Evaluation of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VX-670 in Adult Patients with Myotonic Dystrophy Type 1: A Phase 1/2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **safety** and **tolerability** of VX-670 in adult subjects with **Myotonic Dystrophy Type 1 (DM1)**. This evaluation is conducted through the administration of single ascending doses in Part A and both single and multiple ascending doses in Part B. Understanding the safety profile and tolerability of VX-670 is crucial for determining its potential as a therapeutic option for DM1, a condition characterized by progressive muscle wasting and weakness.

Secondary objectives include:

• Part A: To evaluate the plasma **pharmacokinetics (PK)** of VX-670 and its active molecule, PMO-0221a, following single ascending doses in adult subjects with DM1.
• Part B: To assess the plasma PK of VX-670 and PMO-0221a after single and multiple ascending doses, evaluate the muscle PK of these compounds, and assess muscle spliceopathy in adult subjects with DM1.

The clinical trial involves a total of **19 participants** diagnosed with **Myotonic Dystrophy type 1 (DM1)**. The study population includes both male and female subjects, aged between **18 to 64 years**, who have a documented clinical diagnosis of DM1 with an age of onset greater than one year and a positive genetic test for DM1. Participants are required to have a **body mass index (BMI) less than 35.0 kg/m²** and a total body weight greater than 40 kg. The trial does not include a vulnerable population. Key lifestyle considerations such as diet and physical activity are not specified. The selection criteria ensure that participants have a left ventricular ejection fraction greater than 55% within the past three months. The trial aims to evaluate the safety and tolerability of single and multiple ascending doses of VX 670 in this specific population.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of VX-670 in adult subjects with **myotonic dystrophy type 1**. The trial is structured in two parts: Part A involves single ascending doses, while Part B includes both single and multiple ascending doses. The study is expected to commence recruitment on May 15, 2024, and conclude by November 30, 2025. Participants will be involved in the study for the duration of their assigned dosing schedule, with the possibility of early termination if adverse events or other safety concerns arise.

Study visits are sequenced to ensure comprehensive data collection and participant safety. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on criteria such as age, body mass index, and documented diagnosis of myotonic dystrophy type 1. Subsequent visits will include dosing and monitoring sessions, where participants will receive either VX-670 or a placebo via **intravenous administration**. Follow-up visits will assess safety and tolerability through adverse event monitoring, laboratory tests, and electrocardiograms. The end-of-study visit will finalize data collection and ensure participant well-being post-trial.

Participants are expected to remain in the study unless they experience significant adverse events, fail to comply with study protocols, or choose to withdraw consent. The primary endpoint focuses on the safety and tolerability of VX-670, while secondary endpoints include pharmacokinetic parameter estimates and changes in muscle biopsy splicing index. The trial's design and procedures are meticulously planned to ensure robust data collection and participant safety throughout the study duration.

The clinical trial involves the administration of **VX-670**, a solution for injection/infusion, as the experimental medication. VX-670 is a nucleic acid-based compound developed by Vertex Pharmaceuticals, Incorporated. The pharmaceutical form of VX-670 is a solution intended for intravenous administration. The study is designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of VX-670 in adult subjects with Myotonic Dystrophy Type 1. The dosing regimen includes both single and multiple ascending doses, although specific dosage amounts and frequency are not detailed in the provided data. Participant compliance with the dosing schedule will be monitored throughout the trial.

In addition to the experimental treatment, a **0.9% saline solution (w/v)** is used as a placebo comparator in this randomized, double-blind, placebo-controlled study. The saline solution is administered intravenously, serving as a control to assess the effects of VX-670. The saline solution does not contain any active pharmaceutical ingredients and is used to maintain the study's blinding and control conditions. The administration of the placebo follows the same route as the experimental drug, ensuring consistency in the study's methodology.

Efficacy in the clinical trial evaluating VX-670 for **Myotonic Dystrophy Type 1** will be assessed through several parameters. The primary endpoints focus on the safety and tolerability of VX-670, which will be determined by monitoring adverse events, laboratory test results, standard 12-lead electrocardiograms (ECGs), vital signs, and the Columbia Suicide Severity Rating Scale (C-SSRS). Secondary endpoints include pharmacokinetic (PK) parameter estimates of VX-670 and PMO-0221a derived from plasma concentration time data in both Parts A and B of the study. Additionally, in Part B, PK parameter estimates will also be derived from muscle concentration data, and changes from baseline in the splicing index in tibialis anterior muscle biopsy will be evaluated.