A Study to Evaluate the Safety and Pharmacokinetics With MEDI8367 Administered in Healthy Subjects, and in Subjects With Chronic Kidney Disease

This is a Phase I, FIH, randomized, blinded, placebo-controlled study, to evaluate the safety and PK of MEDI8367 as single ascending doses (SAD) in healthy subjects and as a single dose in healthy subjects of Japanese-descent and in subjects with chronic kidney disease (CKD).

Six cohorts, Cohorts 1 to 5 (healthy volunteers including Japanese subjects in Cohort 5) each consisting of 8 subjects (total 40 subjects), and Cohort 6 (subjects with CKD) consisting of 30 subjects, will participate in the study. The starting dose is dose A of MEDI8367 with up to 3 dose escalations planned (provisional doses of dose B, dose C, and dose D).

The study will comprise of:

• A Screening Period of maximum 28 days;
• A Treatment Period during which subjects will be resident at the Clinical Unit/non-clinical sites from the day before investigational medicinal product (IMP) administration (Day -1) until at least 72 hours after IMP administration; discharged on Day 4; and
• A Follow-up Period (out-patient) with 8 visits; the final Follow-up Visit (Visit 10) within 90 ± 4 days after the last IMP dose. The study day for the last visit may be adjusted based on PK/PD results from the current and previous cohorts.

Dosing for Cohorts 1 to 4 and Cohort 6 will proceed with 2 subjects in a sentinel cohort, such that one subject will be randomized to receive MEDI8367 and one subject will be randomized to receive placebo. The blinded safety data from the sentinel subjects up to 3 days post-dose will be reviewed by the site Principal Investigator (PI) before the remaining subjects in the cohort are dosed. Dosing is proposed to continue based on a lack of significant safety findings in the first 2 subjects dosed per cohort. The remaining 6 subjects in Cohorts 1 to 4, respectively, and 28 subjects in Cohort 6, will be dosed at least 3 days after the sentinel cohort.

Inclusion criteria

• Provision of signed and dated, written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the USA) prior to any study specific procedures.
• Male and/or female subjects aged 18 to 55 years (for Cohort 6 see below), inclusive, at the Screening Visit.
• Females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit/study site, must not be lactating and must be of non-childbearing potential, confirmed at the Screening Visit by fulfilling one of the following criteria:

• Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH levels in the postmenopausal range.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
• Non-sterilized male subjects who are sexually active with a female partner of childbearing potential must use a male condom with spermicide starting from the time of IMP administration until 3 months after the final Follow-up Visit. It is strongly recommended for the female partner of a male subject to also use a highly effective method of contraception throughout this period.
• Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive, at the Screening Visit.
• Ability and willingness to adhere to the visit/protocol schedule and complete the Follow-up Period.

The subjects in Cohort 5 (subjects of Japanese descent) must fulfil the following additional criterion:

• Subjects must be of Japanese descent, defined as having 4 grandparents who are Japanese. This includes second and third generation subjects of Japanese descent whose parents or grandparents are living in a country other than Japan.

The subjects in Cohort 6 (subjects with CKD) must fulfil the following additional criteria:

• Male and/or female subjects aged 18 to 70 years, inclusive, at the Screening Visit.
• Have a BMI between 18 and 45 kg/m2 inclusive and weigh at least 50 kg and no more than 150 kg inclusive, at the Screening Visit.
• Subjects must have CKD, defined as:

• An estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and
• Macroalbuminuria, defined as 300-3000 mg albumin/g creatinine based on the spot urine sample collected at the Screening Visit and the geometric mean of 3 sequential first morning void urine sample s at Visit 2 (Day 1).
• Stable BP meeting all of the following criteria:

• BP ≤ 150/100 mmHg at the Screening Visit and Visit 2 (Day -1).
• A stable dose of Angiotensin converting enzyme inhibitors (ACEi) or Angiotensin receptor blockers (ARB) for at least 4 weeks prior to the Screening Visit, per the local/site guidelines. Subjects who have been deemed unable to tolerate ACEi or ARB therapy due to allergy or complications may be enrolled. Dose adjustment of the next/previous titration dose within 2 weeks of the Screening Visit is acceptable.
• A stable dose of any other antihypertensive medication (including diuretic therapy) for at least 4 weeks prior to the Screening Visit.

Exclusion criteria

• History of any disease or condition that, in the opinion of the site PI and/or medical monitor, would place the subject at an unacceptable risk to participate in this study or interfere with evaluation of the investigational product or interpretation of subject safety or study results, including, but not limited to:

• History of any blood brain barrier (BBB) breakdown such as, but not limited to, recent traumatic brain/spinal injury, multiple sclerosis, active central nervous system vasculitis, recent stroke or cerebral hemorrhage, neurosurgery, meningoencephalitis, active or uncontrolled seizures, or lumbar puncture within the preceding 6 months.
• Prior malignancy other than non-melanoma skin cancer or cervical cancer in situ treated with apparent success with curative therapy (response duration of > 5 years).
• Subjects with renal allografts.
• Proliferative retinopathy confirmed by retinal imaging at the Screening Visit
• History or presence of hematological, hepatic or renal disease (except Cohort 6) or any other condition known to interfere with administration, absorption, distribution, metabolism or excretion of drugs.
• Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP.
• Any clinically relevant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during screening or Day -1 that, in the opinion of the site PI or medical monitor, may compromise the safety of the subject in the study, interfere with the evaluation of the IMP, or reduce the subjects' ability to participate in the study.

