Phase I, KM-819 in Healthy Subjects for Parkinson's Disease
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Intervention: KM-819; Placebo
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 88.0
Sex: All
Minimum age: 19 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: FAF1; Fas (TNFRSF6)-associated factor 1; FAF1 inhibitor; KM-819

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).