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

S.Biomedics Co., Ltd.12 enrolled

Overview

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: Up to 12 subjects. \[Low dose\] 3.15X10\^6 cells/body: 6 subjects. \[High dose\] 6.30X10\^6 cells/body: 6 subjects. Study Design: Single center, open, single dosing, dose-escalation, phase 1/2a study Endpoints: \[Primary Safety Endpoints\] 1. Occurrence of treatment-emergent adverse events (TEAEs) after administration of the IP 2. Failure or rejection of transplantation and occurrence of bleeding and infection at Week 12 (3months), Week 24 (6months), Week 48 (12months) and Week 96 (24months) after administration of the IP 3. 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.

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: Up to 12 subjects \[Low dose\] 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: \[Primary Safety Endpoints\] 1. Occurrence of treatment-emergent adverse events (TEAEs) after administration of the IP 2. 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 3. 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. \[Exploratory Efficacy Endpoints\] 1\. 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) 2. K-MMSE 3. Seoul Neuropsychological screening battery (SNSB, Screening \& Week 96 (24 months)) 4. Hoehn \& Yahr scale 2\. 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 1. K-MoCA 2. Parkinson's Questionnaire (PDQ-39) 3. Schwab and England ADL scale (SEADL) 4Non-Motor Symptoms Scale for Parkinson's Disease (NMS) 3\. 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 4. 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 5. 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 6. 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. 7\. Changes in the following clinical evaluation variables confirmed through the Parkinson's Disease diary at 48 weeks (12 months), 72 weeks (18 months), and 96 weeks (24 months) after administration of the investigational drug compared to baseline: 1. Total waking time 2. Total on-time 3. Total off-time 4. Total dyskinesia time \[Other Safety Endpoints\] 1. Vital signs 2. Laboratory tests 3. Physical examination

Interventions

Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC) Low DoseBIOLOGICAL

Biological/Vaccine: Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC)\_Low Dose 1. IP Name : Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC) 2. Main ingredients and quantities: A9-DPC -Low Dose : 7.0X10\^6 cells (Use 3.15X10\^6 cells of this) 3. Formulation: milky white cell suspension 4. Storage method: Refrigerated storage (5±3#) 5. Expiration date: within 36 hours of manufacture 6. Frequency: single dosing 7. 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.

Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC) High DoseBIOLOGICAL

Biological/Vaccine: Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC)\_High Dose 1. IP Name : Allogenic embryonic stem cell-derived A9 dopamine progenitor cell (A9-DPC) 2. Main ingredients and quantities: A9-DPC -High Dose : 1.4X10\^7 cells (Use 6.30X10\^6 cells of this) 3. Formulation: milky white cell suspension 4. Storage method: Refrigerated storage (5±3#) 5. Expiration date: within 36 hours of manufacture 6. Frequency: single dosing 7. 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.

Eligibility

Sex: ALLMin age: 50 YearsMax age: 75 Years

Medical Language ↔ Plain English

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 1. Platelet count \< 5.0X10\^4/microL 2. Serum creatinine \> 1.5 mg/dL 3. eGFR \< 60 mL/min/1.73 m\^2 4. AST or ALT ≥ 3 x ULN (Upper Limit of Normal) 5. Total bilirubin ≥ 1.5 x ULN (Upper Limit of Normal) 6. Hepatitis B or C 7. 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

Outcomes

Primary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: Up to 96 Weeks (24 months) after IP administration

Secondary Outcomes

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

Time frame: -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).

Time frame: -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.

Time frame: -Day 14 to -Day 4, Week 96

Hoehn & Yahr scale

Change in the Hoehn \& Yahr scale

Time frame: Day 14 to -Day 4, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, 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).

Time frame: -Day 2, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes