Pilot PK/PD Study of DS-1093a in Patients With Chronic Kidney Disease

An Open-Label, Randomised, Parallel Group Pilot Study to Assess the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Single Doses of DS-1093a in Patients With Chronic Kidney Disease

DS-1093a is an inhibitor of hypoxia-inducible factor prolyl hydroxylases, and is expected to produce transient dose / exposure dependent increases in erythropoietin levels in subjects with chronic kidney disease (CKD). This study will be conducted in 2 parts. Part A will involve subjects with stage 3b or 4 CKD, and will be an open, non-controlled parallel group investigation of three single doses of DS-1093a (6 subjects/dose), in which allocation to dose will be randomised. On completion of this part of the study an optional fourth dose may be tested to gain a more complete understanding of the PK/PD behaviour of DS-1093a. Part B will be an open, non-controlled investigation of a single dose of DS-1093a in CKD subjects (n=6) receiving haemodialysis. The dose for Part B will be determined based on the data from Part A.

Inclusion Criteria:

• Male and female patients aged 18 - 70 years (inclusive).
• Female patients must be of non-childbearing potential (post-menopause or surgical sterilization). In women younger than 60 years a follicle-stimulating hormone (FSH) test will be conducted to confirm post-menopausal status (i.e., FSH ≥ 30 mU/mL).
• Part A: CKD stage 3b (eGFR: < 45 to ≥ 30 mL/min) or stage 4 (eGFR: < 30 to ≥ 15 mL/min). The CKD-EPI equation will be used for the eGFR estimation.
• Part B: Patients on chronic haemodialysis for at least 6 months and stable Hb levels (i.e., +/- 1 g/dL) for the last 6 months.
• Patient can be washed out from ESAs for at least 3 weeks (2 weeks prior to dosing and 1 week post-dose).
• Baseline Hb level ≥10 g/dL.
• Willingness to give written consent to participate after reading the ICF, and after having the opportunity to discuss the trial with the Investigator or his delegate.
• Male patients must be willing to use a reliable method of contraception during the trial, and for 4 months afterwards

Exclusion Criteria:

• Use of ESAs within 2 weeks prior to dosing.
• Uncontrolled hypertension despite optimal medical therapy, defined as > 160/100 mmHg after 10 minutes of rest at screening, and > 180/110 mmHg after 10 minutes of rest on Day -1 pre-dose.
• Known haemoglobinopathy.
• Acute renal failure (as judged by the Investigator).
• History of kidney transplant regardless of functionality.
• Start of any new medication or any changes to a current dosage within 7 days prior to study drug administration.
• Chronic liver disease.
• Positive hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody test.
• Positive test for human immunodeficiency virus (HIV)-1 or HIV-2.
• A history of gastrointestinal bleeding.
• History of a thrombotic event (e.g., myocardial infarction, stroke or transient ischemic attack, peripheral embolism, venous thromboembolism, etc.)
• Patients with poorly controlled diabetes despite optimal medical therapy.
• A history of cancer, except basal cell skin cancer, squamous cell skin cancer, or cervical cancer (if judged by the Investigator to be in full remission).
• Hypersensitivity to any components of the study drug.
• Requirement for any concomitant medication that cannot be withheld on Day 1 until 4 hours post-dose (insulin is allowed to cover the breakfast, if necessary).
• Clinically relevant abnormal medical history, physical findings, ECG, or laboratory values at the screening assessments that could interfere with the objectives of the trial or the safety of the patient.
• Participation in another investigational drug trial within 30 days prior to dosing (or 5 times the half-life of the drug, whichever is longer) or exposure to more than three new investigational agents within 12 months prior to enrolment.
• Abuse of drugs or alcohol during the 2 years before the first dose of trial medication.
• Ingestion of alcohol within 72 hours prior to dosing and during confinement. Outside the in-house period, regular alcohol consumption must not exceed 16 units for males and 7 units for females per week (1 unit equals 340 mL of beer, 115 mL of wine or 43 mL of spirits).
• Positive drug screen (if not due to concomitant medication) or alcohol breath test at screening and/or Day -1.
• Patients who smoke more than 10 cigarettes per day (or equivalent), and who would not be able to abstain from smoking during the in-house period.
• Concomitant use of medications known to affect the elimination of serum creatinine (e.g., trimethoprim or cimetidine) and competitors of renal tubular secretion (e.g., probenecid) within 30 days before dosing.
• Use of a strong inducer or inhibitor of CYP enzymes, during the 30 days before dosing.
• Use of any other prohibited medication.
• Loss of more than 400 mL blood, or donation of blood, plasma, platelets, or any other blood components, during the 3 months before the trial, or unwilling to abstain from donating during the study and for 3 months after receipt of the final dose of trial medication.
• Possibility that the patient will not cooperate with the requirements of the protocol