A Study to Evaluate Safety and Efficacy of KM-819 in Healthy Adults and Participants With Parkinson's Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2 Study Evaluating the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of KM-819 in Healthy Older Adults and Participants With Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: KM-819
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1a: Cohort 1.1a Dose 400 mg<br>Healthy older adult participants will receive oral 400 mg dose of KM-819 or matching placebo once-daily for 7 days, after fasting for 2 hours prior to administration of study intervention and will be required to fast for 1 hour after administration of study intervention. | Drug: KM-819<br>* Participants will receive oral doses of KM-819 once-daily<br>Drug: Placebo<br>* Participants will receive matching placebo once-daily<br>|
| Experimental: Part 1a: Cohort 1.2a Dose 600 mg<br>Healthy older adult participants will receive oral 600 mg dose of KM-819 or matching placebo once-daily for 7 days, after fasting for 2 hours prior to administration of study intervention and will be required to fast for 1 hour after administration of study intervention. | Drug: KM-819<br>* Participants will receive oral doses of KM-819 once-daily<br>Drug: Placebo<br>* Participants will receive matching placebo once-daily<br>|
| Experimental: Part 1a: Cohort 1.3a Dose 800 mg<br>Healthy older adult participants will receive oral 800 mg dose of KM-819 or matching placebo once-daily for 7 days, after fasting for 2 hours prior to administration of study intervention and will be required to fast for 1 hour after administration of study intervention. | Drug: KM-819<br>* Participants will receive oral doses of KM-819 once-daily<br>Drug: Placebo<br>* Participants will receive matching placebo once-daily<br>|
| Experimental: Part 1b: Cohort 1.1b Dose 200 mg<br>Participants with Parkinson's disease will receive oral 200 mg dose of KM-819 or matching placebo once-daily for 7 days, after fasting for 2 hours prior to administration of study intervention and will be required to fast for 1 hour after administration of study intervention. | Drug: KM-819<br>* Participants will receive oral doses of KM-819 once-daily<br>Drug: Placebo<br>* Participants will receive matching placebo once-daily<br>|
| Experimental: Part 1b: Cohort 1.2b Dose 400 mg<br>Participants with Parkinson's disease will receive oral 400 mg dose of KM-819 or matching placebo once-daily for 7 days, after fasting for 2 hours prior to administration of study intervention and will be required to fast for 1 hour after administration of study intervention. | Drug: KM-819<br>* Participants will receive oral doses of KM-819 once-daily<br>Drug: Placebo<br>* Participants will receive matching placebo once-daily<br>|
| Experimental: Part 1b: Cohort 1.3b Dose 600 mg<br>Participants with Parkinson's disease will receive oral 600 mg dose of KM-819 or matching placebo once-daily for 7 days, after fasting for 2 hours prior to administration of study intervention and will be required to fast for 1 hour after administration of study intervention. | Drug: KM-819<br>* Participants will receive oral doses of KM-819 once-daily<br>Drug: Placebo<br>* Participants will receive matching placebo once-daily<br>|
| Experimental: Part 2: Cohort 2.1 Dose X<br>Participants with Parkinson's disease will receive oral doses of KM-819 (dose to be determined based on the findings from Part 1) or matching placebo once-daily for 730 days and will be allowed to take study intervention with or without fasting. | Drug: KM-819<br>* Participants will receive oral doses of KM-819 once-daily<br>Drug: Placebo<br>* Participants will receive matching placebo once-daily<br>|
| Experimental: Part 2: Cohort 2.2 Dose Y<br>Participants with Parkinson's disease will receive oral doses of KM-819 (dose to be determined based on the findings from Part 1) or matching placebo once-daily for 730 days and will be allowed to take study intervention with or without fasting. | Drug: KM-819<br>* Participants will receive oral doses of KM-819 once-daily<br>Drug: Placebo<br>* Participants will receive matching placebo once-daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1a,1b and 2: Number of participants with adverse events and serious adverse events | To evaluate the safety and tolerability of multiple ascending doses of KM-819 | 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 | 
| 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 | 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 | From screening (Day -42 to -2) to Day 730 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: AUC from pre-dose (time zero) to 24 hours post-dose [AUC(0-24)] | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: Maximum concentration (Cmax) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: Time to achieve Cmax (tmax) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: Minimum concentration (Cmin) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: AUC normalized to dose administered (AUC_D) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: Cmax normalized to dose administered (Cmax_D) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: AUC from pre-dose (time zero) extrapolated to time infinity [AUC(0-inf)] | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: Apparent terminal elimination half-life (t½) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: Terminal elimination rate constant (λz) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: Percentage of AUCinf that is extrapolated beyond the time of the last quantifiable concentration [%AUC (extrap)] | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: Apparent oral clearance (CL/F) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: AUC(0-t) at steady state (Vz/F) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 1 | 
| Part 1a and 1b: AUC(0-t) at steady state [AUC(0-t_ss)] | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: AUCtau at steady state [AUC(tau_ss)] | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: Cmax at steady state (Cmax,ss) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: tmax at steady state (tmax,ss) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: Ctrough at steady state (Ctrough_ss) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: Minimum concentration at steady state (Cmin,ss) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: Average observed concentration at steady state (Cav,ss) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: Accumulation ratio calculated using AUC [Rac (AUC)] | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: Accumulation ratio calculated using Cmax [Rac (Cmax)] | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: Apparent oral clearance at steady state (CL/Fss) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: AUC normalized to dose administered at steady state (AUCss_D) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: Cmax_ss normalized to dose administered (Cmaxss_D) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in plasma | Day 7 | 
| Part 1a and 1b: Fraction of dose excreted in urine (Fe) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in urine | Day 7 | 
| Part 1a and 1b: Renal clearance (CLR) | To evaluate the pharmacokinetics (PK) of multiple ascending doses (MAD) of KM-819 in urine | Day 7 | 
| Part 2: Sparse plasma PK blood sampling for population PK analysis | 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. | Day 1, Day 7, Day 30 and Day 180 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inhibition of FAF1(Fas (TNFRSF6)-associated factor 1), Multiple Ascending Dose (MAD), Neuroprotection, Alpha-synuclein inhibition, KM-819