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

Inclusion Criteria

• 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:
• (a) Group 2: have severe renal impairment (eGFR < 30 mL/min), not requiring dialysis.
• (b) Group 3 (optional): have moderate renal impairment (eGFR ≥ 30 to < 60 mL/min)
• (c) 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.
• o 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.
• Exclusion Criteria:
• -Medical Conditions
• All participants:
• 1 History of severe allergy/hypersensitivity or ongoing clinically important
• allergy/hypersensitivity, as judged by the investigator, at screening or Day -1, or history
• of hypersensitivity to drugs with a similar chemical structure or class to opemalirsen.
• 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 the study if
• they have any ongoing or recent (ie, during the screening period) minor medical
• complaints that may interfere with the interpretation of study data or if they are
• considered unlikely to comply with study procedures, restrictions, and requirements.
• 4 Liver disease (non-alcoholic and alcoholic steatohepatitis; drug-induced, viral, or
• autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis;
• hemochromatosis; alpha-1 antitrypsin deficiency; Wilson’s disease) including positive
• results for hepatitis B surface antigen, hepatitis B core antibody or hepatitis C virus
• antibody.
• 5 History of cirrhosis and/or hepatic decompensation, including ascites, hepatic
• encephalopathy, or variceal bleeding.
• 6 QTcF > 470 ms in participants without bundle branch block and > 480 ms in participants
• with bundle branch block.
• 7 Any of the following out of range laboratory values:
• (a) ALT or AST > 1.5 × ULN
• (b) TBL > ULN (an isolated increase in TBL in participants with Gilbert syndrome is not
• a reason for exclusion)
• (c) INR > 1.2, unless related to therapeutic anticoagulation
• (d) APTT ≥ 1.3 × normal, unless related to therapeutic anticoagulation
• (e) HbA1c ≥ 10%
• 8 Positive test for human immunodeficiency virus at screening.
• 9 Known history of drug or alcohol abuse within 1 year of screening.
• Healthy matched control participants only (Group 1):
• 10 Any clinically significant disease or disorder (eg, cardiovascular, pulmonary,
• gastrointestinal, liver, renal, neurological, musculoskeletal including bone fractures,
• 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 the results of the study, or affect the
• participant’s ability to participate in the study.
• 11 Abnormal resting vital signs (after resting for 10 minutes) of supine BP > 150 mmHg or
• < 90 mmHg systolic or > 95 mmHg or < 50 mmHg diastolic or supine pulse rate
• ≥ 100 bpm 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):
• 12 Evidence of rapidly deteriorating renal function.
• 13 Presence of unstable medical (eg, diabetes) or psychological conditions which, in the
• opinion of the investigator, would compromise the participant’s safety or successful
• participation in this study.
• 14 Renal transplant patients, that is, participants that have received a kidney transplant or
• participants waiting for organ transplant scheduled to occur during the study, and those
• with a history of acute kidney injury occurring within 3 months prior to screening.
• 15 Abnormal resting vital signs (after resting for 10 minutes) of supine BP > 180 mmHg or
• < 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 of the 3 measurements.
• Prior/Concomitant Therapy
• Healthy matched control participants only (Group 1):
• 16 Use of any prescription or non-prescription drugs (including vitamins, recreational drugs,
• and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential
• enzyme inducer) or 5 half-lives (whichever is longer) before study intervention, unless, in the opinion of the investigator and sponsor, the medication will not interfere with the
• study.
• Participants with renal impairment only (Group 2 and optional Groups 3 and 4):
• 17 Use of concurrent medication, which affect creatinine clearance such as cephalosporin
• antibiotics, ascorbic acid, trimethoprim, cimetidine, quinine within 7 days prior to Day -1.
• Prior/Concurrent Clinical Study Experience
• All participants:
• 18 Has received another new chemical entity (defined as a compound which has not been
• approved for marketing) within 30 days of study intervention in this study or, if known, 5
• half-lives from last dose in the previous study to study intervention in this study,
• whichever is longest.
• 19 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, are not
• excluded.
• Other Exclusions
• All participants:
• 20 Positive screen for drugs of abuse (unless participant has renal impairment and positive
• screen is due to medication[s] prescribed by physician) and/or alcohol test at screening or
• Day -1; a positive result for tetrahydrocannabinol and/or cannabinoids is not considered
• exclusionary.
• 21 Receipt of blood products within 2 months prior to Day -1, plasma or platelets donation
• within 1 month prior to Day -1, or any blood donation/blood loss > 500 mL within
• 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.