Phase 3 Study to Evaluate the Efficacy and Safety of Pegozafermin in Subjects with Compensated Cirrhosis due to Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Research summary

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, global clinical study to assess the efficacy, safety, tolerability and long-term clinical outcomes of pegozafermin administered once-weekly (QW) subcutaneously (SC), in approximately 762 subjects with compensated cirrhosis due to MASH (fibrosis stage F4 per NASH CRN criteria). The study schema is shown in Section 1.2. The study will enroll a broad spectrum of subjects with compensated cirrhosis, comprising those with or without CSPH. The study will enroll approximately 532 subjects with low risk for CSPH5 at baseline, and approximately 230 subjects with high risk for CSPH6, or with evidence of CSPH7 at baseline. At the interim analysis, the primary endpoint will be based on the sub-population with low risk for CSPH and with evidence of steatosis on liver biopsy at baseline (i.e., Histology Interim Analysis Set), while all other endpoints will be based on all randomized subjects. All subjects will be assessed for clinical outcomes at final analysis. Subjects will be randomized 1:1 (pegozafermin 30 mg QW [n=381]: placebo [n=381]). Subject randomization will be stratified by CSPH categories (low risk vs. high risk vs. evidence of CSPH) and by use of non-selective beta blocker (yes vs. no) at Screening. Study treatment for all subjects will continue until adjudicated events are accrued in approximately 238 unique subjects in the pegozafermin and placebo arms combined (i.e., estimated to be at least 60 months of treatment). The total study duration for each subject is estimated to be a minimum of 64 months, comprising up to a 12-week screening period, at least a 60-month double-blind treatment period, and a 4-week safety follow-up period. Actual treatment duration will vary depending on the time to accrue the required number of adjudicated events for the final analysis. Subjects who prematurely discontinue from the study or complete treatment as scheduled will undergo an Early Termination (ET) or End of Treatment (EOT) visit, respectively, one week after the final dose of investigational product (IP) followed by an End of Study (EOS) visit three weeks after the ET/EOT visit. A baseline biopsy, either obtained historically within 6 months prior to the first day of Screening (i.e., day ICF is signed) available to be evaluated for eligibility by the central reader or during screening will be required. Ideally, the liver biopsy should be performed after all non-invasive eligibility criteria are met. Subjects will undergo a second liver biopsy at the 24-month visit (±14 day window). Liver biopsies will be read centrally by liver pathologists who are blinded to the treatment group assignment (refer to Section 6.4.3 for details). Subjects will undergo EGD at Screening (preferably to be performed after liver biopsy eligibility has been determined and before randomization), and at 24 months, 48 months and every 2 years thereafter until EOT. Annual follow-up assessments will be performed in subjects with high risk for CSPH, in subjects with evidence of CSPH (as defined in footnote 6 and 7, respectively), and in subjects who progress to VCTE score ≥ 20 kPa and platelet count < 150,000 μL (De Franchis, 2015).

Principal Investigator

Dr Jeremy Cobbold

Contact us

Email: ouh-tr.ctfresearch@nhs.net

IRAS number

1010199