Efficacy, Safety, and Tolerability of AZD0780 in Dyslipidemia: A Phase IIb Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study

The primary objective of this study is to evaluate the effect of different doses of **AZD0780** on low-density lipoprotein cholesterol (LDL-C) levels compared to placebo in "ideal" scenarios where intercurrent events do not occur. This is clinically relevant as dyslipidemia, characterized by elevated LDL-C, is a significant risk factor for cardiovascular diseases, which are leading causes of mortality and morbidity globally.

Secondary objectives include: - Evaluating the effect of different doses of AZD0780 on LDL-C versus placebo in "real-world" conditions. - Assessing the pharmacokinetics of AZD0780. - Evaluating the effects of different doses of AZD0780 on other lipid parameters and inflammatory markers versus placebo in both "ideal" and "real-world" conditions. - Assessing the safety and tolerability of AZD0780.

The clinical trial involves a total of **166 participants** diagnosed with **dyslipidemia**, specifically focusing on alterations in plasma lipid profiles such as **hypercholesterolemia**. The study population comprises both male and female subjects, aged between 18 and 75 years, who are in general good health and are not part of a vulnerable population. Participants were selected based on specific criteria, including having a fasting low-density lipoprotein cholesterol (LDL-C) level between 70 mg/dL and 190 mg/dL, and fasting triglycerides below 400 mg/dL. All participants are required to have been on moderate or high-intensity statin therapy for at least two months prior to screening, with no planned changes in medication or dosage during the study. Additionally, participants must have a body mass index of at least 19.0 kg/m². The trial does not include individuals with planned medication changes, ensuring a stable treatment regimen throughout the study period.

The clinical trial is a **Phase IIb**, multicenter, randomized, parallel-group, double-blind, placebo-controlled, dose-ranging study designed to evaluate the efficacy, safety, and tolerability of **AZD0780** in participants with **dyslipidemia**. The trial aims to assess the effect of different doses of AZD0780 on low-density lipoprotein cholesterol (LDL-C) levels compared to placebo. The study is expected to last until November 27, 2024, with recruitment starting on February 12, 2024. Participants will be involved for a maximum treatment period of 87 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, LDL-C levels, triglyceride levels, and current statin therapy. The trial will include follow-up visits to monitor the primary endpoint, which is the percent change from baseline of LDL-C at Week 12. Secondary endpoints include changes in other lipid parameters and safety assessments through adverse events, vital signs, ECG, and laboratory evaluations. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

Participants are expected to adhere to the study protocol, with conditions such as planned medication changes or non-compliance potentially leading to early termination from the study. The trial will utilize **film-coated tablets** of AZD0780 and a placebo, administered orally. The study's design ensures that neither the participants nor the investigators know which treatment is being administered, maintaining the double-blind nature of the trial. This methodology is crucial for minimizing bias and ensuring the reliability of the results.

The clinical trial involves the administration of **AZD0780**, an investigational medication developed by AstraZeneca AB. AZD0780 is formulated as a **film-coated tablet** and is classified as a small molecule. The active substance in AZD0780 is chemically identified as 1-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]pyridin-3-yl]pyridin-2-one. The medication is administered orally. The trial is designed to evaluate the efficacy, safety, and tolerability of AZD0780 in participants with dyslipidemia over a maximum treatment period of 87 days. The specific dosage and frequency of administration are not detailed in the provided data.

In addition to the experimental treatment, the study includes a **placebo** group. The placebo is referred to as AZD0780 Placebo, although specific details regarding its pharmaceutical form, active substance, or route of administration are not provided. The placebo is used as a comparator to assess the effects of AZD0780 in a double-blind, placebo-controlled setting. The inclusion of a placebo group is essential for evaluating the true efficacy of the investigational drug by providing a baseline for comparison.

The efficacy of AZD0780 in the treatment of **dyslipidemia** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percent change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 12. Secondary endpoints include the percent change from baseline at Week 12 in total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, non-high-density lipoprotein cholesterol (Non-HDL-C), very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein A-1 (ApoA1), apolipoprotein B-100 (ApoB), lipoprotein (a) (Lp(a)), remnant cholesterol, and high-sensitivity C-reactive protein (hsCRP). Additionally, AZD0780 plasma concentrations will be summarized by sampling timepoints.

Measurements will be collected at baseline and at Week 12, utilizing laboratory tests to determine the levels of the specified biomarkers. The analysis will focus on the percent change from baseline to Week 12, providing insights into the efficacy of AZD0780 compared to placebo. The study is designed as a Phase IIb, multicenter, randomized, parallel-group, double-blind, placebo-controlled, dose-ranging trial, ensuring a robust evaluation of the drug's efficacy in the target population.