| Eligibility |
Inclusion Criteria:
For All Subjects:
Subjects must satisfy all of the following criteria at the Screening visit, unless
otherwise stated:
1. Males or females, of any race, between 18 and 75 years of age, inclusive.
2. Body mass index between 18.0 and 38.0 kg/m^2, inclusive.
3. Females of non-childbearing potential defined as permanently sterile (ie, due to
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or postmenopausal
(defined as females at least 45 years of age with at least 12 months post-cessation of
menses without an alternative medical cause, even with a follicle-stimulating hormone
level =40 mIU/mL, unless on hormone replacement therapy).
4. Males will agree to use contraception
5. Male subjects must not donate sperm from Check-in (Day -1) until 90 days after the
Follow-up visit.
6. Able to comprehend and willing to sign an informed consent form and to abide by the
study restrictions.
For Subjects with Normal Hepatic Function Only:
7. In good health, determined by no clinically significant findings from medical history,
PE, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations at
Screening and Check-in (Day -1), as assessed by the Investigator (or designee).
8. Matched to subjects with mild, moderate, or severe hepatic impairment in sex, age (±10
years), and body mass index (±20%).
For Subjects with Hepatic Impairment Only:
9. Documented chronic stable liver disease (Child-Pugh Class A [mild], B [moderate], or C
[severe] at Screening); diagnosis of hepatic impairment due to parenchymal liver
disease. If the Child-Pugh Class of a subject differs between Screening and Check-in,
the Child-Pugh Class documented at Screening will be utilized for enrollment. This
will exclude biliary liver cirrhosis or other causes of hepatic impairment unrelated
to parenchymal disorder.:
- 'Documented' is defined by at least 1 of the following: medical history, PE,
hepatic ultrasound, computed axial tomography scan, magnetic resonance imaging,
and/or liver biopsy.
- 'Chronic' is defined as >6 months.
- 'Stable' is defined as no clinically significant change in disease status within
the last 3 months (90 days), as documented by the subject's recent medical
history (eg, no worsening of clinical signs of hepatic impairment, or no
worsening of total bilirubin or prothrombin time by more than 50%).
10. Subjects with mild, moderate, or severe hepatic impairment may have medical findings
consistent with their hepatic dysfunction as determined by medical history, PE,
12-lead ECG, vital sign measurements, and clinical laboratory evaluations at Screening
and Check-in (Day -1), as assessed by the Investigator (or designee).
11. Non-hepatic, abnormal clinical laboratory evaluations not clinically relevant, as
judged by the Investigator (or designee) and Covance Medical Monitor.
12. Currently on a stable medication regimen, defined as not starting new drug(s) or
changing drug dose(s) within 30 days of administration of study drug (Day 1).
Concomitant medications administered within 30 days prior to administration of KD025
(Day 1) must be approved by the Investigator (or designee), Sponsor, and Covance
Medical Monitor.
13. Anemia secondary to hepatic disease will be acceptable, if hemoglobin >9 g/dL and
anemia symptoms are not clinically significant as judged by the Investigator (or
designee) and Covance Medical Monitor.
14. Platelet count =35 × 10^9 platelets/L.
15. Subjects with diabetes mellitus may be included, provided the subjects have:
1. Glycosylated hemoglobin A1c values =9.5% at Screening. Subjects with values
outside this range may be allowed by the Covance Medical Monitor on a
case-by-case basis.
2. Blood glucose values =240 mg/dL at Screening and Check-in (Day -1) while on
subjects' normal diabetes medication.
Exclusion Criteria:
Subjects will be excluded from the study if they satisfy any of the following criteria at
the Screening visit, unless otherwise stated:
For All Subjects:
1. Significant history or clinical manifestation of any metabolic, allergic,
dermatological, renal, hematological, pulmonary, cardiovascular, gastrointestinal,
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the
Investigator (or designee).
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound,
food, or other substance, unless approved by the Investigator (or designee).
3. History of stomach or intestinal surgery or resection that would potentially alter
absorption and/or excretion of orally administered drugs (uncomplicated appendectomy
and hernia repair will be allowed).
4. Clinically significant physical examination abnormality, as determined by the
Investigator (or designee).
5. Use or intend to use any drugs known to be moderate or strong inhibitors or inducers
of CYP3A4 within 14 days prior to dosing, unless deemed acceptable by the Investigator
(or designee) in consultation with the Covance Medical Monitor.
6. Use or intend to use any proton pump inhibitors or H2 antagonists within 14 days prior
to dosing, unless deemed acceptable by the Investigator (or designee) in consultation
with the Covance Medical Monitor.
7. Use or intend to use any phytotherapeutic/herbal/plant-derived preparations within 7
days prior to Check-in (Day -1), unless deemed acceptable by the Investigator (or
designee).
8. History of alcoholism or drug/chemical abuse within 2 years prior to Check-in.
9. Alcohol consumption of >21 units per week for males and >14 units for females. One
unit of alcohol equals 12 oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL)
wine.
