Parkinson Disease
Conditions
Keywords
Inhibition of FAF1(Fas (TNFRSF6)-associated factor 1), Multiple Ascending Dose (MAD), Neuroprotection, Alpha-synuclein inhibition, KM-819
Brief summary
The goal of this study is to test KM-819 in halting or slowing the progression of Parkinson's disease. The study evaluates the safety and tolerability of multiple ascending doses of KM-819 in healthy older adults and participants with Parkinson's disease.
Detailed description
The overall study will consist of three parts (Part 1a, Part 1b and Part 2). Part 1 of this study will evaluate the safety, tolerability and plasma PK of multiple ascending doses (MAD) of KM-819 in healthy older adults (Part 1a) and participants with Parkinson's disease (Part 1b). * Part 1a is a randomized, double-blind, Multiple Ascending Dose (MAD) study in healthy older adults that will include 3 cohorts. * Part 1b is a randomized, double-blind, MAD study in participants with Parkinson's disease that will include 3 cohorts. Part 2 of the study is a randomized, double-blind, multiple dose study in participants with Parkinson's disease that will include 2 cohorts. It is designed to test the safety, tolerability, plasma PK and pharmacodynamic effects of KM-819 in participants with Parkinson's disease. The study will also assess the degree to which those treated with KM-819 will experience gains in overall daily function within the context of improved Parkinson's disease motor and non-motor symptoms in comparison to placebo. Participants will be randomized to receive KM-819 or matching placebo at doses to be determined based on the findings from Part 1 in a 2:1 ratio.
Interventions
DRUGKM-819
Participants will receive oral doses of KM-819 once-daily
DRUGPlacebo
Participants will receive matching placebo once-daily
Sponsors
Parexel
FAScinate Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-Blinded
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Participant is a healthy volunteer or has a clinical diagnosis of idiopathic Parkinson's disease. * Participant is on a stable dose of medications to treat Parkinson's disease at least 8 weeks prior to randomization * Presence of idiopathic Parkinson's disease Hoehn and Yahr Stage ≤ 4 * History or current use of dopamine/dopaminergic drugs, levodopa with decarboxylase inhibitor or dopaminergic agonists, with a stable dosage for at least 30 days prior to Screening * Body mass index (BMI) within the range 18.5 to 35 kg/m2 (inclusive) * A male participant must not have a pregnant or breastfeeding partner and must agree to use a highly effective contraception method starting from Screening and refrain from donating sperm during this period * A female participant is eligible to participate if she is not pregnant, not breastfeeding
Exclusion criteria
* Diagnosis of neurodegenerative disorder other than idiopathic Parkinson's disease resulting in dementia or atypical parkinsonism * Life-time history of a suicide attempt as determined by the Columbia-Suicide Severity Rating Scale (C-SSRS) for the Screening * Evidence of cognitive decline defined by the Montreal Cognitive Assessment (MoCA) score ≤25 for healthy normal population (Part 1a) and ≤21 for the patient population (Part 1b and Part 2) * History of levodopa-induced motor fluctuations or dyskinesia * Prior surgical treatment for Parkinson's disease * Clinically significant brain abnormalities on or contraindication to a structural magnetic resonance imaging (MRI) * Significant respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, pancreatic, musculoskeletal, genitourinary, immunological or dermatological disorders.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Change from baseline in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II: Activities of Daily Living (ADL) Score at Day 730 | From screening (Day -42 to -2) to Day 730 | Activities of Daily living (ADL) will be assessed via MDS-UPDRS score. MDS-UPDRS Part II is a self-administered questionnaire that assesses the motor experience of daily living in participants with Parkinson's disease. Score: 0: Normal, 1: Slight, 2: Mild, 3: Moderate, 4: Severe. Higher the score, the more severe the condition or symptom |
| Part 1a,1b and 2: Number of participants with adverse events and serious adverse events | Part 1a and Part 1b: From screening (Day -42 to -3) up to 7 days and Part 2: From screening (Day -42 to -2) to 730 days | To evaluate the safety and tolerability of multiple ascending doses of KM-819 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1a and 1b: AUC normalized to dose administered (AUC_D) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Area under the concentration-time curve (AUC) from pre-dose (time zero) to the time of the last quantifiable concentration AUC(0-t) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: AUC from pre-dose (time zero) to 24 hours post-dose [AUC(0-24)] | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Maximum concentration (Cmax) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Time to achieve Cmax (tmax) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Cmax normalized to dose administered (Cmax_D) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: AUC from pre-dose (time zero) extrapolated to time infinity [AUC(0-inf)] | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Apparent terminal elimination half-life (t½) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Terminal elimination rate constant (λz) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Percentage of AUCinf that is extrapolated beyond the time of the last quantifiable concentration [%AUC (extrap)] | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Apparent oral clearance (CL/F) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: AUC(0-t) at steady state (Vz/F) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: AUC(0-t) at steady state [AUC(0-t_ss)] | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Cmax at steady state (Cmax,ss) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: tmax at steady state (tmax,ss) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Ctrough at steady state (Ctrough_ss) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Minimum concentration at steady state (Cmin,ss) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Average observed concentration at steady state (Cav,ss) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Accumulation ratio calculated using AUC [Rac (AUC)] | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Accumulation ratio calculated using Cmax [Rac (Cmax)] | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Apparent oral clearance at steady state (CL/Fss) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: AUC normalized to dose administered at steady state (AUCss_D) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Cmax_ss normalized to dose administered (Cmaxss_D) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Fraction of dose excreted in urine (Fe) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in urine |
| Part 1a and 1b: Renal clearance (CLR) | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in urine |
| Part 2: Sparse plasma PK blood sampling for population PK analysis | Day 1, Day 7, Day 30 and Day 180 | Sparse plasma population PK sampling will be collected, and population PK modeling will be used to characterize the PK of KM-819 in participants with Parkinson's disease. |
| Part 1a and 1b: AUCtau at steady state [AUC(tau_ss)] | Day 7 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
| Part 1a and 1b: Minimum concentration (Cmin) | Day 1 | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma |
Other
| Measure | Time frame | Description |
|---|---|---|
| Digital biomarkers using the Parkinson's Disease Digital Biomarker Solutions from Roche Molecular Solutions. | From screening (Day -42 to -2) to 2 years | Measurements of active and passive monitoring of Parkinson's disease symptoms utilizing smartphone based devices and software |
Countries
United States
Outcome results
None listed