A Phase 2, randomised, double-blind, placebo-controlled, 2-way crossover study to evaluate the efficacy, safety, and tolerability of NMD670 in ambulatory adults with Type 3 spinal muscular atrophy

NMD670 is an inhibitor of skeletal muscle-specific chloride channel protein 1
(ClC-1) that enhances neuromuscular transmission and is being developed by NMD
Pharma for the treatment of neuromuscular diseases with neuromuscular junction
impairments. Spinal muscular atrophy (SMA) is a genetic disease characterised
by loss of motor neurons and impaired motor function and disability because of
progressive muscle wasting, in which the neuromuscular junctions are defective
in a significant proportion of patients (Arnold et al 2021, Stam et al 2018a).
Enhancing the neuromuscular junction function in patients with SMA may improve
performance and reduce physical fatigue. This proof-of-concept study aims to
evaluate the clinical efficacy on muscle strength and function, safety, and
tolerability of NMD670 administered daily for 3 weeks in ambulatory adults with
Type 3 SMA.

This study has been transitioned to CTIS with ID 2024-516321-31-00 check the CTIS register for the current data.

The purpose of this study is to measure clinical efficacy on muscle strength
and function, safety, and tolerability of NMD670 compared with placebo in
ambulatory participants with Type 3 SMA

• This is a Phase 2, multicentre, randomised, double-blind, placebo-controlled,
2-way crossover study.
• The study will enrol 18 to 75-year-old male and female ambulatory
participants diagnosed with Type 3 SMA with neuromuscular junction (NMJ)
deficits.
• After screening, eligible participants will be randomised to either receive
NMD670 (treatment period 1) followed by placebo (treatment period 2) or receive
placebo (treatment period 1) followed by NMD670 (treatment period 2). Both the
participant and Investigator will be blinded to treatment sequence assignment
and will not know which treatment is given during each treatment period.
• During the study, participants will continue receiving their usual SMA
treatment per standard
of care. Participants who receive SMA treatment that is not allowed during the
study will not
be eligible to participate in the study.

After a screening period of up to 4 weeks, each treatment period in the 2-way
crossover design will last 21 days (preceded 1 day before dosing by a baseline
visit), separated by a 7-day inter-treatment period and followed by a 7-day
follow-up period after the last dose of study
treatment.

The study duration will be approximately 8 to 13 weeks for each participant.
The treatment duration will be 3 weeks in each of the 2 treatment periods,
separated by a 1-week inter-treatment period.

Participants will be randomised in a 1:1 ratio to receive one of the following
treatment
sequences:
• NMD670 (Treatment Period 1) then placebo (Treatment Period 2)
• Placebo (Treatment Period 1) then NMD670 (Treatment Period 2)

NMD670 treatment will consist of oral doses of 400 mg (one 300-mg tablet plus
one 100-mg tablet) twice daily (bid) for 21 days. Placebo treatment will follow
the same dosing regimen with matching tablets containing placebo.

As of November 2022, no serious or severe side effects were reported among 57
healthy subjects and 12 Myasthenia Gravis subjects who received NMD670 in a
clinical study.
The following adverse effects (related or unrelated to the study therapy) were
reported in the study. All of them were mild in severity except the events of
myotonia (delayed muscle relaxation), gastroenteritis and tooth extraction (all
single occurrences) which were moderate in severity at a dose higher than used
in the present study:
• Muscular and skeletal symptoms such as flank pain, muscle cramps, muscle
and/or bone stiffness, muscle pain, and slowed or impaired relaxation of the
muscles
• Gastroenterology symptoms such as abdominal pain, abdominal distension, upper
abdominal pain, constipation, diarrhea, indigestion, frequent bowel movement,
nausea, and bleeding from the anus
• Nervous system symptoms such as dizziness, headache, partial or total loss of
sensation in a part of your body, sensory disturbance, and sleepiness
• General disorders such as fatigue and feeling abnormal
• Skin symptoms such as macular rash
• Events linked to investigations such as alkaline phosphatase increase,
creatinine increase, hepatic enzyme increase, and blood pressure decrease or
increase.

In addition, a dose related decrease in uric acid levels in blood has been
reported in previous studies with NMD670 but this was not considered clinically
relevant and not reported as an AE.