Investigation of 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 following criteria apply:
• •Age
• •1. Participant must be 18 to 80 years of age, inclusive, at the time of signing the informed consent. Type of Participant and Disease Characteristics For all participants, 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 medical history, physical examination, clinical laboratory profiles, vital signs, or 12-lead ECGs, 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) 6 Participants on angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, beta-blocker, diuretics, or on any other cardiorenal relevant treatment should be on a stable dose for at least 2 weeks prior to screening. Weight 7 Body weight 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 by participants should be consistent with local regulations regarding the methods of contraception 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 been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone levels in the postmenopausal range.
• •Females ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. (i) Female participants should be stable on the chosen method of contraception for a minimum of 3 months before entering the study. (ii) Female participants of childbearing potential must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. Females of childbearing potential who are sexually active with a non-sterilised male partner must agree to use one highly effective method of birth control, as defined below, throughout the study and until at least 3 months after discharge. Cessation of contraception after this point should be discussed with a responsible physician. Note: contraception is not required for female participants of non-childbearing potential.
• •* Highly effective birth control methods include:
• •* Non-hormonal • Total sexual abstinence provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments) • a vasectomised partner (confirmed absence of sperm in semen) • bilateral tubal occlusion
• •• intrauterine device (copper)
• •* Hormonal contraceptives associated with inhibition of ovulation levonorgestrel intrauterine system • medroxyprogesterone injections • combined Oral or transdermal contraceptives (ethinyl estradiol plus progestin) • intravaginal device (eg, EE and etonogestrel) The following are not acceptable methods of contraception: female condom, periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea.