Evaluation of Safety, Tolerability, and Efficacy of VX-264 Implant in Patients with Type 1 Diabetes Mellitus

The primary objective of this Phase 1/2 study is to **evaluate the safety and tolerability** of VX-264 in subjects with **Type 1 Diabetes Mellitus** (T1D) during Part A and Part B. Additionally, the study aims to assess the function of VX-264 in subjects with T1D in Part B and Part C. The clinical relevance of these objectives lies in determining the potential of VX-264 as a therapeutic option for managing T1D, focusing on its safety profile and functional efficacy.

Secondary objectives include evaluating the effect of VX-264 on:

• Exogenous insulin dose (Part C)
• Insulin independence (Part C)
• Metabolic control (Part C)

The clinical trial involves a total of **13 participants** diagnosed with **Type 1 Diabetes Mellitus**. The study population includes both male and female subjects, aged between 18 and 65 years. Participants were selected based on specific criteria, including a clinical history and laboratory evidence of Type 1 Diabetes, insulin dependence for at least five years, and consistent use of continuous glucose monitoring (CGM) devices. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have a body habitus supportive of the implantation of the planned number of VX-264 units. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect the participants' welfare.

The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of the **VX-264 Implant** in subjects with **Type 1 Diabetes Mellitus**. This is a Phase 1/2 study, structured as a randomized, double-blind, controlled trial. The trial is expected to commence recruitment on October 13, 2023, and conclude by March 30, 2027. Participants will be involved in the study for a duration that varies depending on the specific part of the trial they are enrolled in, with the longest involvement extending up to 365 days.

The trial is divided into three parts: Part A, Part B, and Part C. Each part has specific objectives and endpoints. Part A focuses on assessing the safety and tolerability of the VX-264 Implant, with primary endpoints including the incidence and severity of treatment-emergent adverse events (TEAEs), adverse device effects (ADEs), and other clinical assessments. Part B continues to evaluate safety and tolerability, while Part C primarily assesses changes in metabolic control, including peak C-peptide levels and insulin independence.

Study visits are sequenced to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will determine eligibility based on criteria such as age, HbA1c levels, and clinical history of Type 1 Diabetes. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will finalize data collection and assess the overall outcomes of the trial. Participants may be withdrawn from the study early if they experience significant adverse events or if they do not adhere to the study protocol.

Inclusion criteria require participants to be between 18 and 65 years old, with a history of insulin dependence for at least five years and specific HbA1c levels. Exclusion criteria are not explicitly detailed in the provided data. The trial will utilize a human channel array device (HCAD) to protect the implanted cells from immune rejection and facilitate nutrient and oxygen exchange. The study aims to provide valuable insights into the potential of VX-264 as a treatment for Type 1 Diabetes Mellitus, with a focus on both safety and functional outcomes.

The clinical trial involves the use of **VX-264 Implant**, an experimental medication developed by Vertex Pharmaceuticals, Incorporated. The **VX-264 Implant** is classified as a **Combination ATIMP** (Advanced Therapy Medicinal Product) and is designed for the treatment of Type 1 Diabetes Mellitus. The pharmaceutical form of the medication is an **implant**, which is administered via **implantation**. The active substance in the implant is **VX-264**, a structurally diverse substance categorized under cell therapy. The implant is designed to be placed within the body, where it functions to protect the encapsulated cells from immune rejection while promoting nutrient and oxygen exchange, and minimizing foreign body response (FBR). The human channel array device (HCAD) is an integral component of the implant, serving to house and safeguard the therapeutic cells.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial's primary objective is to evaluate the safety, tolerability, and efficacy of the **VX-264 Implant** in subjects with Type 1 Diabetes Mellitus. The study does not include a pediatric formulation, and the implant is not classified as an orphan drug. The trial does not specify a maximum daily dose, total dose, or treatment period for the **VX-264 Implant**. Participant compliance with the treatment regimen will be monitored throughout the study to ensure adherence to the protocol.

The efficacy of the VX-264 Implant in subjects with Type 1 Diabetes Mellitus will be assessed through a series of primary and secondary endpoints. In Part C of the trial, the primary efficacy endpoint is the change from baseline in peak **C-peptide** levels during the Mixed Meal Tolerance Test (MMTT) at Day 90. Secondary efficacy endpoints include the change from baseline in peak C-peptide during MMTT over time, change from baseline in C-peptide area under the curve (AUC) during MMTT over time, and the proportion of subjects achieving specific peak C-peptide thresholds (≥100, ≥200, ≥400, and ≥1000 pmol/L) during MMTT over time. Additionally, the trial will evaluate changes from baseline in average total daily insulin dose over time, the proportion of subjects with at least a 50% reduction in insulin dose from baseline and HbA1c <7.0% at Day 365, and the proportion of subjects who achieve insulin independence at any point between Day 180 and Day 365. Metabolic control will also be assessed through changes from baseline in HbA1c values, continuous glucose monitoring (CGM)-derived time-in-range (TIR), glucose variability (CGM, CV%), and glucose management indicator (GMI). These efficacy parameters will be measured and analyzed at specified timepoints throughout the trial to determine the therapeutic impact of the VX-264 Implant on Type 1 Diabetes Mellitus.