| Eligibility |
Inclusion Criteria:
All Subjects:
1. Individuals who provide freely given written consent for participating in the study.
2. Men and women aged = 18 and = 75 years at the date of providing informed consent.
3. Subjects with a BMI in the range 18.0 to 40.0 kg/m2.
4. Females will not be pregnant or lactating, and females of childbearing potential and
males will agree to use contraception.
5. Able to comprehend and willing to sign an ICF and to abide by the study restrictions.
Subjects with Hepatic Impairment:
6. Subjects must meet the criteria for mild or moderate hepatic impairment based on CP
classification. Subjects will be classified at Screening based on CP score and
classification will be repeated at Check-in. If the hepatic function classification
for the subject is not the same at the 2 timepoints, enrollment of the subject into a
hepatic category group will be based on the CP score at Screening.
7. Subjects have stable hepatic function with a diagnosis of chronic disease of > 6
months, defined as no clinically significant change in disease status within the 60
days prior to the Screening visit or 90 days prior to drug administration on Day 1
(whichever is longer), as documented by the subject's recent medical history.
8. Subjects are on a stable medication dose(s) and/or treatment regimen(s) for treatment
of hepatic impairment during the 30 days preceding the first dose of IMP. Drugs known
to be moderate-to-potent inhibitors or inducers of CYP3A4/5 enzyme will not be
allowed. Subjects requiring medications that are moderate-to-potent inhibitors or
inducers of CYP3A4/5 may have these medications discontinued for purposes of
qualifying for at least 30 days prior to dosing day for this study. Adjustments may be
made if deemed medically safe and also acceptable to the Sponsor and Medical Monitor.
9. Subjects with mild or moderate hepatic impairment may have medical findings consistent
with their hepatic dysfunction, as determined by medical history, physical
examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations
at Screening and Check-in. Subjects with abnormal findings considered not clinically
significant by the Investigator will be eligible. Vital signs between the following
ranges and stable (measured in a supine position after a minimum of 5 minutes supine):
1. Systolic blood pressure = 90 and = 160 mmHg
2. Diastolic blood pressure = 50 and = 95 mmHg
3. Pulse rate = 45 and = 100 bpm
Healthy Subjects with Normal Hepatic Function:
10. Subjects with no clinically significant abnormalities in liver function test results
(AST, ALT, gamma-glutamyl transferase [?-GTP], alkaline phosphatase, total bilirubin,
albumin [Alb], and PT) at Screening and Check-in. In good health, determined by no
clinically significant findings from medical history, physical examination, 12-lead
ECG, vital signs measurements, and clinical laboratory evaluations (congenital
nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert's syndrome based on total
and direct bilirubin] is not acceptable) at Screening and Check-in as assessed by the
Investigator. Vital signs between the following ranges and stable (measured in a
supine position after a minimum of 5 minutes supine):
1. Systolic blood pressure = 95 and = 150 mmHg mmHg
2. Diastolic blood pressure = 50 and = 90 mmHg
3. Pulse rate = 45 and = 100 bpm
Exclusion Criteria:
All Subjects:
1. Significant history or clinical manifestation of any metabolic, allergic,
dermatological, renal, hematological, pulmonary, cardiovascular, gastrointestinal,
neurological, respiratory, endocrine, or clinically significant psychiatric disorder,
as determined by the Investigator. History of significant hypersensitivity,
intolerance, or allergy to any drug compound, food, or other substance, unless
approved by the Investigator.
2. History of stomach or intestinal surgery or resection that would potentially alter
absorption and/or excretion of orally administered drugs (uncomplicated appendectomy,
hernia repair, and cholecystectomy will be allowed).
3. Use of any prescriptions or substances that are known to be moderate to strong
inducers or inhibitors of CYP3A4/5 within 30 days prior to dosing and during the
study.
4. Use or intend to use any medications/products known to alter drug absorption,
metabolism, or elimination processes, including St. John's wort, within 30 days prior
to dosing, unless deemed acceptable by the Investigator.
5. Consumption of foods and beverages containing poppy seeds, grapefruit, or Seville
oranges from 7 days prior to dosing until End of Study.
6. Consumption of caffeine-containing foods and beverages from 48 hours prior to
Check-in.
7. Poor peripheral venous access.
8. Engaged in strenuous exercise within 7 days of Check-in.
9. Alcohol consumption is prohibited from 72 hours prior to dosing and during the study.
10. Subjects who were dosed in another clinical trial, or equivalent study of a drug or
medical device, within 30 days, or 5 times the half-life of the IMP (whichever is
longer) prior to IMP administration in the current study.
11. Subjects with receipt of blood products within 2 months prior to Check-in.
12. Subjects with donation of blood (> 200 mL) from 3 months prior to Screening, donation
of plasma from 2 weeks prior to Screening, or donation of platelets from 6 weeks prior
to Screening.
13. Subjects who test positive for acquired human immunodeficiency virus, including
positive serology test results for hepatitis B surface antigen and/or human
immunodeficiency virus 1/2. Subjects whose results are compatible with prior
immunization for hepatitis B or natural immunity, and who tested positive for isolated
hepatitis B core antibody with viral load negative may be included at the discretion
of the Investigator.
14. Subjects who test positive for drugs of abuse at Screening and Check-in, with the
exception of prescribed opioids and tetrahydrocannabinols (THC, marijuana) for pain
management (Investigator verification required).
