Efficacy, Safety, and Tolerability of NMD670 in Ambulatory Adults with Type 3 Spinal Muscular Atrophy: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate changes in **muscle strength** and function following administration of NMD670 at a dosage of 400 mg twice daily for 21 days, compared with placebo, in participants with Type 3 **spinal muscular atrophy** (SMA). This is clinically relevant as it aims to determine the potential therapeutic benefits of NMD670 in improving motor function in individuals affected by this neuromuscular disorder.

Secondary objectives include: - Assessing changes in muscle strength after NMD670 treatment compared to placebo. - Further evaluating changes in muscle strength and function post-treatment. - Assessing changes in **neuromuscular junction** transmission following NMD670 administration. - Evaluating the safety and tolerability of NMD670 compared to placebo over the 21-day dosing period. These objectives are crucial for understanding the broader impact of NMD670 on neuromuscular health and its safety profile in the target population.

The clinical trial involves a total of **24 participants** diagnosed with **Type 3 spinal muscular atrophy**. The study population comprises both male and female subjects, aged between **18 to 75 years**. Participants are required to be ambulatory, capable of walking at least 50 meters without walking aids, and must have a body mass index (BMI) within the range of 19-35 kg/m². Genetic confirmation of the diagnosis is necessary, with participants having 2 to 5 copies of the survival of motor neuron 2 gene (SMN2). The trial population was selected based on specific inclusion criteria, ensuring that participants are not part of a vulnerable population. Lifestyle considerations such as contraceptive use are mandated to align with local regulations, and participants must be capable of providing informed consent. The trial does not focus on any particular lifestyle habits such as diet or physical activity beyond the ability to perform a 6-minute walk test.

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled, 2-way crossover study designed to evaluate the efficacy, safety, and tolerability of **NMD670** in ambulatory adults with **Type 3 spinal muscular atrophy**. The trial aims to assess changes in muscle strength and function after administering NMD670 at a dose of 400 mg twice daily for 21 days, compared with a placebo. The primary endpoint is the change from baseline in the 6-minute walk test (6MWT) total distance after 21 days of dosing. Secondary endpoints include changes in individual muscle groups' maximum strength, fatigue index, revised Hammersmith scale score, and jitter and blocking measured via single-fiber electromyography (sfEMG) after 21 days of dosing. Safety assessments will include adverse events, physical examinations, clinical laboratory parameters, vital signs, electrocardiograms (ECG), and the Columbia-Suicide Severity Rating Scale (C-SSRS).

The trial is expected to last until July 31, 2025, with participant recruitment starting on August 18, 2023. Participants will be involved in the study for a maximum of 21 days, with the possibility of early termination if they do not meet the inclusion criteria or if they experience adverse events that necessitate withdrawal. The study visits will include an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess the final outcomes. The inclusion criteria require participants to be between 18 and 75 years of age, ambulatory, with a clinical and genetic diagnosis of Type 3 spinal muscular atrophy, and a body mass index (BMI) within the range of 19-35 kg/m². Participants must also comply with contraceptive requirements and provide informed consent. The trial excludes individuals who do not meet these criteria or who have conditions that could interfere with the study's objectives.

The clinical trial involves the administration of **NMD670**, an experimental medication formulated as a tablet. **NMD670** is a chemical compound that acts as a partial inhibitor of the skeletal muscle ClC-1 channel, thereby enhancing neuromuscular transmission. The medication is administered orally, with a dosage of 400 mg taken twice daily (bid) for a maximum treatment period of 21 days. The maximum daily dose is 800 mg. The trial aims to evaluate the efficacy, safety, and tolerability of **NMD670** in ambulatory adults with Type 3 spinal muscular atrophy (SMA).

In addition to the experimental treatment, the study includes the use of placebo tablets as a comparator. Two types of placebo tablets are utilized: a 300 mg tablet and a 100 mg tablet. These placebo tablets are designed to match the appearance of the **NMD670** tablets but do not contain any active pharmaceutical ingredients. The placebo is administered in a similar manner to the experimental medication to maintain the double-blind nature of the study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The study is conducted in a randomized, double-blind, placebo-controlled, 2-way crossover design to assess changes in muscle strength and function in participants receiving **NMD670** compared to those receiving placebo.

The efficacy of the investigational product **NMD670** in the treatment of Type 3 spinal muscular atrophy will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the total distance covered during the 6-minute walk test (6MWT) after a 21-day dosing period. This test is a widely accepted measure of functional exercise capacity in clinical trials.

Secondary endpoints include changes from baseline in maximum strength of individual muscle groups, which will be measured using a dynamometer. Additional secondary measures include changes in the 6MWT fatigue index, revised Hammersmith scale score, and jitter and blocking as measured by single-fiber electromyography (sfEMG) after the 21-day dosing period. Safety and tolerability will also be evaluated through adverse events, physical examinations, clinical laboratory parameters, vital signs, electrocardiograms (ECG), and the Columbia-Suicide Severity Rating Scale (C-SSRS).