Note: Abnormal urinary findings will not exclude subjects in Cohort 6.

• Any laboratory values with the following deviations at screening or admission (for Cohort 6 see below):

• ALT > Upper limit of normal (ULN).
• AST > ULN.
• Total bilirubin (TBL) > ULN (unless due to Gilbert's syndrome).
• Creatinine > ULN.
• WBC count < lower limit of normal (LLN).
• Hb < LLN.
• Impaired renal function, defined as eGFR < 90 mL/min/1.73 m2 based on the CKD-EPI equation.
• Any positive result at the Screening Visit for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).
• Abnormal vital signs at Screening or Visit 2 (Day -1), after 10 minutes supine rest, defined as any of the following:

• SBP < 90 mmHg or ≥ 140 mmHg.
• DBP < 50 mmHg or ≥ 90 mmHg.
• HR < 45 or > 85 beats per minute (bpm).
• Any clinically important abnormalities in rhythm, conduction or morphology of the resting 12-lead ECG as considered by the site PI that may interfere with the interpretation of QTc interval changes, including abnormal ST-T-wave morphology or left ventricular hypertrophy, at screening or admission.

• Prolonged QTcF > 450 ms.
• Family history of long QT syndrome.
• PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).
• PR (PQ) interval prolongation (> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.
• Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS > 110 ms. Subjects with QRS > 110 ms but < 120 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation.
• Known or suspected history of drug abuse as judged by the site PI.
• History of alcohol and/or substance abuse within the last 6 months or excessive intake of alcohol as judged by the site PI.
• Positive screen for drugs of abuse, including recreational marijuana, at the Screening Visit or upon admission to the Clinical Unit/study. Subjects who utilize benzodiazepines for chronic anxiety or sleep disorders may be permitted to enter the study.
• History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the site PI or history of hypersensitivity to drugs with a similar chemical structure or class to MEDI8367.

• History of severe allergic reaction requiring hospitalization or,
• History of severe reaction to any medication including biologic agents or human gamma globulin therapy or,
• History of allergy or reaction to any component of the IMP formulation.
• Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega-dose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals with the 2 weeks or 5 half-lives prior to the first administration of IMP (Day 1) (whichever is longer). Further clarification regarding specific medications is provided below:

• Female subjects will be allowed to take hormone replacement therapy.
• Current or previous use of systemic corticosteroids within 60 days prior to Day 1 is prohibited
• Topical, intra-articular, nasal, inhaled, and ophthalmic corticosteroids are permitted.
• Antiplatelet therapy (i.e., aspirin, clopidogrel [Plavix], ticagrelor [Brilinta], or prasugrel), anticoagulation therapy (i.e., warfarin, factor Xa inhibitors, direct thrombin inhibitors, or heparin), and thrombolytic use, in the past month prior to Day 1 or planned use during the duration of the study, are prohibited.
• Plasma donation within one month of the Screening Visit or any blood donation/blood loss > 500 mL during the 3 months prior to Day 1 (or > 1200 mL in the year prior to Day 1).
• Has received another new chemical or biologic entity (defined as a compound which has not been approved for marketing) within 4 months or 5 half-lives prior to the Screening Visit (whichever is longer), or planned participation in such a study prior to the end of the follow-up period.

Note: subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded.

• Scheduled surgery, including dental surgery, within 8 weeks of the scheduled completion date of the study.
• Involvement of any AstraZeneca, Clinical Unit, Contract Research Organization (CRO), or study site employee or their close relatives, regardless of the employee's role.
• Judgement by the site PI that the subject should not participate in the study if they have any ongoing or recent (i.e., during the Screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements.
• Subjects who cannot communicate reliably with the site PI.
• Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

The following exclusion criteria apply to subjects in Cohort 6 (subjects with CKD):

• Clinically significant late diabetic complications, including symptoms consistent with angina, congestive heart failure, and peripheral arterial disease (claudication), or other complications such as proliferative retinopathy, maculopathy, or gastroparesis.
• Chronic kidney disease due to abnormal anatomy of the urinary system or autosomal dominant polycystic kidney disease (ADPKD).
• Aggressive or serious neuropathies, in particular immune related demyelinating neuropathies such as Guillain-Barré, or one of its variants.
• Any laboratory values with the following deviations at screening or admission:

• ALT > 2 x ULN.
• AST > 2 x ULN.
• TBL > ULN (unless due to Gilbert's syndrome).
• Hb <100 g/L
• Glycated hemoglobin (HbA1C) > 10.5% measured at the Screening Visit.
• Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, mega-dose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals with the 2 weeks or 5 half-lives prior to the first administration of IMP (Day 1) (whichever is longer). Further clarification regarding specific medications is provided below:

• Subjects may take their usual prescribed medication, or any other medication taken on the advice of their physician with the exception of systemic corticosteroids. They should have been on a stable drug regimen with no changes in agents or doses for at least 4 weeks prior to participation in the study. Dose adjustment of the next/previous titration dose within 2 weeks of the Screening Visit is acceptable.
• Any serum creatinine-altering drugs within 1 month prior to the Screening Visit including but not limited to amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, probenecid, ranolazine, trimethoprim, aminoglycosides, or cephalosporins are prohibited.
• Use of insulin is prohibited.