Study to Evaluate the Safety and Efficacy of ESC-derived Dopamine Progenitor Cell Therapy in PD Patients

Study Overview
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Brief Summary
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Study Period: Approximately 35 months from the date of approval by the Institutional Review Board (IRB) (However, it can be extended depending on the subject enrollment period or the time to study closure) Indication: Patients who were diagnosed with Parkinson's disease ≥ 5 years ago Purpose: To find the maximum tolerable dose and evaluate the safety and exploratory efficacy of allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC) therapy in patients who were diagnosed with Parkinson's disease ≥ 5 years ago, as a treatment for delaying or stopping the progression of Parkinson's disease or inducing recovery of damaged brain. Number of Subjects: It aims to recruit up to 12 subjects for the dose-escalation study with two phases. [Low dose] Dose: 3.15X10^6 cells/body | Study group(A9-DPC): 6 subjects [High dose] Dose: 6.30X10^6 cells/body | Study group(A9-DPC): 6 subjects Study Design: Single center, open, single dosing, dose-escalation, phase 1/2a study Endpoints: [Primary Safety Endpoints] Occurrence of treatment-emergent adverse events (TEAEs) after administration of the IP Failure or rejection of transplantation and occurrence of bleeding and infection at Week 12 (3 months), Week 24 (6 months), Week 48 (12 months) and Week 96 (24 months) after administration of the IP Occurrence of adverse event of special interest (AESI)* after administration of the IP AESI: a) death, b) generation of a neoplasm or malignant tumor in tissues or organs, c) onset of an immune reaction including worsening of a previous autoimmune disease or new occurrence, and d) other delayed adverse events related to this embryonic stem cell treatment. [Exploratory Efficacy Endpoints] Change in the following clinical endpoints at Week 4 (1 month), Week 12 (3 months), Week 24 (6 months), Week 36 (9 months), Week 48 (12 months), Week 72 (18 months) and Week 96 (24 months) after administration of the IP compared to screening ① MDS-UPDRS Total Score, part Ⅲ & part Ⅳ (defined on/off) Defined-on condition: condition that the most positive functional effect, as agreed by the subject and the tester, after treatment with drugs for controlling the symptoms of Parkinson's disease Defined-off condition: condition after 12 hours off drugs for controlling the symptoms of Parkinson's disease ② K-MMSE ③ Seoul Neuropsychological screening battery (SNSB, Screening & Week 96 (24 months)) Change in the following clinical endpoints at Week 4 (1 month), Week 12 (3 months), Week 24 (6 months), Week 36 (9 months), Week 48 (12 months), Week 72 (18 months) and Week 96 (24 months) after administration of the IP compared to baseline K-MoCA Parkinson's Questionnaire (PDQ-39) Schwab and England ADL scale (SEADL) Non-Motor Symptoms Scale for Parkinson's Disease (NMS) Change in Graft size through MRI at Week 12 (3 months), Week 24 (6 months), Week 48 (12 months) and Week 96 (24 months) after administration of the IP compared to baseline Change in Cerebral FDG uptake and Striatal FDG uptake at Week 48 (12 months) and Week 96 (24 months) after administration of the IP compared to baseline Change in density of dopamine transporters as measured by FP-CIT PET at Week 48 (12 months) and Week 96 (24 months) after administration of the IP compared to screening Percentage of subjects who used concomitant medication related to Parkinson-mobility or Parkinson-Non-mobility during the whole clinical trial period and change in dose of each concomitant medication (per component) at 12 week intervals compared to the dose of each concomitant medication (per component) from the date of administration of IP to Week 12. [Other Safety Endpoints] Vital signs Laboratory tests Physical examination

Official Title