15. Subjects with positive urine drug screen for drugs of abuse at Screening and Check-in
(opiates, amphetamines, methamphetamines, cannabinoids, benzodiazepines, cocaine,
barbiturates, or methadone) or positive alcohol test (at Check-in only). Additionally,
subjects who test positive for benzodiazepines may be allowed if prescribed under the
care of a physician and reviewed/verified by Investigator.
16. Subjects with suicidal ideation or a positive score on the Baseline Columbia-Suicide
Severity Rating Scale (C-SSRS).
17. Subjects with current or a history of significant hypersensitivity, intolerance, or
allergy to any drug compound, food, or other substance, unless approved by the
Investigator.
18. Subjects who contracted an infectious disease requiring hospitalization within 8 weeks
prior to Screening.
19. Subjects who have previously received KW-6356.
20. Any other subjects who are determined by the Principal Investigator to be unsuitable
for participation in this study.
21. Subjects with any current disease requiring treatment making study participation
difficult, as determined by the Principal Investigator. Specifically, subjects with
cardiovascular, clinically significant psychiatric, or gastrointestinal disorders are
excluded.
Subjects with Hepatic Impairment:
22. Subject smokes more than 10 cigarettes (ie, 1/2 pack) per day or equivalent (eg,
e-vapor cigarette, pipe, cigar, chewing tobacco, nicotine patch, nicotine gum) and is
unable to abstain from the use of tobacco products within 2 hours prior to and 4 hours
after dose administration.
23. Subject has an alpha-fetoprotein level > 50 ng/mL.
24. History of paracentesis within 3 months prior to Check-in. Subject has required new
medication for hepatic encephalopathy or an increase in dose of present medication for
hepatic encephalopathy within 3 months prior to Check-in.
25. Subject has used prescription drugs within 14 days of IMP administration, with the
exception of established therapy for hepatic disease and the treatment of disorders
that have been stable for at least 30 days before IMP administration, as approved by
the Investigator and in consultation with the Sponsor's Medical Monitor.
26. History of drug abuse within 1 year prior to Screening.
27. History of alcohol abuse within 3 months prior to Screening or consumes > 21 units per
week for males and > 14 units per week for females. One unit of alcohol equals 12 oz
(360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL) wine.
28. Subject has evidence of hepatorenal syndrome or creatinine clearance < 60 mL/minute as
calculated by using the Cockcroft-Gault equation.
29. Subject has a current functioning organ transplant or is waiting for an organ
transplant.
30. History of unstable diabetes mellitus as evidenced by hemoglobin A1c = 9% at
Screening.
31. Subjects with severe ascites and/or pleural effusion at Screening and Check-in.
32. Subject has had esophageal banding within 3 months prior to Check-in or required any
other treatment for gastrointestinal bleeding within 6 months prior to Check-in.
33. Subjects with history of or current severe hepatic encephalopathy (Grade 2 or higher)
within 3 months.
34. History or 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 (eg, sustained
ventricular tachycardia, second- or third- degree atrioventricular block without
a pacemaker).
5. Uncontrolled hypertension.
35. Subjects with mild or moderate hepatic impairment ECG findings deemed clinically
significant by the Investigator or Medical Monitor.
36. Subjects with any of the following laboratory results at Screening and Check-in:
- Platelet count < 50,000/mm3
- Hemoglobin <9 g/dL
37. Subjects with biliary liver cirrhosis or other causes of hepatic impairment not
related to parenchymal disorder and/or disease of the liver, including hepatocellular
carcinoma.
38. Subjects with history of portacaval shunt surgery, including transjugular intrahepatic
portosystemic shunts.
39. Subjects with other causes of CP scores between 5 and 9 (inclusive) that are unrelated
to hepatic impairment.
Healthy Subjects with Normal Hepatic Function:
40. Use or intend to use any prescription medications/products other than hormone
replacement therapy (HRT), and oral, implantable, transdermal, injectable, or
intrauterine contraceptives within 30 days prior to dosing, unless deemed acceptable
by the Investigator.
41. Use or intend to use any nonprescription medications/products including vitamins,
minerals, and phytotherapeutic-/herbal-/plant-derived preparations within 7 days prior
to Check-in, unless deemed acceptable by the Investigator. The occasional use of
paracetamol/acetaminophen (not more than 2 g/day for up to 3 consecutive days) or
other medication will be approved by Sponsor on a case-by-case basis.
42. History of drug abuse within 2 years prior to Screening.
43. History of alcohol abuse within 12 months prior to Screening or consumes > 21 units
per week for males and > 14 units per week for females. One unit of alcohol equals 12
oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL) wine.
44. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in.
45. Positive urine cotinine test at Screening or Check-in.
46. Subject has creatinine clearance < 80 mL/minute as calculated by using the
Cockcroft-Gault equation.
47. Use or intend to use slow-release medications/products considered to still be active
within 30 days prior to IMP administration, unless deemed acceptable by the
Investigator.
48. Subjects who tested positive at Screening for hepatitis C antibody indicating acute or
chronic infection.
49. Significant history or clinical manifestation of any hepatic disease, as determined by
lab abnormalities: aspartate aminotransferase, alanine aminotransferase, alkaline
phosphatase, or alpha-fetoprotein > 1 × upper limit of normal or as deemed clinically
significant by the Investigator.
50. Ventricular dysfunction or history of risk factors for Torsades de Pointes (eg,
unexplained syncope, known long QT syndrome, heart failure, and cardiomyopathy).
Subjects will be excluded if there is a family history of long QT syndrome. QTcF must
not be > 450 ms for male subjects or > 470 ms for female subjects, or ECG findings
deemed clinically significant by the Investigator or Medical Monitor.
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