An Open-label, Dose-Finding, Phase 1/2 Study to Evaluate the Safety and Tolerability of a Single Intravenous Dose of LY3884961 in Subjects with Peripheral Manifestations of Gaucher Disease

The primary objective of this study is to evaluate the **safety** and tolerability of a single intravenous dose of LY3884961 in subjects with peripheral manifestations of Type 1 Gaucher Disease. This is clinically relevant as it aims to determine the potential risks and adverse effects associated with the treatment, which is crucial for ensuring patient safety and guiding future therapeutic use.

Secondary objectives include evaluating the clinical and biomarker effects of LY3884961 at predefined timepoints following infusion. This will provide insights into the drug's efficacy and its impact on disease biomarkers, contributing to a comprehensive understanding of its therapeutic potential.

The clinical trial involves a total of **9 participants** diagnosed with **Type 1 Gaucher Disease** (Peripheral/Non-neuronopathic Manifestations). The study population includes both male and female subjects, aged between **18 and 65 years**. Participants were selected based on specific criteria, including confirmed bi-allelic GBA1 mutations and a history of being on enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) for at least two years, with a stable, maximum tolerated dose for at least three months prior to screening. The trial population is not restricted by gender, and both males and females of childbearing potential are required to use highly effective contraception throughout the study. Participants are also required to abstain from blood donations for at least the first year of the study. The trial does include a vulnerable population, ensuring comprehensive safety and tolerability evaluation of the investigational product, LY3884961.

The clinical trial is designed to evaluate the safety and tolerability of a single intravenous dose of **LY3884961** in subjects with peripheral manifestations of Type 1 Gaucher Disease. This study is structured as an open-label, dose-finding, Phase 1/2 trial. The trial is expected to commence recruitment on October 2, 2023, and is estimated to conclude by January 1, 2031. Participants will be involved in the study for a duration that includes the initial treatment phase and a long-term follow-up period. The trial will include several key visits: an inclusion (screening) visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will confirm eligibility based on criteria such as age, genetic confirmation of bi-allelic **GBA1** mutations, and stable treatment with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). Follow-up visits will monitor the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), as well as changes in clinical laboratory parameters, vital signs, and other health indicators. The end-of-study visit will assess the overall safety and efficacy outcomes. Participants are expected to adhere to study protocols, including the use of effective contraception and abstaining from blood donations during the study. Conditions that may lead to early termination from the study include non-compliance with study requirements or the occurrence of significant adverse events. The primary endpoints focus on the safety profile, while secondary endpoints include changes in spleen volume, platelet count, and enzyme activity levels. The trial aims to provide valuable insights into the potential therapeutic benefits of **LY3884961** for individuals with Type 1 Gaucher Disease.

The clinical trial involves the administration of **LY3884961**, an experimental medication formulated as a solution for injection. The active substance is an adeno-associated viral vector serotype 9 expressing a codon-optimized human GBA gene. This gene therapy is administered via intravenous infusion. The primary objective is to evaluate the safety and tolerability of a single intravenous dose in subjects with peripheral manifestations of Gaucher Disease. Participant compliance will be monitored through regular assessments and follow-up visits.

**Sirolimus** is utilized as an auxiliary treatment in the trial. It is available in the form of coated tablets and is administered orally. Sirolimus functions as an immunosuppressant and is included to support the primary treatment regimen. The dosing schedule and frequency are determined based on the participant's response and clinical condition, with compliance monitored through pill counts and patient diaries.

**Eculizumab** is another auxiliary treatment used in the study. It is provided as a concentrate for solution for infusion and is administered via infusion. Eculizumab is an orphan drug designated for specific conditions and is used to complement the primary treatment. The administration schedule is tailored to the participant's needs, with adherence monitored through infusion records and clinical evaluations.

**Methylprednisolone** is included as an auxiliary treatment in the form of a solution for injection. It is administered either as an intravenous bolus injection or via IV infusion. Methylprednisolone serves as an immunosuppressant, and its use is adjusted according to the participant's clinical response. Compliance is ensured through administration records and clinical monitoring.

**Prednisone** is also used as an auxiliary treatment, available in tablet form and administered orally. As an immunosuppressant, prednisone is included to support the primary treatment regimen. The dosing schedule is individualized based on the participant's condition, with adherence monitored through pill counts and patient-reported outcomes.

**Solu-Medrol**, a formulation of methylprednisolone, is used as an auxiliary treatment in the form of a solution for injection. It is administered via intravenous bolus injection or IV infusion. Solu-Medrol is included to provide additional immunosuppressive support, with dosing and administration tailored to the participant's clinical needs. Compliance is monitored through administration records and clinical assessments.

The efficacy of the clinical trial will be assessed using a range of primary and secondary endpoints. Primary endpoints include the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), as well as clinically significant changes in vital signs, clinical laboratory parameters, 12-lead ECGs, results of abdominal and bone MRIs, physical and neurological examinations, and measurements of waist circumference and weight over time. Additionally, changes from baseline in complement proteins, and the presence of anti-AAV9 and anti-GCase antibodies, as well as ELISPOT GCase and ELISPOT rAAV9, will be evaluated.

Secondary endpoints focus on changes and percent changes from baseline in spleen volume (MN), platelet count, and **GCase** enzyme activity and protein levels, along with GluSph levels. The time from administration of LY3884961 to the discontinuation of enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), and the time from discontinuation to re-initiation of ERT/SRT, will also be measured. These endpoints will be assessed at various time points throughout the study to determine the efficacy of the treatment.