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A Single Center, Open, Single Dosing, Dose-escalation, Phase 1/2a Study to Evaluate the Safety and Exploratory Efficacy of Embryonic Stem Cell-derived A9 Dopamine Progenitor Cell (A9-DPC) Therapy in Patients With Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: A9-DPC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with Parkinson's disease based on UK PD Society Brain Bank criteria at the time of the screening visit Patient with Parkinson's disease at the age of 50 to 75 years old at the time of the screening visit Patient who was diagnosed with Parkinson' disease ≥ 5 years ago at the time of the screening visit Patient on a stable dose of medicine such as levodopa for ≥ 3 months before screening who has wearing off for ≥ 2 hours a day or freezing of gait responding to dopamine supplement or motor complications such as dyskinesia At least moderate impairment in activity of daily living (MDS-UPDRS part II ≥13) Patient on a stabile dose of standard treatment for Parkinson's disease (e.g., levodopa, dopamine agonists, MAO-B inhibitors, amantadine, anticholinergics, etc.) for ≥ 3 months before screening ≥ 40% in L-dopa responsiveness at the time of the screening visit Hoehn & Yahr stage ≥ 3 during the off state and stage ≤ 3 during the on state at the time of the screening visit Decreased dopamine transporters as measured by FP-CIT PET at the time of the screening visit Able to undergo MRI Signed consent after being sufficiently informed of the study Exclusion Criteria: Parkinson's disease dementia based on the Movement Disorders Society Task Force criteria Parkinsonism plus syndrome confirmed by PET and MRI images at the screening visit Patient that does not meet the criteria for Parkinson's disease dementia but has major visual hallucination Freezing of gait with no or ambiguous response to L-dopa Drug-induced parkinsonism History of uncontrolled seizure disorders within 24 weeks before screening Congenital developmental delay Past or current coagulation factor related diseases at the time of the screening visit Ongoing malignancies at the time of the screening visit or diagnosis of malignancies within the past 5 years Active tuberculosis, autoimmune disease, or decreased immunity at the time of the screening visit (treatment with chemotherapy within the past 3 years or white blood cell [WBC] <3X10^3 cells/µL) Patient diagnosed with diabetes mellitus Participation in another clinical trial within 4 weeks before screening History of treatment with cell therapy, except for blood transfusion, before study participation Side effects to anesthetics, contrast agents, etc. Past or current clinically significant diseases in the liver (including liver transplant), kidney, respiratory system, cardiovascular system, etc. or clinically significant laboratory test results at the time of the screening visit Platelet count < 5.0X10^4/microL Serum creatinine > 1.5 mg/dL eGFR < 60 mL/min/1.73 m^2 AST or ALT ≥ 3 x ULN (Upper Limit of Normal) Total bilirubin ≥ 1.5 x ULN (Upper Limit of Normal) Hepatitis B or C Human immunodeficiency virus (HIV) positive History of brain surgery Pregnant and lactating woman Positive pregnancy test at the time of screening; or woman of childbearing potential and man who plan a pregnancy during the study or who do not agree to use clinically appropriate methods of contraception* described below Hormone contraceptives (subdermal contraceptive implants, injections, oral contraceptives, etc.), intrauterine device (IUD) (or intra uterine system [IUS]), subject's or partner's surgical sterilization (vasectomy, tubal ligation, etc.), double barrier method (combined use of barrier methods such as cervical cap or diaphragm in combination with male condom) Ineligible for other reasons based on the judgment of the investigator

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 rule-based method
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose Group<br>IP Name : Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC) Study group : 6 subjects Dosage: 3.15X10^6 cells/body (6 tracks in total, 52.5X10^4 cells per track) | Drug: A9-DPC<br>* IP Name : Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC) Main ingredients and quantities: A9-DPC 7.0X10^6 cells (Use 3.15X10^6 cells of this) 1.4X10^7 cells (Use 6.30X10^6 cells of this) Formulation: milky white cell suspension Storage method: Refrigerated storage (5±3℃) Expiration date: within 24 hours of manufacture Dosage: 1st Stage Dosage: 3.15X10^6 cells/body (6 tracks in total, 52.5X10^4 cells per track) 2nd Stage Dosage: 6.30X10^6 cells/body (6 tracks in total, 105X10^4 cells per track) Frequency: single dosing Method: The subject pierces a burr hole in the skull on the day of surgery. Then the cells are injected at a predetermined stem cell administration point of the putamen in the brain of the subject. One side is administered in three tracks per putamen (6 tracks total brain). Do the same for the other side.<br>|
