Clinical trial NCT03022799: Phase I, KM-819 in Healthy Subjects for Parkinson's Disease
Official title: A First in Human, Randomized, Double-blind, Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Following Single and Multiple Oral Doses of KM-819 in Healthy Young Adult and Elderly Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Parkinson's Disease
Keywords: FAF1
Fas (TNFRSF6)-associated factor 1
FAF1 inhibitor
KM-819
Lead sponsor: Kainos Medicine Inc.
Sponsor class: INDUSTRY
First posted: 2017-01-18
Enrollment: 88
Sex: ALL
Minimum age (years): 19
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This first in human, single-center, randomized, placebo-controlled, double blind, sequential group Phase 1 study in healthy subjects will be conducted to evaluate the safety, tolerability, PK, and PD following the escalation of single and multiple doses of KM-819.

The study will consist of 2 parts. In Part A, up to 5 cohorts of young adult male subjects, and 1 single dose cohort of elderly male or post menopausal female subjects will receive escalating single doses of KM-819. In Part B, up to 4 cohorts of healthy young adult male subjects and 1 multiple dose cohort of elderly male or post menopausal female subjects will receive escalating multiple doses of KM-819. Part B will be conducted after completion of all cohorts of young adult male subjects in Part A.

Dose escalation to the next level will be determined using safety, tolerability, and PK data of the previous cohort.

Part A, Single Ascending Dose (SAD) Up to 40 healthy young adult male subjects and 8 healthy elderly male or post menopausal female subjects will be enrolled and randomized to receive either KM-819 or placebo.

Each of the 5 dose escalation cohorts consists of 8 healthy young adult male subjects; 6 subjects will receive 10, 30, 100, 200, or 400 mg of KM-819 and 2 subjects will receive placebo. In each single dose cohort, dosing of subjects will be sentinel, i.e., 2 subjects will be dosed on the first day (1 subject will receive active treatment and 1 subject will receive placebo) and the remaining 6 subjects will be dosed at least 24 hours after the first 2 subjects.

Cohorts will be dosed sequentially with escalating doses. Eight elderly male or post-menopausal female subjects will be enrolled into an additional cohort; 6 subjects will receive 200 mg KM-819 and 2 subjects will receive placebo.

Part A consists of a Screening period of up to 28 days, and a 3 day Confinement period when subjects are hospitalized for study activities. Subjects are required to return for outpatient visits on Day 4, 7 and for the Follow up Visit on Day 14.

Part B, Multiple Ascending Dose (MAD) Up to 32 healthy young adult male subjects and 8 healthy elderly male or post menopausal female subjects will be enrolled and randomized to receive either KM-819 or placebo.

Each of the 4 dose escalation cohorts consists of 8 healthy young adult male subjects; 6 subjects will receive 30, 100, 200, or 400 mg of KM-819 once a day (QD) for 7 days and 2 subjects will receive placebo. Cohorts will be dosed sequentially with escalating doses.

Eight elderly male or post-menopausal female subjects will be enrolled into an additional cohort; 6 subjects will receive 200 mg KM-819 QD for 7 days and 2 subjects will receive placebo.


Eligibility criteria: Inclusion Criteria:

1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2. Male subject should be 19 to 45 years old (for young adult cohorts) or over 60 years old (for elderly cohorts).
3. Subject has a body mass index (BMI) range of 18.5 to 30 kg/m2 inclusive at Screening.
4. Male subject and his female spouse/partner who is of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (at least one of which must be a barrier method) starting at Screening and continuing throughout the study period and for 90 days after final study drug administration. Highly effective contraception is defined as:

   * Established use of oral, injected, or implanted hormonal methods of contraception
   * Placement of an intrauterine device or intrauterine system
   * Barrier methods of contraception: condom with spermicidal foam, gel, film, cream, suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, cream, or suppository
5. Male subject must not donate sperm starting at Screening, throughout the study period and for at least 90 days after final study drug administration.
6. Female subject must be over 60 years old and post-menopausal (defined as at least 1 year without any menses) prior to Screening.
7. Subject agrees not to participate in another investigational study while on study treatment.

