable to delay taking their normal dose the morning of the HepQuant SHUNT test; b. Allergy to any ingredient in the formulations or components in the HepQuant Lab Developed kit.
Outcome results
None listed