Clinical trial NCT05887466: Study to Evaluate the Safety and Efficacy of ESC-derived Dopamine Progenitor Cell Therapy in PD Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Parkinson's Disease
Lead sponsor: S.Biomedics Co., Ltd.
Sponsor class: INDUSTRY
Collaborators: name: Yonsei University
First posted: 2023-06-02
Enrollment: 12
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 3+3 rule-based method
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Eligibility criteria: 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

Primary outcomes:
measure: Occurrence of treatment-emergent adverse events (TEAEs) after administration of the IP
timeFrame: Up to 96 Weeks (24 months) after IP administration
measure: Failure or rejection of transplantation
timeFrame: Week 12 (3 months)
measure: Failure or rejection of transplantation
timeFrame: Week 24 (6 months)
measure: Failure or rejection of transplantation
timeFrame: Week 48 (12 months)
measure: Failure or rejection of transplantation
timeFrame: Week 96 (24 months)
measure: Occurrence of bleeding
timeFrame: Week 12 (3 months)
measure: Occurrence of bleeding
timeFrame: Week 24 (6 months)
measure: Occurrence of bleeding
timeFrame: Week 48 (12 months)
measure: Occurrence of bleeding
timeFrame: Week 96 (24 months)
measure: Occurrence of infection
timeFrame: Week 12 (3 months)
measure: Occurrence of infection
timeFrame: Week 24 (6 months)
measure: Occurrence of infection
timeFrame: Week 48 (12 months)
measure: Occurrence of infection
timeFrame: Week 96 (24 months)
measure: Occurrence of adverse event of special interest (AESI)* after administration of the IP
timeFrame: Up to 96 Weeks (24 months) after IP administration
Secondary outcomes:
measure: Change in the MDS-UPDRS Total Score, part Ⅲ (defined on/off) & part Ⅳ
timeFrame: -Day 14 to -Day 4, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Change in the K-MMSE
timeFrame: -Day 14 to -Day 4, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Change in the Seoul Neuropsychological screening battery (SNSB, Screening & Week 96 (24 months))
timeFrame: -Day 14 to -Day 4, Week 96
measure: Hoehn & Yahr scale
timeFrame: Day 14 to -Day 4, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Change in the K-MoCA
timeFrame: -Day 2, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Change in the Parkinson's Questionnaire (PDQ-39)
timeFrame: -Day 2, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Change in the Schwab and England ADL scale (SEADL)
timeFrame: -Day 2, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Change in the Non-Motor Symptoms Scale for Parkinson's Disease (NMS)
timeFrame: -Day 2, Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Change in Graft size through MRI
timeFrame: -Day 2, Week 12, Week 24, Week 48, Week 96
measure: Change in Cerebral FDG uptake and Striatal FDG uptake
timeFrame: -Day 2, Week 48, Week 96
measure: Change in density of dopamine transporters as measured by FP-CIT PET
timeFrame: -Day 14 to -Day 4, Week 48, Week 96
measure: 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)
timeFrame: Day 0 (Postoperative day #0), Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Parkinson's Disease diary
timeFrame: Day 0 (POD #0), Week 48, Week 72, Week 96
Other outcomes:
measure: Vital signs
timeFrame: -Day14 to -Day 4, -Day 2, Day 0 (Postoperative day #0), Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Laboratory tests
timeFrame: -Day 14 to -Day 4, Day 0 (Postoperative day #0), Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
measure: Physical examination
timeFrame: -Day 14 to -Day 4, -Day 2, Day 0 (Post operative day #0), Week 4, Week 12, Week 24, Week 36, Week 48, Week 72, Week 96
Locations:
city: Seoul
country: Korea, Republic of
facility: Yonsei University Health System, Severance Hospital
Study officials:
affiliation: Yonsei Universitiy Health System, Severance Hospital
name: Phil-hyu Lee, MD, Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rowland NC, Starr PA, Larson PS, Ostrem JL, Marks WJ Jr, Lim DA. Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease. Mov Disord. 2015 Feb;30(2):190-5. doi: 10.1002/mds.26083. Epub 2014 Dec 17.
citation: Schweitzer JS, Song B, Herrington TM, Park TY, Lee N, Ko S, Jeon J, Cha Y, Kim K, Li Q, Henchcliffe C, Kaplitt M, Neff C, Rapalino O, Seo H, Lee IH, Kim J, Kim T, Petsko GA, Ritz J, Cohen BM, Kong SW, Leblanc P, Carter BS, Kim KS. Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease. N Engl J Med. 2020 May 14;382(20):1926-1932. doi: 10.1056/NEJMoa1915872.
citation: Barker RA, Drouin-Ouellet J, Parmar M. Cell-based therapies for Parkinson disease-past insights and future potential. Nat Rev Neurol. 2015 Sep;11(9):492-503. doi: 10.1038/nrneurol.2015.123. Epub 2015 Aug 4.