Exclusion Criteria:

1. Subject has a known or suspected hypersensitivity to KM-819, or any components of the formulation(s) used.
2. Subject has previously participated in a clinical study with KM-819.
3. Subject has any of the liver enzymes (aspartate aminotransferase \[AST\], alanine transaminase \[ALT\], alkaline phosphatase, γ glutamyl transferase) or total bilirubin (TBIL) above the ULN. If any liver enzyme is \> 1 × ULN but \< 1.5 × ULN, the assessment may be repeated once during the Screening period or on check-in. If the repeated assessment is above the ULN, it is exclusionary. If the initial value is \> 1.5 × ULN, it cannot be repeated and is exclusionary.
4. Subject has any clinically significant history of allergic conditions (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, allergic rhinitis or rhino-conjunctivitis, or house dust mite allergy at time of dosing).
5. Subject with a history of a suicide attempt or suicidal behavior. Any recent suicidal ideation (a level of 4 or 5) within the last 3 months, or having a positive C-SSRS at check-in (Day -1), or who is at significant risk to commit suicide, as judged by the Investigator using the C SSRS at Screening.
6. Subject has/had febrile illness or symptomatic viral, bacterial (including upper respiratory infection) or fungal (non-cutaneous) infection within 1 week before site check-in.
7. Subject has any clinically significant abnormality following the Investigator's review of the physical examination, ECG, and protocol-defined clinical laboratory tests at Screening or site check-in.
8. Subject has a mean pulse \< 40 or \> 90 beats per minute (bpm); mean systolic blood pressure (SBP) \> 140 mmHg; or mean diastolic blood pressure (DBP) \> 90 mmHg (measurements taken in triplicate after subject has been resting in the supine position for 5 minutes; pulse will be measured automatically) at Screening or check-in. If the mean pulse, mean SBP, or mean DBP is out of the range specified above, 1 additional triplicate measurement may be taken at Screening and check-in.
9. Subject has a mean QTcF interval of \> 430 msec (for males) and \> 450 msec (for females) at Screening or check-in. If the mean QTcF exceeds the limits above, 1 additional triplicate ECG can be taken. If this triplicate also gives an abnormal result, the subject should be excluded.
10. Subject has a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsade de pointes, structural heart disease, or a family history of Long QT Syndrome.
11. Subject has use of any prescribed or non-prescribed drugs (including vitamins, hormone replacement therapy, natural and herbal remedies, e.g., St. John's Wort) in the 2 weeks before study drug administration. Acetaminophen up to 2000 mg/day is allowed.
12. Subject has had any use of tobacco- or nicotine-containing products within 6 months prior to Screening.
13. Subject has history of consuming more than 14 units of alcoholic beverages per week within 6 months prior to Screening or has a history of alcoholism or abuse of amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates (drugs-of-abuse) within the past 2 years prior to Screening (Note: 1 unit = 355 mL of beer, 118 mL of wine, or 29 mL of spirits/hard liquor) or the subject tests positive at Screening or site admission for alcohol or drugs of-abuse.
14. Subject has used any drugs-of-abuse within 3 months before check in.
15. Subject has used any inducers of metabolism (e.g., barbiturates, rifampin) in the 3 months prior to check-in.
16. Subject has any significant blood loss, donated 1 unit (450 mL) of blood or more, or received a transfusion of any blood, or blood products within 60 days or donated plasma within 7 days before check-in.
17. Subject has a positive serology test for hepatitis B surface antigen (HbsAg), anti hepatitis A virus Immunoglobulin M (HAV IgM), anti-hepatitis C virus (HCV Ab), or anti-human immunodeficiency virus (HIV Ab).
18. Subject has participated in any interventional clinical study or has been treated with any investigational drugs within 3 months or 5 half lives, whichever is longer, before the initiation of Screening.
19. Subject has (recent history of) any other condition which, in the opinion of the Investigator, precludes the subject's participation in the trial.
20. Subject is an employee of the Kainos Medicine, Inc. or vendors involved in the study.

    Additional Exclusion Criteria for Young Adult Subjects
21. For young adult cohorts, subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy, as judged by the Investigator or designee.

Exclusion Criteria for Elderly Subjects Replacement for Exclusion No. 8 above 8. Subject has a mean pulse \< 50 or \> 90 bpm; mean SBP \> 160 mmHg; mean DBP \> 100 mmHg (measurements taken in triplicate after subject has been resting in supine position for 5 minutes; pulse will be measured automatically).

Replacement for Exclusion No. 21 above 21. For elderly cohorts, subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy that is not well managed and stable, as judged by the Investigator or designee.

