AstraZeneca has initiated two Phase I clinical trials to evaluate AZD2389, an investigational compound targeting liver fibrosis and metabolic dysfunction-associated steatohepatitis (NASH). The studies aim to establish the safety profile and pharmacokinetic characteristics of this novel therapeutic candidate in patients with varying degrees of liver impairment.
Primary Safety and Tolerability Study
The first trial (D7930C00002) represents a randomized, placebo-controlled study designed to measure the safety, tolerability, and pharmacokinetic properties of AZD2389 in participants with liver fibrosis and compensated cirrhosis. The study will examine how the body absorbs, distributes, and metabolizes the compound compared to placebo over a comprehensive 63-day evaluation period.
The trial employs a two-cohort design with parallel-group structure, maintaining participant blinding to treatment allocation. Cohort A will focus on approximately 18 participants with presumed NASH accompanied by fibrosis, while Cohort B will evaluate 18 participants with steatotic liver disease (SLD) featuring advanced fibrosis, including compensated cirrhosis. Each cohort will randomize participants in a 2:1 ratio, with 12 receiving AZD2389 and 6 receiving placebo.
The study protocol includes an intensive monitoring schedule spanning 28 days of active treatment. Participants will undergo a 24-hour in-clinic stay on Day 1, followed by outpatient visits on Days 7 and 14, a telephone consultation on Day 21, and an extended 24-48 hour in-clinic observation period on Day 28. A follow-up visit occurs on Day 35 to complete the assessment period.
Hepatic Impairment Pharmacokinetic Study
The second investigation (D7930C00004) takes a different approach, examining how hepatic impairment affects AZD2389's pharmacokinetic profile and fibroblast activation protein activity. This single-dose, non-randomized, open-label study will compare participants across four distinct cohorts based on liver function status.
Cohort 1 includes participants with normal hepatic function, serving as controls matched for sex, age, and body mass index. Cohorts 2 and 3 will evaluate participants with mild hepatic impairment (Child-Pugh Class A) and moderate hepatic impairment (Child-Pugh Class B), respectively. An optional fourth cohort may assess participants with severe hepatic impairment (Child-Pugh Class C), pending safety data from the earlier cohorts.
The study incorporates a careful safety monitoring approach, requiring assessment of safety, tolerability, and 48-hour plasma pharmacokinetic data from at least four participants in both the mild and moderate hepatic impairment cohorts before proceeding to evaluate severe hepatic impairment cases.
Clinical Development Strategy
These parallel Phase I studies reflect AstraZeneca's systematic approach to understanding AZD2389's therapeutic potential in liver disease. The compound appears to target fibroblast activation protein activity, suggesting a mechanism focused on the fibrotic processes underlying progressive liver disease.
The screening requirements indicate substantial patient populations, with approximately 75 participants screened for each cohort in the primary study to achieve the target randomization numbers. This screening-to-randomization ratio suggests specific inclusion criteria designed to identify appropriate patient populations for this early-stage development program.
The studies' design acknowledges the complex pathophysiology of liver fibrosis and NASH, conditions that represent significant unmet medical needs in hepatology. By evaluating both safety parameters and pharmacokinetic profiles across different degrees of liver impairment, AstraZeneca aims to establish a comprehensive understanding of AZD2389's therapeutic window and dosing considerations for future development phases.
