(ASK-PD0-CS002) Long-Term Safety and Efficacy Follow-up of AB-1005 Gene Transfer Study Participants with Parkinson’s Disease or Multiple System Atrophy

The primary objective is to evaluate the long-term safety and tolerability of **AB-1005** in participants with **Parkinson's disease** or **multiple system atrophy-parkinsonian subtype**. This assessment is clinically relevant to determine the durability of the safety profile following **gene transfer** with an **adeno-associated viral vector serotype 2** encoding **glial cell line-derived neurotrophic factor**, administered via **intraputaminal** injection. Understanding long-term safety outcomes is essential for establishing the therapeutic viability of this **gene therapy** approach in neurodegenerative disorders characterized by progressive dopaminergic neuronal loss.

The secondary objective is to evaluate the long-term efficacy of AB-1005 in participants with Parkinson's disease or multiple system atrophy-parkinsonian subtype. This objective addresses the sustained therapeutic benefit of the intervention over an extended follow-up period, which is critical for assessing whether the **neuroprotective** or **neuroregenerative** effects of GDNF gene delivery translate into clinically meaningful and durable improvements in motor and non-motor symptoms in these patient populations.

This clinical trial enrolled a total of **90 participants** diagnosed with either **Parkinson's Disease** or **Multiple System Atrophy-Parkinsonian subtype**. The study population included both **male** and **female** subjects. Eligible participants were adults and elderly individuals who were currently enrolled or had previously participated in an interventional study involving AB-1005. The trial did not involve vulnerable populations. Selection of participants was based on prior or current enrollment in AB-1005 interventional studies and provision of informed consent. The sponsor did not provide information regarding specific lifestyle considerations such as diet, physical activity, or habits for this trial population.

This clinical trial is designed to evaluate the long-term safety and tolerability of **AB-1005** in participants with **Parkinson's Disease** or **Multiple System Atrophy-Parkinsonian subtype**. The study represents a follow-up investigation for participants who are currently enrolled or were previously enrolled in an interventional AB-1005 study. The trial phase is classified as a long-term safety follow-up study, with justification based on monitoring participants dosed in Phase 1 and Phase 2 studies. The overall trial duration extends from the estimated recruitment start date in December 2026 to the estimated end date in December 2037, representing an extended observational period necessary for assessing long-term outcomes of **gene therapy** interventions.

The investigational product AAV2-GDNF is administered as a **solution for injection** via **intraputaminal** route, representing a **recombinant adeno-associated viral vector serotype 2** encoding **glial cell line-derived neurotrophic factor**. The maximum daily and total dose is 12000000000000 units, administered during a single-day treatment period. Auxiliary medicinal products include **Carbidopa** administered as an oral **tablet** with a maximum daily and total dose of 200 mg, and **Fluorodopa (18F)** administered as a solution for injection via **intravenous** route with a maximum daily dose of 222 **megabecquerels** and a maximum total dose of 888 megabecquerels over a four-day period. The active substance in AAV2-GDNF is classified as a structurally diverse substance, while Carbidopa and Fluorodopa (18F) contain chemical active substances.

The primary endpoint focuses on the incidence and severity of **adverse events**, both serious and non-serious, to comprehensively assess safety and tolerability over the extended follow-up period. Secondary endpoints are differentiated based on the medical condition being studied. For Parkinson's Disease participants, secondary endpoints include normalized PD motor diary times measuring Good ON, ON with troublesome **dyskinesia**, and OFF states, as well as **MDS-UPDRS** parts I, II (OFF and ON), III (OFF and ON), and IV assessments. Additional secondary endpoints for this population include **levodopa equivalent daily dose** and **18F-DOPA PET** imaging. For Multiple System Atrophy participants, secondary endpoints comprise **UMSARS** parts I, II (ON), III, and IV assessments, along with MSA-QoL quality of life measurements.

Principal inclusion criteria require that participants have Parkinson's Disease or Multiple System Atrophy-Parkinsonian subtype and are currently enrolled or were previously enrolled in an interventional AB-1005 study, with provision of informed consent being mandatory. The expected length of participant involvement spans the duration of the long-term follow-up period, which may extend for several years following initial treatment in the parent interventional studies. The study design facilitates comprehensive longitudinal assessment of both safety parameters and efficacy measures specific to each disease population, enabling evaluation of sustained therapeutic effects and identification of any delayed adverse events associated with the gene therapy intervention.

The experimental treatment **AAV2-GDNF** (sponsor product code **AB-1005**) is a **recombinant adeno-associated viral vector serotype 2** encoding **glial cell line-derived neurotrophic factor**. This **gene therapy** product is formulated as a **solution for injection** and is administered via **intraputaminal** route. The maximum daily dose is 12000000000000 units, with a maximum total dose of 12000000000000 units administered over a treatment period of 1 day. AAV2-GDNF contains GDNF complementary DNA under a human cytomegalovirus internal-enhancer promoter and is flanked by short inverted terminal repeats sequences. This product represents an **in vivo gene transfer** approach and is classified as an **advanced therapy medicinal product**.

**Carbidopa** is administered as an **auxiliary medicinal product** in this clinical trial. The product is supplied in **tablet** form for **oral** administration. The maximum daily dose of carbidopa is 200 milligrams, with a maximum total dose of 200 milligrams administered over a treatment period of 1 day. Carbidopa contains a chemical active substance and is classified under ATC code N04BA02 as a **levodopa and decarboxylase inhibitor**.

**Fluorodopa (18F)**, also known as **FDOPA**, serves as an auxiliary medicinal product in the study. This **radiopharmaceutical** agent is formulated as a **solution for injection** and is administered via **intravenous** route. The maximum daily dose is 222 megabecquerels, with a maximum total dose of 888 megabecquerels administered over a treatment period of 4 days. Fluorodopa (18F) contains a chemical active substance and is used for diagnostic imaging purposes in the evaluation of study participants.

The primary endpoint for assessing efficacy is the incidence and severity of adverse events, both serious and non-serious. For participants with Parkinson's disease, secondary efficacy parameters include normalized PD motor diary times, specifically Good ON time, ON time with troublesome dyskinesia, and OFF time. Additional assessments comprise the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III evaluated in both OFF and ON states, MDS-UPDRS part II assessed in OFF and ON states, MDS-UPDRS part I, and MDS-UPDRS part IV. Levodopa equivalent daily dose and 18F-DOPA PET imaging are also utilized as efficacy measures. For participants with multiple system atrophy, efficacy will be evaluated using the Unified Multiple System Atrophy Rating Scale (UMSARS) parts I, II in the ON state, III, and IV, as well as the MSA Quality of Life scale.