Effects of NNC0194-0499 alone and in combination with semaglutide, of semaglutide alone, and of cagrilintide alone and in combination with semaglutide on liver damage and alcohol use in people with alcohol-related liver disease

The primary objective of this study is to investigate the efficacy of NNC0194-0499, cagrilintide, semaglutide alone and NNC0194-0499 or cagrilintide in combination with semaglutide versus placebo on liver damage and function in people with alcohol-related liver disease. This objective addresses the critical need to evaluate potential therapeutic interventions that may modify hepatic injury and improve hepatic function in patients with alcohol-induced hepatopathy, a condition associated with significant morbidity and mortality.

The secondary objectives are:

• To investigate the safety and tolerability of NNC0194-0499, cagrilintide, and semaglutide alone and NNC0194-0499 or cagrilintide in combination with semaglutide versus placebo in people with alcohol-related liver disease.

• To investigate the efficacy of NNC0194-0499, cagrilintide, semaglutide alone and NNC0194-0499 or cagrilintide in combination with semaglutide versus placebo on alcohol intake and dependency in people with alcohol-related liver disease.

• To investigate the efficacy of NNC0194-0499, cagrilintide, semaglutide alone and NNC0194-0499 or cagrilintide in combination with semaglutide versus placebo on cardiometabolic factors in people with alcohol-related liver disease.

This clinical trial enrolled a total of **147 participants** diagnosed with **alcohol-related liver disease**. The study population included both **male and female** participants aged **18 years and above**, with the minimum age requirement also meeting the legal drinking age according to local regulations. Participants were selected based on a patient-reported history of **alcohol overuse** for at least 5 years, with documented consumption of a mean of at least 50 grams per day for males or 40 grams per day for females during the year preceding informed consent. Additionally, participants were required to have an **Enhanced Liver Fibrosis (ELF) score** of 9.0 units or higher, indicating significant liver damage. The trial population represented individuals with established patterns of chronic alcohol consumption and measurable hepatic impairment, forming a clinically relevant cohort for evaluating interventions targeting liver damage and function in this patient group.

This clinical trial investigates the efficacy of zalfermin, cagrilintide, and semaglutide administered alone or in combination compared to placebo on liver damage and function in individuals with alcohol-related liver disease. The trial is designed as a phase 4 study with an estimated recruitment start date of May 20, 2024, and an estimated completion date of January 16, 2026. The investigational medicinal products are administered as solution for injection via the subcutaneous route. The treatment period is 28 weeks. The trial evaluates multiple treatment arms including zalfermin alone, cagrilintide alone, semaglutide alone, zalfermin in combination with semaglutide, cagrilintide in combination with semaglutide, and placebo.

Participants eligible for inclusion must meet specific criteria. Informed consent must be obtained before any study-related activities. Participants must be male or female, aged 18 years or above, and at the legal drinking age according to local requirements at the time of signing informed consent. A patient-reported history of alcohol overuse for at least 5 years is required, with a mean alcohol consumption of at least 50 grams per day for males or 40 grams per day for females during the year prior to informed consent. Additionally, participants must have an Enhanced Liver Fibrosis (ELF) score of at least 9.0 units at screening.

The primary endpoint of the trial is the change in Enhanced Liver Fibrosis (ELF) score from baseline. Supportive secondary endpoints include changes in Pro-peptide of Collagen 3 (Pro-C3), liver stiffness assessed by Vibration Controlled Transient Elastography (VCTE), liver steatosis assessed by Controlled Attenuated Parameter (CAP), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST). Additional supportive secondary endpoints related to secondary objectives include the number of treatment-emergent adverse events, changes in Phosphatidylethanol (PEth), changes in alcohol amount measured by timeline follow-back (TLFB), and changes in total cholesterol.

The trial involves a screening visit to assess eligibility and baseline parameters, followed by regular study visits during the 28-week treatment period for safety monitoring, efficacy assessments, and administration of the investigational products. An end-of-study visit is conducted to evaluate final outcomes and safety parameters. The expected length of participant involvement spans from the screening phase through the completion of the treatment period and final assessments. Early termination from the study may occur under specific conditions as defined in the protocol, including safety concerns, withdrawal of consent, or investigator discretion.

This clinical trial investigates multiple experimental medications and placebo comparators in participants with alcohol-related liver disease. The experimental treatments include cagrilintide, semaglutide, zalfermin, and combination products containing cagrilintide with semaglutide. All investigational medicinal products are synthetically produced and administered via the subcutaneous route. The maximum treatment period for all products is 28 weeks. Dosage is measured in milligrams, though specific dose amounts are not detailed in the source data.

Cagrilintide is formulated as a solution for injection and contains the active substance cagrilintide, which is classified as a protein. The substance is also known by alternative designations including NNC0174-0833, NN9838, and N-alfa-[(S)-4-Carboxy-4-(19-carboxynonadecanoylamino)butyryl]-[Glu14,Arg17,Pro25,Pro28,Pro29,Pro37]-human amylin. Multiple formulations of cagrilintide monotherapy are utilized in this trial, all administered subcutaneously.

Semaglutide is formulated as a solution for injection and contains the active substance semaglutide, a protein also identified by the synonym NNC0113-0217. Semaglutide is administered as a monotherapy via subcutaneous injection.

Zalfermin is formulated as a solution for injection containing the active substance zalfermin, a protein with alternative designations including NNC0194-0499, NN-9499, and Fibroblast growth factor 21 [alanyl, 121-glutamine, 168-leucine, 180-[S-[(28S)-28,46-dicarboxy-2,7,16,25,30-pentaoxo-9,12,18,21-tetraoxa-3,6,15,24,29-pentaazahexatetracont-1-yl]cysteine]]. The product is administered subcutaneously.

The combination product cagrilintide semaglutide is formulated as a solution for injection containing two active substances: cagrilintide and semaglutide, both classified as proteins. Multiple formulations of this combination product are employed in the trial, all administered via subcutaneous injection.

The trial includes placebo comparators to assess treatment efficacy. One placebo formulation consists of placebo for zalfermin combined with placebo for semaglutide. Another placebo formulation comprises placebo for cagrilintide combined with placebo for semaglutide. These placebo treatments serve as control arms for comparison against the active investigational products.

The primary efficacy endpoint is the change in Enhanced Liver Fibrosis (ELF) score. Supportive secondary endpoints include changes in Pro-peptide of Collagen 3 (Pro-C3), liver stiffness assessed by Vibration Controlled Transient Elastography (VCTE), liver steatosis assessed by Controlled Attenuated Parameter (CAP), Alanine Aminotransferase (ALT), and Aspartate Aminotransferase (AST). Additional supportive secondary endpoints related to alcohol use include changes in Phosphatidylethanol (PEth) levels and alcohol amount measured by timeline follow-back (TLFB). Change in total cholesterol is also assessed as a supportive secondary endpoint. The trial evaluates these parameters to determine the efficacy of the investigational treatments on liver damage, liver function, and alcohol use in participants with alcohol-related liver disease.