This is a prospective, single-arm, single-dose clinical study designed to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of LY-N001 Injection in patients with moderate-to-advanced Parkinson's disease carrying GBA1 mutations. The study consists of a main study phase and a long-term follow-up phase.
This is a prospective, single-arm, single-dose clinical study designed to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of LY-N001 Injection in patients with moderate-to-advanced Parkinson's disease carrying GBA1 mutations. The study consists of a main study phase and a long-term follow-up phase. Three dose cohorts are pre-specified in this study, including a de-escalation dose cohort (0.5 × 10¹¹ vg/g brain weight), a low-dose cohort (1.0 × 10¹¹ vg/g brain weight), and a high-dose cohort (2.0 × 10¹¹ vg/g brain weight). The low-dose cohort serves as the starting dose of this study, and the dose design is presented in Table 1. The first participant will be enrolled at the starting dose of 1.0 × 10¹¹ vg/g brain weight. Subsequent participants will be enrolled only after safety confirmation following the DLT observation period.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
LY-N001 Injection shall be administered as a single intracerebroventricular (ICV) injection, with one administration only
The First Affiliated Hospital of Anhui Medical University
Hefei, Anhui, China
Incidence of dose-limiting toxicity (DLT) events occurring within at least 28 days following a single intracranial administration of LY-N001
DLT events will be assessed per CTCAE Version 6.0.
Time frame: Within 28 days post-administration
Incidence of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) occurring during the treatment period
All AEs and SAEs will be graded per CTCAE Version 6.0 and adjudicated in accordance with SAE criteria.
Time frame: Within 52 weeks post-administration
Change from baseline in Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) motor examination scores during OFF and ON medication states
Efficacy was assessed via the change from baseline in the MDS-UPDRS Part III total score. The maximum possible total score of the scale is 132, and higher scores correspond to greater disease severity.
Time frame: Within 52 weeks post-administration
Parkinson's disease medication use: changes in daily oral levodopa (L-DOPA) dose or levodopa equivalent dose (LED)
Assessment was based on the change from baseline in daily Parkinson's disease medication usage.
Time frame: within 52 weeks post-administration
Motor fluctuations assessed via patient diaries: changes in "ON" time without dyskinesia or without troublesome dyskinesia, and changes in "OFF" time
Assessment was conducted based on changes in ON/OFF time recorded in patient diaries.
Time frame: Within 52 weeks post-administration
Changes in scores of the MDS Unified Parkinson's Disease Rating Scale (MDS-UPDRS Part I, MDS-UPDRS Part II and MDS-UPDRS Part IV)
Assessment was performed based on the scores of MDS-UPDRS Part I, MDS-UPDRS Part II and MDS-UPDRS Part IV.The maximum total scores of MDS-UPDRS Part I, Part II and Part IV are 52, 52 and 24 respectively. Higher scores indicate more severe disease.
Time frame: Within 52 weeks post-administration
Change from baseline in Mini-mental State Examination (MMSE) score
Assessment will be performed based on the change from baseline in MMSE score. The total maximum score of MMSE is 30, and lower scores indicate more severe cognitive impairment.
Time frame: Within 52 weeks post-administration
Change from baseline in Montreal Cognitive Assessment (MoCA) score
Assessment will be evaluated based on the change from baseline in MoCA score. The total maximum score of MoCA is 30, with lower scores indicating more severe cognitive impairment.
Time frame: Within 52 weeks post-administration
Change from baseline in Geriatric Depression Scale (GDS) score
Assessment will be conducted based on the change from baseline in total GDS score. The maximum total score of GDS is 15, and higher scores represent more severe depressive symptoms.
Time frame: Within 52 weeks post-administration
Change from baseline in Parkinson's Disease Sleep Scale-2 (PDSS-2) score
Assessment will be performed based on the change from baseline in total PDSS-2 score. The maximum total score of PDSS-2 is 150, and higher scores indicate more severe Parkinson's disease-related sleep disturbances.
Time frame: Within 52 weeks post-administration
Change from baseline in Parkinson's Disease Questionnaire-39 (PDQ-39) score
Assessment will be evaluated by the change from baseline in total PDQ-39 score. The maximum total score of PDQ-39 is 156, and higher scores mean more severe impairment of Parkinson's disease-related quality of life.
Time frame: Within 52 weeks post-administration
Change from baseline in Dopamine Transporter Positron Emission Tomography (DAT-PET) and Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) parameters.
Assessment will be performed via DAT-PET and FDG-PET examinations.
Time frame: Within 52 weeks post-administration
Change from baseline in blood glucocerebrosidase (GCase) activity level
Assessment will be conducted based on the change from baseline in blood GCase test results.
Time frame: Within 52 weeks post-administration
Change from baseline in blood lyso-glucosylsphingosine (Lyso-GL1) levels
Assessment will be conducted based on the change from baseline in Lyso-GL1 test results.
Time frame: Within 52 weeks post-administration
Change from baseline in cerebrospinal fluid glucocerebrosidase (GCase) activity levels
Assessment will be performed based on the change from baseline in cerebrospinal fluid GCase activity levels.
Time frame: Within 52 weeks post-administration
Change from baseline in cerebrospinal fluid lyso-glucosylsphingosine (Lyso-GL1) levels
Assessment will be conducted based on the change from baseline in cerebrospinal fluid Lyso-GL1 test results.
Time frame: Within 52 weeks post-administration
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