Additional Exclusion Criteria 22. Elderly subject is excluded if the Glomerular Filtration Rate (calculated based on Cockcroft-Gault formula) is \< 60 mL/min/1.73 m2.

23. Clinically significant abnormal findings in the lumbar X-ray examination (only for elder subjects for MAD study).

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: From screening (Day-28 to Day -2), Day -1 to Day 4, Day 7, and follow-up visit Day 14.
Secondary outcomes:
measure: Cmax (Maximum Plasma Concentration Determined Directly From the Concentration-time Profile)
timeFrame: Part A: Day1 to Day 4. Part B: Day-1 to Day 8
measure: Tmax (Time to Achieve Maximum Observed Plasma Concentration Determined Directly From the Concentration-time Profile)
timeFrame: Part A:Day 1 to 4; Part B: Day 1 to Day 8
measure: t½ (Apparent Terminal Elimination Half Life)
timeFrame: Part A: Day 1 to Day 4. Part B: Day1 to Day 8
measure: Tlag (Lag Time)
timeFrame: Part A: Day1 to Day 4. Part B: Day 1 to Day 8
measure: AUClast (Area Under the Plasma Concentration-time From Predose (Time 0) to the Last Quantifiable Concentration)
timeFrame: Part A: Day 1 to 4; Part B: Day 1 to Day 8
measure: AUCinf (Area Under the Plasma Concentration-time Curve From Predose (Time 0) Extrapolated to Infinity)
timeFrame: Part A: Day 1 to 4; Part B: Day 1 to Day 8
measure: %AUCex (Percentage of AUCinf That is Due to Extrapolation Beyond Tlast)
timeFrame: Part A: Day 1 to 4; Part B: Day 1 to Day 8
measure: CL/F (Apparent Oral Clearance)
timeFrame: Part A: Day 1 to 4; Part B: Day 1 to Day 8
measure: Vz/F (Apparent Volume of Distribution)
timeFrame: Part A: Day 1 to 4; Part B: Day 1 to Day 8
measure: AUCtau (Area Under the Plasma Concentration-time Curve for a Dosing Interval) (Part B)
timeFrame: Part B: Day 1 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose, predose on Days 2, 3, 4, 5, 6, and on Day 7 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1,
measure: Rac(AUC) (Observed Accumulation by AUC) (Part B)
timeFrame: Part B: Day 1 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose, predose on Days 2, 3, 4, 5, 6, and on Day 7 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1,
measure: Rac (Cmax) (Observed Accumulation by Cmax) (Part B)
timeFrame: Part B: Day 1 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose, predose on Days 2, 3, 4, 5, 6, and on Day 7 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1,
measure: AUCtau_D (AUCtau Divided by Dose) (Part B)
timeFrame: Part B: Day 1 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose, predose on Days 2, 3, 4, 5, 6, and on Day 7 predose (within 30 minutes prior to study drug administration) and 0.25, 0.5, 1,
measure: Change From Baseline for Bond and Lader Visual Analogue Scale (VAS)
timeFrame: At Day 1 (3 hours post dose), Day2, Day 3, Day 4, and Day 8.
measure: Korean Wechsler Adult Intelligence Scale-IV (K-WAIS-IV)
timeFrame: Part A: Day 1; Part B: Day 7
measure: Alpha Synuclein Oligomer in Plasma and CSF (Part B)
timeFrame: Plasma - Part B: Day 7 (at 1 hour after last dosing) / CSF - Part B: Day 7 (at 1 hour after last dosing)
measure: Change From Baseline Total Tau in CSF (Part B)
timeFrame: CSF - Part B: Day 1 (at -120 minutes to 0 minute prior to the first dosing) and on Day 7 (at 1 hour after last dosing)
measure: Change From Baseline Phospho-Tau in CSF (Part B)
timeFrame: CSF - Part B: Day 1 (at -120 minutes to 0 minute prior to the first dosing) and on Day 7 (at 1 hour after last dosing)
measure: Ratio of CSF Concentration/Plasma Cmax (Part B)
timeFrame: Plasma - Part B: Day 7 (at 1 hour after last dosing) / CSF - Part B: on Day 7 (at 1 hour after last dosing)
Other outcomes:
Locations:
city: Seongnam
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
state: Gyeonggi-do
Study officials:
affiliation: Kainos Medicine Inc.
name: Jae Moon Lee, PhD
role: STUDY_DIRECTOR
References: