Efficacy and Safety of NNC0194-0499 and Semaglutide in Non-Alcoholic Steatohepatitis with Fibrosis Stages F2-F4: A Dose-Ranging, Placebo-Controlled Trial

The primary objective of this study is to confirm the effect of **NNC0194-0499** 30 mg administered once weekly in combination with **semaglutide** 2.4 mg once weekly, compared to placebo, on fibrosis in subjects with non-alcoholic steatohepatitis (NASH) and fibrosis stages 2 to 4 (F2-F4). This is clinically relevant as it aims to address the progression of fibrosis, a critical factor in the management and prognosis of NASH.

Secondary objectives include:

• Confirming the effect of NNC0194-0499 at doses of 7.5 mg and 15 mg once weekly in combination with semaglutide 2.4 mg once weekly versus placebo on fibrosis.
• Confirming the effect of NNC0194-0499 30 mg once weekly versus placebo on fibrosis.
• Confirming that NNC0194-0499 at doses of 7.5 mg, 15 mg, and 30 mg once weekly contributes to the effect of the corresponding combination with semaglutide 2.4 mg once weekly on fibrosis.
• Confirming that semaglutide 2.4 mg once weekly contributes to the effect of the combination with NNC0194-0499 on NASH resolution.
• Investigating the dose-response relationship of NNC0194-0499 in combination with semaglutide on liver histology and tolerability.
• Investigating the safety and tolerability of NNC0194-0499 alone and in combination with semaglutide, as well as NNC0174-0833 in combination with semaglutide.
• Comparing and investigating the effects versus placebo of NNC0194-0499 alone and in combination with semaglutide, and NNC0174-0833 in combination with semaglutide on fibrosis, NASH resolution, cardiovascular disease, cardio-metabolic factors, body weight, NASH biomarkers, and patient-reported outcomes.
• Comparing and investigating the effects versus semaglutide of NNC0174-0833 in combination with semaglutide on fibrosis, NASH resolution, cardiovascular disease, cardio-metabolic factors, body weight, NASH biomarkers, and patient-reported outcomes.

The clinical trial involves a total of **533 participants** diagnosed with **non-alcoholic steatohepatitis (NASH)**, specifically those with fibrosis stages 2 to 4. The study population includes both male and female subjects, aged 18 years and older, with specific age requirements for participants from the Republic of Korea, Japan, and Singapore. Participants were selected based on histological evidence of NASH and fibrosis, as confirmed by a central pathologist's evaluation of a liver biopsy. The trial does not include a vulnerable population. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The selection criteria ensure that participants have a non-alcoholic fatty liver disease activity score meeting the study's requirements, with a focus on steatosis, lobular inflammation, and hepatocyte ballooning.

The clinical trial is designed to evaluate the **efficacy** and safety of NNC0194-0499 co-administered with **semaglutide** in subjects with non-alcoholic steatohepatitis (NASH). This is a Phase 2, randomized, double-blind, active and placebo-controlled, double-dummy, parallel-group, multinational trial. The trial aims to assess the safety and efficacy of three doses of NNC0194-0499 in combination with semaglutide versus placebo. The trial also includes treatment arms for NNC0194-0499 alone, semaglutide alone, and NNC0174-0833 in combination with semaglutide. The primary objective is to confirm the effect of NNC0194-0499 30 mg once weekly in combination with semaglutide 2.4 mg once weekly versus placebo on fibrosis in subjects with NASH and fibrosis stage 2-4 (F2-F4). The primary endpoint is the improvement in liver fibrosis and no worsening of NASH from baseline to week 52.

The trial duration is estimated to be 52 weeks, with an expected end date in March 2025. Participants will be involved in the study for the entire duration unless early termination is warranted. Conditions that may lead to early termination include significant adverse events or withdrawal of consent. The study visits are structured as follows: an initial inclusion (screening) visit to confirm eligibility based on histological evidence of NASH and fibrosis, followed by regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess the primary and secondary endpoints. The inclusion criteria require participants to be aged 18 years or older, with histological evidence of NASH and fibrosis stage 2, 3, or 4. The trial will utilize subcutaneous administration of the investigational products, with the use of devices such as the NovoPen® 4 and PDS290 pen-injector for delivery.

Secondary endpoints include resolution of steatohepatitis, improvement in steatohepatitis with at least a 2-point reduction in NAS, and changes in various biochemical markers from baseline to week 52. The trial will also monitor the number of treatment-emergent adverse events from baseline to week 59. The trial is not classified as low intervention and is conducted under the regulatory framework to ensure the protection of commercially confidential information. The trial's structured data and related documents will be made publicly available at the time of decision or assessment, subject to the deferral mechanism for transparency rules.

The clinical trial involves the administration of **NNC0194-0499**, a solution for injection, with a concentration of 50 mg/mL. This experimental medication is administered subcutaneously using the NovoPen® 4, a reusable pen-injector designed for single-subject use. The dosing schedule for NNC0194-0499 is once weekly, with a maximum treatment period of 52 weeks. The active substance, NNC0194-0499, is a protein of other origin, and the product is manufactured by Novo Nordisk A/S.

**Semaglutide B 3.0 mg/mL PDS290** is another experimental medication used in this trial. It is also a solution for injection, administered subcutaneously once weekly. The PDS290 pen-injector, a disposable, pre-filled, multi-dose device, is used for the administration of semaglutide. The active substance, semaglutide, is provided by Novo Nordisk A/S, and the treatment duration is up to 52 weeks.

**Cagrilintide A 10 mg/mL cartridge** is included in the trial as an experimental treatment. This solution for injection is administered subcutaneously using the NovoPen® 4 device. The dosing schedule is once weekly, with a treatment period of up to 52 weeks. Cagrilintide, the active substance, is a protein of other origin, synthetically produced, and supplied by Novo Nordisk A/S.

The trial also includes the use of **placebos** to serve as comparator treatments. These include Placebo C, Semaglutide B placebo PDS290 pen-injector, and NNC0174-0833 A Placebo. These placebos are administered in a manner consistent with their corresponding active treatments, ensuring blinding and maintaining the integrity of the trial's placebo-controlled design.

The efficacy of the investigational treatment in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the improvement in liver fibrosis without worsening of **non-alcoholic steatohepatitis (NASH)** from baseline to week 52. Secondary endpoints include the resolution of steatohepatitis without worsening of liver fibrosis, improvement in steatohepatitis with at least a 2-point reduction in the non-alcoholic fatty liver disease (NAFLD) activity score, and changes in histology-assessed liver collagen proportionate area, all measured from baseline to week 52.

Additional secondary endpoints involve the assessment of various liver and metabolic parameters, such as changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), high-sensitivity C-reactive protein (HsCRP), enhanced liver fibrosis (ELF) score, and lipid profiles including triglycerides, free fatty acids, LDL cholesterol, and HDL cholesterol. The trial will also evaluate changes in body weight, SF-36 bodily pain, NASH-CHECK pain, and PROMIS Fatigue score over the same period. The number of treatment-emergent adverse events (TEAEs) will be recorded from baseline to week 59.

These efficacy parameters will be measured and collected at specified timepoints, with baseline assessments at week 0 and follow-up assessments at week 52. The trial employs a double-blind, placebo-controlled design to ensure the reliability of the efficacy data. The use of validated scales and laboratory tests will facilitate the accurate evaluation of the treatment's impact on the progression of NASH and associated metabolic conditions.