| Experimental: High Dose Group<br>IP Name : Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC) Study group : 6 subjects Dosage: 6.30X10^6 cells/body (6 tracks in total, 105X10^4 cells per track) | Drug: A9-DPC<br>* IP Name : Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC) Main ingredients and quantities: A9-DPC 7.0X10^6 cells (Use 3.15X10^6 cells of this) 1.4X10^7 cells (Use 6.30X10^6 cells of this) Formulation: milky white cell suspension Storage method: Refrigerated storage (5±3℃) Expiration date: within 24 hours of manufacture Dosage: 1st Stage Dosage: 3.15X10^6 cells/body (6 tracks in total, 52.5X10^4 cells per track) 2nd Stage Dosage: 6.30X10^6 cells/body (6 tracks in total, 105X10^4 cells per track) Frequency: single dosing Method: The subject pierces a burr hole in the skull on the day of surgery. Then the cells are injected at a predetermined stem cell administration point of the putamen in the brain of the subject. One side is administered in three tracks per putamen (6 tracks total brain). Do the same for the other side.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of treatment-emergent adverse events (TEAEs) after administration of the IP | Present frequency and percentage by each dose group about occurrence of treatment-emergent adverse events (TEAEs) after administration of the IP | Up to 96 Weeks (24 months) after IP administration | 
| Failure or rejection of transplantation | Present frequency and percentage by each dose group about failure or rejection of transplantation at Week 12 (3 months) after administration of the IP | Week 12 (3 months) | 
| Failure or rejection of transplantation | Present frequency and percentage by each dose group about failure or rejection of transplantation at Week 24 (6 months) after administration of the IP | Week 24 (6 months) | 
| Failure or rejection of transplantation | Present frequency and percentage by each dose group about failure or rejection of transplantation at Week 48 (12 months) after administration of the IP | Week 48 (12 months) | 
| Failure or rejection of transplantation | Present frequency and percentage by each dose group about failure or rejection of transplantation at Week 96 (24 months) after administration of the IP | Week 96 (24 months) | 
| Occurrence of bleeding | Present frequency and percentage by each dose group about occurrence of bleeding at Week 12 (3 months) after administration of the IP | Week 12 (3 months) | 
| Occurrence of bleeding | Present frequency and percentage by each dose group about occurrence of bleeding at Week 24 (6 months) after administration of the IP | Week 24 (6 months) | 
| Occurrence of bleeding | Present frequency and percentage by each dose group about occurrence of bleeding at Week 48 (12 months) after administration of the IP | Week 48 (12 months) | 
| Occurrence of bleeding | Present frequency and percentage by each dose group about occurrence of bleeding at Week 96 (24 months) after administration of the IP | Week 96 (24 months) | 
| Occurrence of infection | Present frequency and percentage by each dose group about occurrence of infection at Week 12 (3 months) after administration of the IP | Week 12 (3 months) | 
| Occurrence of infection | Present frequency and percentage by each dose group about occurrence of infection at Week 24 (6 months) after administration of the IP | Week 24 (6 months) | 
| Occurrence of infection | Present frequency and percentage by each dose group about occurrence of infection at Week 48 (12 months) after administration of the IP | Week 48 (12 months) | 
| Occurrence of infection | Present frequency and percentage by each dose group about occurrence of infection at Week 96 (24 months) after administration of the IP | Week 96 (24 months) | 
