AZD8233 is a PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. This study aims to evaluate the dose-dependent reduction in LDL-C after SC administration of multiple doses of AZD8233 as well as the associated adverse effects profile. The data generated will be used to guide choice of doses, dosing regimens, and sample sizes, as well as safety and PD monitoring in the further clinical development program.

This is a randomized parallel, double-blind, placebo-controlled, dose-ranging Phase 2b study in approximately 108 participants with dyslipidemia. The primary objective of the study is to investigate the effect of AZD8233 on LDL-C across different dose levels. The study will be conducted at up to 25 sites in up to 4 countries.

The screening period starts up to 42 days before the randomization visit and ends on Day -1. Eligible participants will attend 7 visits during the treatment period and 7 additional visits during the safety follow up period. Eligible participants are randomized across four different treatment arms in a 1:1:1:1 ratio for a 12-week treatment period. The planned treatment arms are AZD8233 low dose, AZD8233 medium dose, AZD8233 high dose, and Placebo. Participants will be dosed SC on Days 1, 8, 29, and 57.

Key Inclusion Criteria:

• Male or female.
• Participant must be 18 to 75 years of age.
• Body mass index between 19 and 40 kg/m2.
• Participants who have a fasting LDL-C ≥ 70 mg/dL but < 190 mg/dL.
• Have fasting triglycerides < 400 mg/dL.
• Should be receiving moderate- or high-intensity statin therapy.
• Should be on stable medication for ≥ 3 months prior to screening with no planned medication or dose change during study participation. The exception to this restriction is for fenofibrate; if the participant is receiving fenofibrate, the therapy must be stable for at least 6 weeks prior to randomization at a dose that is appropriate for the duration of the study in the judgement of the Investigator. Other fibrate therapy (and derivatives) are prohibited.

Key Exclusion Criteria:

• Estimated glomerular filtration rate < 40 mL/min/1.73m2 CKD-EPI.

• Any uncontrolled or serious disease, or any medical dysfunction or surgical condition that, in the opinion of the Investigator, may either interfere with participation in the clinical study and/or put the participant at significant risk.

• Poorly controlled type 2 diabetes mellitus, defined as HbA1c > 10% at Visit 1.

• Acute ischaemic cardiovascular event in the last 12 months prior to randomization.

• Heart failure with New York Heart Association (NYHA) Class III-IV.

• High-risk of bleeding as judged by the Investigator.

• Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal

• Carcinoma in-situ, or Stage 1 prostate carcinoma) within the last 10 years.

• LDL or plasma apheresis within 12 months prior to randomization.

• Uncontrolled hypertension defined as average supine SBP > 160 mmHg or DBP > 90 mmHg at Visit 1 or Visit 3.

• Heart rate after 10 minutes supine rest < 50 bpm or > 100 bpm.

• Any laboratory values with the following deviations at Screening:

  • Positive result on screening for hepatitis B, hepatitis C or HIV.
  • ALT > 1.5 × ULN.
  • AST > 1.5 × ULN.
  • TBL > ULN.
  • ALP > 1.5 × ULN.
  • WBC < LLN.
  • Haemoglobin < 12 g/dL in men or < 11 g/dL in women.
  • Platelet count ≤ LLN.
  • aPTT > ULN and PT > ULN.
  • UACR > 11.3 mg/mmol (100 mg/g).
  • UPCR > 300 mg/g.

• Any clinically important abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically important abnormalities in the 12-lead ECG as judged by the Investigator.

• Mipomersen, or lomitapide within 12 months prior to randomization.

• Previous administration of AZD8233/AZD6615.

• Previous administration of PCSK9 inhibition treatment.

• Participation in another clinical study with a study intervention administered in the last 3 months prior to randomization or 5 half-lives from last dose to first administration of study intervention, whichever is the longest.