A Phase I Study to Investigate the Effects of Renal Impairment on the Pharmacokinetics, Safety, and Tolerability of Opemalirsen (AZD2373)

Inclusion Criteria:

• Participants are eligible to be included in the study only if all of the followingcriteria apply:

Age

1. Participant must be 18 to 80 years of age, inclusive, at the time of signing theinformed consent. Type of Participant and Disease Characteristics For allparticipants, BSA-adjusted eGFR will be determined by the local laboratory,calculated based on serum creatinine using the CKD-EPI equation (see Section 4.1). Healthy matched control participants only (Group 1):

2. Participant must be medically healthy with no clinically significant medicalhistory, physical examination, clinical laboratory profiles, vital signs, or 12-leadECGs, as deemed by the investigator at screening and Day -1.

3. Have an eGFR of ≥ 90 mL/min determined at screening.

Participants with renal impairment only (Group 2 and optional Groups 3 and 4):

4 Diagnosis of chronic kidney disease with stable renal function in the 3 months prior to dosing, as determined by the investigator, based on medical history or eGFR, and not requiring dialysis. 5 Participants with renal impairment, as follows, based on CKD-EPI equation (BSA-adjusted eGFR) at screening:

1. Group 2: have severe renal impairment (eGFR < 30 mL/min), not requiring dialysis.

2. Group 3 (optional): have moderate renal impairment (eGFR ≥ 30 to < 60 mL/min)

3. Group 4 (optional): have mild renal impairment (eGFR ≥ 60 to < 90 mL/min) 6Participants on angiotensin-converting enzyme inhibitors/angiotensin II receptorblockers, beta-blocker, diuretics, or on any other cardiorenal relevant treatmentshould be on a stable dose for at least 2 weeks prior to screening. Weight 7 Bodyweight of at least 50 kg and body mass index (BMI) within the range 18 to 40 kg/m2 (inclusive). Sex and Contraceptive/Barrier Requirements 8 Male and/or female,assigned at birth, inclusive of all gender identities. 9 Contraceptive use byparticipants should be consistent with local regulations regarding the methods ofcontraception for those participating in clinical studies.

(a) Male participants must agree to the following contraception guidance for the duration of the study (from the time of study intervention administration) until 3 months after discharge: (i) Non-sterilised male participants should avoid fathering a child by either true abstinence or by using (together with their female partner/spouse) a highly effective contraception form of birth control in combination with a barrier method, starting from the time of study intervention administration until 3 months after discharge. Acceptable methods of preventing pregnancy include birth control pills, injections, implants, or patches, IUDs, tubal ligation/occlusion, and vasectomy. (ii) Male participants who have been sterilised are required to use one barrier method of contraception (condom) from the time of study intervention administration until after discharge. A barrier method is not necessary if the female partner is sterilised. (iii) Male participants should not donate sperm from the time of study intervention administration until 3 months after discharge. (b) Female participants: must not be pregnant and must have a negative pregnancy test at screening (all female participants) and check-in (WOCBP) and must not be lactating.

Women of Childbearing Potential (WOCBP): A woman is considered of childbearing potential if she is capable of conceiving. While this is typically the case following menarche and up until she becomes post-menopausal, adolescents can ovulate prior to first menarche, and women with irregular menses may also be fertile. Women Not of Childbearing Potential (WNOCBP): Females not of childbearing potential are defined as females who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are post-menopausal. Females will be considered post-menopausal if they have been amenorrhoeic for 12 months prior to the planned date of dose administration without an alternative medical cause. The following age-specific requirements apply:

• Females < 50 years old would be considered postmenopausal if they have beenamenorrhoeic for 12 months or more following cessation of exogenous hormonaltreatment and follicle stimulating hormone levels in the postmenopausal range.

• Females ≥ 50 years old would be considered postmenopausal if they have beenamenorrhoeic for 12 months or more following cessation of all exogenous hormonaltreatment. (i) Female participants should be stable on the chosen method ofcontraception for a minimum of 3 months before entering the study. (ii) Femaleparticipants of childbearing potential must use one highly effective form of birthcontrol. A highly effective method of contraception is defined as one that canachieve a failure rate of less than 1% per year when used consistently andcorrectly. Females of childbearing potential who are sexually active with anon-sterilised male partner must agree to use one highly effective method of birthcontrol, as defined below, throughout the study and until at least 3 months afterdischarge. Cessation of contraception after this point should be discussed with aresponsible physician. Note: contraception is not required for female participantsof non-childbearing potential.

• Highly effective birth control methods include:

• Non-hormonal • Total sexual abstinence provided it is the usual lifestyleof the participant (defined as refraining from heterosexual intercourseduring the entire period of risk associated with the study treatments) • avasectomised partner (confirmed absence of sperm in semen) • bilateraltubal occlusion • intrauterine device (copper)

• Hormonal contraceptives associated with inhibition of ovulationlevonorgestrel intrauterine system • medroxyprogesterone injections •combined Oral or transdermal contraceptives (ethinyl estradiol plusprogestin) • intravaginal device (eg, EE and etonogestrel) The followingare not acceptable methods of contraception: female condom, periodicabstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea.