| Occurrence of adverse event of special interest (AESI)* after administration of the IP | Present frequency and percentage by each dose group about occurrence of adverse event of special interest (AESI)* after administration of the IP *AESI: a) death, b) generation of a neoplasm or malignant tumor in tissues or organs, c) onset of an immune reaction including worsening of a previous autoimmune disease or new occurrence, and d) other delayed adverse events related to this embryonic stem cell treatment. | Up to 96 Weeks (24 months) after IP administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the MDS-UPDRS Total Score, part Ⅲ (defined on/off) & part Ⅳ | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about changes in the MDS-UPDRS Total Scores, part Ⅲ (defined on/off) & part Ⅳ up to 96 Weeks (24 months) after IP administration compared to baseline (-Day 14 to -Day 4). Defined-on condition: condition that the most positive functional effect, as agreed by the subject and the tester, after treatment with drugs for controlling the symptoms of Parkinson's disease Defined-off condition: condition after 12 hours off drugs for controlling the symptoms of Parkinson's disease | -Day 14 to -Day 4, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96 | 
| Change in the K-MMSE | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about changes in the K-MMSE up to 96 Weeks (24 months) after IP administration compared to baseline (-Day 14 to -Day 4). | -Day 14 to -Day 4, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96 | 
| Change in the Seoul Neuropsychological screening battery (SNSB, Screening & Week 96 (24 months)) | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about changes in the Seoul Neuropsychological Screening battery (SNSB) between baseline (-Day 14 to -Day 4) and 96 Weeks (24 months) after IP administration. | -Day 14 to -Day 4, Week 96 | 
| Change in the K-MoCA | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about changes in the K-MoCA up to 96 Weeks (24 months) after IP administration compared to baseline (-Day 2). | -Day 2, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96 | 
| Change in the Parkinson's Questionnaire (PDQ-39) | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about changes in the Parkinson's Questionnaire (PDQ-39) up to 96 Weeks (24 months) after IP administration compared to baseline (-Day 2). | -Day 2, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96 | 
| Change in the Schwab and England ADL scale (SEADL) | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about changes in the Schwab and England ADL scale (SEADL) up to 96 Weeks (24 months) after IP administration compared to baseline (-Day 2). | -Day 2, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96 | 
| Change in the Non-Motor Symptoms Scale for Parkinson's Disease (NMS) | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about changes in the Non-Motor Symptoms Scale for Parkinson's Disease (NMS) up to 96 Weeks (24 months) after IP administration compared to baseline (-Day 2). | -Day 2, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96 | 
| Change in Graft size through MRI | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about change in Graft size through MRI at Week 12 (3 months), Week 24 (6 months), Week 48 (12 months) and Week 96 (24 months) after administration of the IP compared to baseline (-Day 2) | -Day 2, Week 12, Week 24, Week 48, Week 96 | 
| Change in Cerebral FDG uptake and Striatal FDG uptake | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about change in Cerebral FDG uptake and Striatal FDG uptake at Week 48 (12 months) and Week 96 (24 months) after administration of the IP compared to baseline (-Day 2) | -Day 2, Week 48, Week 96 | 
| Change in density of dopamine transporters as measured by FP-CIT PET | Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about change in density of dopamine transporters as measured by FP-CIT PET at Week 48 (12 months) and Week 96 (24 months) after administration of the IP compared to screening (-Day 14 to -Day 4) | -Day 14 to -Day 4, Week 48, Week 96 | 
| Percentage of subjects who used concomitant medication related to Parkinson-mobility or Parkinson-Non-mobility during the whole clinical trial period and Change in dose of each concomitant medication (per component) | Present the frequency and percentage use of concomitant medication related to Parkinson-mobility or Parkinson-Non-mobility during the whole clinical trial period by each dose group. Also Present descriptive statistics (number of subjects, average, standard deviation, median, minimum, maximum) by each dose group about change in dose of each concomitant medication (per component) at 12 week intervals compared to the dose of each concomitant medication (per component) from the date of administration of IP to Week 12. | Day 0 (Postoperative day #0), Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96 |