Evaluation of Safety and Efficacy of LY3884961 in Parkinson's Disease Patients with GBA1 Mutation: A Phase 1/2a Open-Label Ascending Dose Study

The primary objective of this study is to evaluate the **safety**, **tolerability**, and **immunogenicity** of two dose levels of LY3884961 administered via suboccipital injection into the cisterna magna in patients with Parkinson’s Disease with at least one GBA1 mutation. This is clinically relevant as it aims to determine the potential risks and immune response associated with the treatment, which is crucial for ensuring patient safety and guiding future therapeutic strategies.

Secondary objectives include:

• Evaluating the effect of LY3884961 on **GCase enzyme activity** and GCase protein levels in blood and cerebrospinal fluid (CSF).
• Assessing the effect of LY3884961 on **glycolipid levels** in blood and CSF.

The clinical trial involves a total of **20 participants** diagnosed with **Parkinson's Disease** with at least one GBA1 mutation. The study population includes both male and female subjects, aged between **35 to 80 years**. Participants are required to have a body weight ranging from **40 kg to 110 kg**. The selection criteria ensure that individuals have a confirmed pathogenic GBA1 mutation and low GCase enzyme activity, while excluding those with bi-allelic GBA1 mutations or monogenic forms of Parkinson's Disease. Participants must have a stable use of background medications for at least eight weeks prior to the administration of the investigational product. Additionally, a negative screening test for Mycobacterium tuberculosis is required. The trial population includes individuals who are not pregnant or lactating, and each participant must have a reliable study partner to provide information on their health status and cognitive and functional abilities. The study focuses on a vulnerable population, ensuring that participants and their legally authorized representatives understand the study's purpose and risks, providing informed consent.

The clinical trial is designed to evaluate the **safety**, tolerability, and immunogenicity of two dose levels of LY3884961, a **solution for injection** containing an adeno-associated viral vector serotype 9 expressing a codon-optimized human GBA gene. This investigational product is administered via suboccipital injection into the cisterna magna in patients diagnosed with **Parkinson's Disease** with at least one GBA1 mutation. The trial follows an open-label, ascending dose design and is categorized as a Phase 1/2a study. The estimated duration of the trial extends from the recruitment start date in June 2025 to the anticipated end date in February 2031.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, body weight, and the presence of a pathogenic GBA1 mutation. The primary endpoints include the incidence and severity of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), as well as the immunogenicity of the viral vector and glucocerebrosidase. Secondary endpoints focus on changes from baseline in glycolipid and glucocerebrosidase levels, and enzyme activity in both blood and cerebrospinal fluid.

The expected length of participant involvement will vary depending on individual response and the occurrence of any adverse events. Conditions that may lead to early termination from the study include the development of significant AEs or SAEs, non-compliance with study procedures, or withdrawal of consent. Follow-up visits will be scheduled to monitor safety and efficacy, with an end-of-study visit to assess the overall outcomes and collect final data. The trial is not classified as a low-intervention study, and it integrates both Phase I and Phase II components to comprehensively assess the investigational product's effects.

The clinical trial involves the administration of the experimental medication **LY3884961**, which is a **solution for injection**. This investigational product is a **recombinant adeno-associated viral vector serotype 9** that expresses a codon-optimized human **GBA gene**. The pharmaceutical form of LY3884961 is a solution intended for **intracisternal use**, specifically administered via suboccipital injection into the cisterna magna. The study is designed to evaluate two dose levels of LY3884961, although specific dosing amounts are not provided. The administration schedule and frequency are determined by the study protocol, with a focus on assessing the safety, tolerability, and immunogenicity of the treatment in patients with Parkinson's disease who have at least one GBA1 mutation.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The study is open-label, meaning that both the researchers and participants are aware of the treatment being administered. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The investigational product is not a pediatric formulation and is not classified as an orphan drug. The trial aims to provide insights into the potential therapeutic effects of LY3884961 in the target patient population.

The efficacy of the investigational product LY3884961 in the clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints focus on the incidence and severity of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), as well as the incidence of procedure or treatment-emergent safety findings. Additionally, the trial will evaluate the treatment-emergent changes from baseline in the immunogenicity of **adeno-associated viruses serotype 9** and glucocerebrosidase.

Secondary endpoints will include changes from baseline in glycolipid and glucocerebrosidase levels, as well as glucocerebrosidase enzyme activity in both blood and cerebrospinal fluid. These parameters will be measured to assess the biochemical impact of the treatment. The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, although specific timepoints are not detailed in the provided data. The trial aims to provide comprehensive data on the biochemical and clinical effects of LY3884961 in patients with Parkinson’s Disease with at least one GBA1 mutation.