Exclusion Criteria:

• Medical Conditions

All participants:

1. History of severe allergy/hypersensitivity or ongoing clinically importantallergy/hypersensitivity, as judged by the investigator, at screening or Day -1, orhistory of hypersensitivity to drugs with a similar chemical structure or class toopemalirsen.

2. History of any major surgical procedure within 30 days prior to study intervention.

3. Judgement by the investigator that the participant should not participate in thestudy if they have any ongoing or recent (ie, during the screening period) minormedical complaints that may interfere with the interpretation of study data or ifthey are considered unlikely to comply with study procedures, restrictions, andrequirements.

4. Liver disease (non-alcoholic and alcoholic steatohepatitis; drug-induced, viral, orautoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis;hemochromatosis; alpha-1 antitrypsin deficiency; Wilson's disease) includingpositive results for hepatitis B surface antigen, hepatitis B core antibody orhepatitis C virus antibody.

5. History of cirrhosis and/or hepatic decompensation, including ascites, hepaticencephalopathy, or variceal bleeding.

6. QTcF > 470 ms in participants without bundle branch block and > 480 ms inparticipants with bundle branch block.

7. Any of the following out of range laboratory values:

8. ALT or AST > 1.5 × ULN

9. TBL > ULN (an isolated increase in TBL in participants with Gilbert syndrome isnot a reason for exclusion)

10. INR > 1.2, unless related to therapeutic anticoagulation

11. APTT ≥ 1.3 × normal, unless related to therapeutic anticoagulation

12. HbA1c ≥ 10%

13. Positive test for human immunodeficiency virus at screening.

14. Known history of drug or alcohol abuse within 1 year of screening. Healthy matched control participants only (Group 1):

15. Any clinically significant disease or disorder (eg, cardiovascular, pulmonary,gastrointestinal, liver, renal, neurological, musculoskeletal including bonefractures, endocrine including adrenal insufficiency, metabolic, malignant,psychiatric, major physical impairment) which, in the opinion of the investigator,may put the participant at risk because of participation in the study, influence theresults of the study, or affect the participant's ability to participate in thestudy.

16. Abnormal resting vital signs (after resting for 10 minutes) of supine BP > 150 mmHgor < 90 mmHg systolic or > 95 mmHg or < 50 mmHg diastolic or supine pulse rate ≥ 100bpm or ≤ 45 bpm. Note: the blood pressure values will be based on the average of the 3 measurements. Participants with renal impairment only (Group 2 and optional Groups 3 and 4):

17. Evidence of rapidly deteriorating renal function.

18. Presence of unstable medical (eg, diabetes) or psychological conditions which, inthe opinion of the investigator, would compromise the participant's safety orsuccessful participation in this study.

19. Renal transplant patients, that is, participants that have received a kidneytransplant or participants waiting for organ transplant scheduled to occur duringthe study, and those with a history of acute kidney injury occurring within 3 monthsprior to screening.

20. Abnormal resting vital signs (after resting for 10 minutes) of supine BP > 180 mmHgor < 110 mmHg systolic or > 110 mmHg or < 60 mmHg diastolic or supine pulse rate ≥ 100 bpm or ≤ 40 bpm. Note: the blood pressure values will be based on the average ofthe 3 measurements. Prior/Concomitant Therapy Healthy matched control participants only (Group 1):

21. Use of any prescription or non-prescription drugs (including vitamins, recreationaldrugs, and dietary or herbal supplements) within 7 days (or 14 days if the drug is apotential enzyme inducer) or 5 half-lives (whichever is longer) before studyintervention, unless, in the opinion of the investigator and sponsor, the medicationwill not interfere with the study. Participants with renal impairment only (Group 2 and optional Groups 3 and 4):

22. Use of concurrent medication, which affect creatinine clearance such ascephalosporin antibiotics, ascorbic acid, trimethoprim, cimetidine, quinine within 7days prior to Day -1. Prior/Concurrent Clinical Study Experience All participants:

23. Has received another new chemical entity (defined as a compound which has not beenapproved for marketing) within 30 days of study intervention in this study or, ifknown, 5 half-lives from last dose in the previous study to study intervention inthis study, whichever is longest.

24. Previous enrolment in the present study. Note: participants consented and screened,but not receiving study intervention in this study or a previous Phase I study, arenot excluded. Other Exclusions All participants:

25. Positive screen for drugs of abuse (unless participant has renal impairment andpositive screen is due to medication[s] prescribed by physician) and/or alcohol testat screening or Day -1; a positive result for tetrahydrocannabinol and/orcannabinoids is not considered exclusionary.

26. Receipt of blood products within 2 months prior to Day -1, plasma or plateletsdonation within 1 month prior to Day -1, or any blood donation/blood loss > 500 mLwithin

3 months prior to Day -1. 22 Involvement of any AstraZeneca or clinical unit employee or their close relatives.

23 Vulnerable participants, eg, kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order. 24 Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.