10. Positive urine drug screen at Screening and/or Check-in (Day -1) that is not otherwise
explained by permitted concomitant medication, or positive alcohol test result at
Check-in (Day -1). Either a breath or urine alcohol test may be performed in
accordance with the standard practice of each CRU.
11. Positive human immunodeficiency virus test.
12. Participation in a clinical study involving administration of an investigational drug
(new chemical entity) in the past 30 days or 5 half-lives (whichever is longer) of the
investigational drug, prior to dosing.
13. Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages
within 7 days prior to Check-in (Day -1).
14. Receipt of blood products within 2 months prior to Check-in.
15. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to
Screening, or platelets from 6 weeks prior to Screening.
16. Poor peripheral venous access.
17. Have previously completed or withdrawn from this study or any other study
investigating KD025, and have previously received KD025.
18. Subjects who, in the opinion of the Investigator (or designee) should not participate
in this study.
For Subjects with Normal Hepatic Function Only:
19. QT interval corrected for heart rate using Fridericia's method (QTcF) >450 ms
confirmed by repeat measurement.
20. Evidence of hepatorenal syndrome and/or estimated creatinine clearance range <90
mL/min, as determined by the Investigator (or designee), calculated using the
Cockcroft-Gault equation at Screening and Check-in (Day -1).
For male subjects: ([1.23 × {140-age} × {weight in kg})])/(serum creatinine in µmol/L)
For female subjects: ([1.04 × {140-age} × {weight in kg})])/(serum creatinine in
µmol/L)
21. Ventricular dysfunction or history of risk factors for Torsade de Pointes (e.g.,
unexplained syncope, known long QT syndrome, heart failure, and cardiomyopathy).
Subjects will be excluded if there is a family history of long QT syndrome.
22. Use or intend to use any prescription medications/products other than hormone
replacement therapy, within 14 days prior to dosing, unless deemed acceptable by the
Investigator (or designee).
23. Use or intend to use slow-release medications/products considered to still be active
within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or
designee).
24. Use or intend to use any nonprescription medications/products including vitamins, and
minerals within 7 days prior to Check-in, unless deemed acceptable by the Investigator
(or designee).
25. Positive hepatitis panel. Subjects whose results are compatible with prior
immunization may be included at the discretion of the Investigator.
26. Clinically significant abnormal laboratory values (clinical chemistry, hematology,
coagulation, and urinalysis), as determined by the Investigator (or designee).
27. Significant history or clinical manifestation of hepatic disorder, as determined by
the Investigator (or designee).
28. History or presence of liver disease or liver injury as indicated by any clinically
significant deviations from normal reference ranges in liver function tests, unless
approved by the Investigator (or designee).
29. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in (Day
-1), or positive continine test at Screening or Check-in.
For Subjects with Hepatic Impairment Only:
30. QTcF >450 ms (for mild and moderate hepatic impairment) or >470 ms (for severe hepatic
impairment), confirmed by repeat measurement
31. Evidence of hepatorenal syndrome and/or estimated creatinine clearance range <90
mL/min (for mild and moderate hepatic impairment) or <60 mL/min (for severe hepatic
impairment), as determined by the Investigator (or designee), calculated using the
Cockcroft-Gault equation at Screening and Check-in (Day -1) For male subjects: ([1.23
× {140-age} × {weight in kg})])/(serum creatinine in µmol/L) For female subjects:
([1.04 × {140-age} × {weight in kg})])/(serum creatinine in µmol/L)
32. History of current diagnosis of uncontrolled or significant cardiac disease indicating
significant risk of safety for participation in the study including any of the
following:
1. Recent myocardial infarction (within 6 months of Check-in)
2. New York Heart Association Class III or IV congestive heart failure
3. Unstable angina (within 6 months of Check-in)
4. Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained
ventricular tachycardia, second or third degree atrioventricular block without a
pacemaker
5. Uncontrolled hypertension
6. Unexplained syncope
33. Use or intend to use any prescription medications/products within 14 days of study
drug administration, with the exception of stable medication regimen, as approved by
the Investigator (or designee), Sponsor, and Covance Medical Monitor; see Inclusion
Criterion #12; and prescribed hormone replacement therapy
34. Values outside the normal range for liver function tests that are not consistent with
their hepatic condition, as determined by the Investigator (or designee).
35. Clinically significant abnormal PE, vital signs, and/or ECG findings that are not
consistent with their degree of hepatic dysfunction, as determined by the Investigator
(or designee).
36. Recent history, or the treatment of, esophageal bleeding (within the past 180 days of
Screening), unless banded. If banded, it must not have occurred within 90 days of
Screening.
37. Presence of a portosystemic shunt.
38. Recent history of paracentesis within 30 days prior to Check-in (Day -1).
39. Current functioning organ transplant or awaiting organ transplant.
40. Evidence of severe ascites.
41. Current symptoms or recent history of hepatic encephalopathy (Grade 2 or above) within
3 months prior to Screening.
42. Smoke more than 10 cigarettes, or use the equivalent tobacco- or nicotine-containing
products, per day or inability to refrain from tobacco use 2 hours pre-dose until 4
hours post-dose.
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