Evaluation of AZD2693 Sodium Efficacy, Safety, and Tolerability in Non-Cirrhotic NASH with Fibrosis and PNPLA3 rs738409 148M Allele Carriers

The primary objective of this study is to evaluate the effect of **AZD2693** versus placebo on the histological resolution of non-cirrhotic non-alcoholic steatohepatitis (NASH) in participants with fibrosis who are carriers of the PNPLA3 rs738409 148M risk allele after 52 weeks. This is clinically relevant as achieving histological resolution of NASH can potentially halt or reverse liver damage, reducing the risk of progression to cirrhosis and associated complications.

Secondary objectives include:

• Assessing the effects of AZD2693 versus placebo on histological fibrosis improvement.
• Evaluating the effect of AZD2693 versus placebo on a ≥ 2-point improvement in the NAFLD Activity Score (NAS).
• Assessing the effect of AZD2693 versus placebo on improvement in fibrosis by at least one stage.

The clinical trial involves a total of **169 participants** diagnosed with **non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis**. The study population includes both male and female subjects, aged between 18 to 75 years. Participants were selected based on their status as carriers of the PNPLA3 rs738409 148M risk allele and must have histological evidence of NASH, as confirmed by a central pathologist's evaluation of a liver biopsy. The trial specifically targets individuals with fibrosis stages F2 or F3, according to the NASH CRN fibrosis staging system. The study does not restrict participation based on lifestyle factors such as diet or physical activity, but it does include a vulnerable population. The selection criteria ensure that the participants have a definitive diagnosis of NASH with a NAS score of 4 or higher, with at least one point in each component of steatosis, lobular inflammation, and ballooning.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy, safety, and tolerability of AZD2693 in participants with **non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis** who are carriers of the PNPLA3 rs738409 148M risk allele. The trial is a Phase 2b study with an estimated duration of 52 weeks for each participant, with the overall trial expected to conclude by November 2025. Participants will be randomly assigned to receive either AZD2693 or a placebo, both administered as a **solution for injection** via subcutaneous use.

The study will commence with an inclusion (screening) visit to assess eligibility based on specific criteria, including age (18 to 75 years) and histological evidence of NASH. Participants must have a liver biopsy confirming definitive NASH with a NAS ≥ 4 and fibrosis stage F2 or F3. Following successful screening, participants will be enrolled and randomized into the treatment or placebo group. The primary endpoint is the resolution of NASH without worsening of liver fibrosis after 52 weeks, assessed by the NASH CRN/NAS score. Secondary endpoints include improvement in liver fibrosis and NAS score.

Study visits will occur at regular intervals throughout the trial to monitor safety, efficacy, and adherence to the protocol. These visits will include assessments such as physical examinations, laboratory tests, and imaging studies as required. The end-of-study visit will occur at the conclusion of the 52-week treatment period, where final evaluations will be conducted to assess the primary and secondary endpoints.

Participant involvement is expected to last for the full 52 weeks unless early termination is warranted. Conditions that may lead to early termination include adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial is not classified as a low-intervention study, and all procedures will adhere to the highest standards of clinical research to ensure participant safety and data integrity.

The clinical trial involves the administration of **AZD2693**, a synthetic small molecule developed by AstraZeneca AB. The experimental medication is formulated as a **solution for injection** and is intended for **subcutaneous use**. The active substance in this formulation is **AZD2693 sodium**, which originates from nucleic acid. The trial is designed to evaluate the efficacy, safety, and tolerability of AZD2693 in participants with non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis who are carriers of the PNPLA3 rs738409 148M risk allele. The maximum treatment period for AZD2693 is 52 weeks, with the dosing schedule and specific dosage details to be determined based on the study protocol. Participant compliance with the dosing regimen will be monitored throughout the trial.

The study also includes a **placebo** group, where participants will receive a placebo solution for injection that is identical in appearance to the AZD2693 solution. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered via the same route and frequency as the experimental medication, ensuring consistency in the administration process. The use of a placebo control allows for a more accurate assessment of the treatment's efficacy and safety by providing a baseline for comparison.

The efficacy of the investigational product AZD2693 in the treatment of **Non-alcoholic Steatohepatitis (NASH)** will be assessed through a randomized, double-blind, placebo-controlled, multi-centre Phase 2b clinical trial. The primary endpoint for evaluating efficacy is the resolution of NASH without any worsening of liver fibrosis after 52 weeks of treatment. This resolution is defined by a ballooning score of 0, an inflammation score of 0 to 1, and a steatosis score of any degree (0 to 3), as assessed by the NASH Clinical Research Network (CRN) and the Nonalcoholic Steatohepatitis Activity Score (NAS). Worsening of fibrosis is characterized by an increase in the NASH CRN fibrosis score.

Secondary endpoints include at least one stage of liver fibrosis improvement with no worsening of NASH after 52 weeks, improvement in fibrosis by at least one stage based on biopsy after Week 52, and a ≥2-point improvement in NAS after 52 weeks. These endpoints will be measured using liver biopsy evaluations conducted by a central pathologist. The trial aims to assess the histological resolution of NASH in participants who are carriers of the PNPLA3 rs738409 148M risk allele and have non-cirrhotic NASH with fibrosis. The study will span a maximum treatment period of 52 weeks, with efficacy assessments scheduled at the end of this period.