citation: Kikuchi T, Morizane A, Doi D, Magotani H, Onoe H, Hayashi T, Mizuma H, Takara S, Takahashi R, Inoue H, Morita S, Yamamoto M, Okita K, Nakagawa M, Parmar M, Takahashi J. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model. Nature. 2017 Aug 30;548(7669):592-596. doi: 10.1038/nature23664.
citation: Mendez I, Sanchez-Pernaute R, Cooper O, Vinuela A, Ferrari D, Bjorklund L, Dagher A, Isacson O. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease. Brain. 2005 Jul;128(Pt 7):1498-510. doi: 10.1093/brain/awh510. Epub 2005 May 4.
citation: Parmar M, Grealish S, Henchcliffe C. The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci. 2020 Feb;21(2):103-115. doi: 10.1038/s41583-019-0257-7. Epub 2020 Jan 6.
citation: Barker RA; TRANSEURO consortium. Designing stem-cell-based dopamine cell replacement trials for Parkinson's disease. Nat Med. 2019 Jul;25(7):1045-1053. doi: 10.1038/s41591-019-0507-2. Epub 2019 Jul 1.
citation: Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, Dickson D, Duyckaerts C, Cummings J, Gauthier S, Korczyn A, Lees A, Levy R, Litvan I, Mizuno Y, McKeith IG, Olanow CW, Poewe W, Sampaio C, Tolosa E, Emre M. Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007 Dec;22(16):2314-24. doi: 10.1002/mds.21844.
citation: Baek MJ, Kim K, Park YH, Kim S. The Validity and Reliability of the Mini-Mental State Examination-2 for Detecting Mild Cognitive Impairment and Alzheimer's Disease in a Korean Population. PLoS One. 2016 Sep 26;11(9):e0163792. doi: 10.1371/journal.pone.0163792. eCollection 2016.
citation: Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, Giladi N, Holloway RG, Moore CG, Wenning GK, Yahr MD, Seidl L; Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord. 2004 Sep;19(9):1020-8. doi: 10.1002/mds.20213.
citation: Hoehn MM, Yahr MD. Parkinsonism: onset, progression, and mortality. 1967. Neurology. 2001 Nov;57(10 Suppl 3):S11-26. No abstract available.
citation: Koh SB, Kim JW, Ma HI, Ahn TB, Cho JW, Lee PH, Chung SJ, Kim JS, Kwon DY, Baik JS. Validation of the korean-version of the nonmotor symptoms scale for Parkinson's disease. J Clin Neurol. 2012 Dec;8(4):276-83. doi: 10.3988/jcn.2012.8.4.276. Epub 2012 Dec 21.
citation: Shulman LM, Armstrong M, Ellis T, Gruber-Baldini A, Horak F, Nieuwboer A, Parashos S, Post B, Rogers M, Siderowf A, Goetz CG, Schrag A, Stebbins GT, Martinez-Martin P. Disability Rating Scales in Parkinson's Disease: Critique and Recommendations. Mov Disord. 2016 Oct;31(10):1455-1465. doi: 10.1002/mds.26649.
citation: Park HJ, Sohng KY, Kim S. Validation of the Korean version of the 39-Item Parkinson's Disease Questionnaire (PDQ-39). Asian Nurs Res (Korean Soc Nurs Sci). 2014 Mar;8(1):67-74. doi: 10.1016/j.anr.2014.02.004. Epub 2014 Mar 6.
citation: Kefalopoulou Z, Politis M, Piccini P, Mencacci N, Bhatia K, Jahanshahi M, Widner H, Rehncrona S, Brundin P, Bjorklund A, Lindvall O, Limousin P, Quinn N, Foltynie T. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 2014 Jan;71(1):83-7. doi: 10.1001/jamaneurol.2013.4749.
citation: Rasiah NP, Maheshwary R, Kwon CS, Bloomstein JD, Girgis F. Complications of Deep Brain Stimulation for Parkinson Disease and Relationship between Micro-electrode tracks and hemorrhage: Systematic Review and Meta-Analysis. World Neurosurg. 2023 Mar;171:e8-e23. doi: 10.1016/j.wneu.2022.10.034. Epub 2022 Oct 13.
citation: Li W, Englund E, Widner H, Mattsson B, van Westen D, Latt J, Rehncrona S, Brundin P, Bjorklund A, Lindvall O, Li JY. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci U S A. 2016 Jun 7;113(23):6544-9. doi: 10.1073/pnas.1605245113. Epub 2016 May 2.
citation: Yasuhara T, Kameda M, Sasaki T, Tajiri N, Date I. Cell Therapy for Parkinson's Disease. Cell Transplant. 2017 Sep;26(9):1551-1559. doi: 10.1177/0963689717735411.
citation: Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, van Hilten JJ, LaPelle N; Movement Disorder Society UPDRS Revision Task Force. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008 Nov 15;23(15):2129-70. doi: 10.1002/mds.22340.
citation: Okun MS. Deep-brain stimulation for Parkinson's disease. N Engl J Med. 2012 Oct 18;367(16):1529-38. doi: 10.1056/NEJMct1208070. No abstract available.