Evaluation of Laroprovstat (AZD0780) on LDL-C Levels in Heterozygous Familial Hypercholesterolemia: A Phase III Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of **AZD0780** compared to placebo on low-density lipoprotein cholesterol (**LDL-C**) levels at 12 weeks in patients with heterozygous familial hypercholesterolaemia. This is clinically relevant as reducing LDL-C is crucial in managing cardiovascular risk in these patients.

Secondary objectives include:

• Comparing the effect of AZD0780 versus placebo on LDL-C at 12, 28, and 52 weeks in patients on background statin therapy.
• Assessing the probability of achieving LDL-C levels below 70 mg/dL and 55 mg/dL at 12 weeks in patients with baseline LDL-C ≥ 70 mg/dL.
• Evaluating the impact on apolipoprotein B, non-high-density lipoprotein cholesterol, total cholesterol, and lipoprotein(a) at 12 weeks.

The clinical trial involves a total of **253 participants** diagnosed with **heterozygous familial hypercholesterolaemia** (HeFH). The study population includes both male and female subjects, aged 18 years and older, who have been genetically confirmed or have a definite clinical diagnosis of HeFH. Participants are required to have a fasting serum LDL-C level of at least 55 mg/dL if they have clinical atherosclerotic cardiovascular disease (ASCVD) or at least 70 mg/dL if they do not have clinical ASCVD. All participants are on a maximally tolerated lipid-lowering regimen, which includes a maximally tolerated statin, with ezetimibe strongly recommended. Those unable to tolerate high-intensity statins may be included if treated with a low- or moderate-intensity statin dose. The trial population was selected based on these criteria, ensuring that participants are on a stable dose of lipid-lowering therapies for more than 28 days before screening. The study does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is a **Phase III**, randomized, double-blind, placebo-controlled, parallel group study designed to assess the effect of **AZD0780** on low-density lipoprotein cholesterol (LDL-C) in patients with **heterozygous familial hypercholesterolaemia**. The primary objective is to compare the effect of treatment with AZD0780 versus placebo on LDL-C at 12 weeks. The trial is expected to commence recruitment on May 30, 2025, and conclude by March 26, 2027, with a maximum treatment period of 52 weeks.

Participants will be randomly assigned to receive either AZD0780, a synthetic molecule administered as a film-coated tablet for oral use, or a placebo. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be 18 years or older, have a confirmed diagnosis of heterozygous familial hypercholesterolaemia, and be on a stable lipid-lowering regimen. Exclusion criteria are not specified in the provided data.

The expected length of participant involvement is up to 52 weeks, with the possibility of early termination if safety concerns arise or if the participant withdraws consent. The primary endpoint is the relative change in LDL-C from baseline to 12 weeks, with secondary endpoints including various lipid profile changes over 12, 28, and 52 weeks. The study aims to provide valuable insights into the efficacy and safety of AZD0780 in managing LDL-C levels in the target population.

The clinical trial involves the administration of **AZD0780**, an experimental medication designed to assess its effect on low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolemia. **AZD0780** is a synthetic molecule with the active substance **laroprovstat**. It is provided in the form of a film-coated tablet and is intended for oral use. The dosage is measured in milligrams per square meter (mg/m²), although specific dosing details are not provided. The maximum treatment period for **AZD0780** is 52 weeks. The medication is manufactured by AstraZeneca AB and is not a pediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the study.

The study also includes a placebo group, where participants will receive the **AZD0780 Placebo**. The placebo is designed to match the experimental medication in appearance but does not contain the active substance **laroprovstat**. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who is receiving the active treatment or the placebo. This helps to eliminate bias and allows for a more accurate assessment of the treatment's efficacy. The placebo is administered in the same manner as the active medication, ensuring consistency in the study protocol.

The efficacy of the investigational product AZD0780 will be assessed in a Phase III, randomized, double-blind, placebo-controlled, parallel-group study. The primary endpoint for evaluating efficacy is the relative change in low-density lipoprotein cholesterol (**LDL-C**) from baseline to 12 weeks. Secondary endpoints include the relative change in LDL-C from baseline to 12 weeks in patients on background statin therapy, indicators for achieving LDL-C levels below 70 mg/dL and 55 mg/dL at 12 weeks, and the relative change in LDL-C at 28 and 52 weeks. Additional secondary endpoints involve the relative change in apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, and lipoprotein(a) [Lp(a)] from baseline to 12 weeks.

Measurements of LDL-C and other lipid parameters will be conducted at specified time points, including baseline, 12 weeks, 28 weeks, and 52 weeks. These assessments will be performed using validated laboratory tests to ensure accuracy and reliability. The data collected will be analyzed to determine the efficacy of AZD0780 in reducing LDL-C levels compared to placebo, with particular attention to the changes observed at the 12-week mark, which is the primary endpoint of the study.