Efficacy and Safety Evaluation of NMD670 in Ambulatory Adults with Charcot-Marie-Tooth Disease Types 1 and 2: A Randomized, Double-Blind, Placebo-Controlled Phase 2a Trial

Trial ID: 2023-507892-23-00
Protocol: NMD670-02-0003
Sponsor: NMD Pharma A/S

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Diseases & Conditions

Hereditary motor and sensory neuropathy

Objectives

The primary objective of this Phase 2a, randomized, double-blind, placebo-controlled study is to assess the **clinical efficacy** of NMD670 in ambulatory adult patients with Charcot-Marie-Tooth Disease Type 1 and Type 2, as rated by clinicians. This evaluation is clinically relevant as it aims to determine the potential therapeutic benefits of NMD670, which could lead to improved management of this progressive neurological disorder characterized by muscle weakness and atrophy.

Secondary objectives include evaluating the **tolerability** of NMD670, which is crucial for understanding the safety profile and potential side effects of the treatment. This information is essential for determining the feasibility of NMD670 as a long-term treatment option for patients with Charcot-Marie-Tooth Disease.

Participants

The clinical trial involves a total of **28 participants** diagnosed with **Charcot-Marie-Tooth Disease Type 1 and Type 2**, confirmed by genetic testing. The study population includes both male and female subjects, aged between 18 and 70 years. Participants are required to have a **body mass index** between 18 and 35 kg/m² and a minimum weight of 40 kg. The trial population was selected based on specific physical capabilities, such as the ability to perform a 6-minute walk test within one standard deviation of the mean adjusted by age and sex, and bilateral ankle dorsiflexion strength of 4 or less on the manual muscle testing scale. Participants are expected to maintain stable doses of any medication for muscle cramps or pain and continue any existing physical or occupational therapy regimens. The study includes individuals who are capable of providing informed consent and requires the use of highly effective contraception methods for participants of childbearing potential. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the clinical efficacy of NMD670 as rated by clinicians.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy, safety, and tolerability of NMD670 in ambulatory adult patients with **Charcot-Marie-Tooth Disease Type 1 and Type 2**. The trial will span a period of 21 days, during which participants will be administered either NMD670 or a placebo in tablet form. The primary objective is to assess the clinical efficacy of NMD670 as rated by clinicians, with primary endpoints including changes from baseline to day 21 in the total distance walked during the 6-minute walk test (6MWT), time to complete the 10-meter walk/run test (10MW/RT), and total time taken to perform the timed up and go test (TUG).

Participants will be involved in the study for a maximum of 21 days, with the trial estimated to conclude by May 2026. The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, genetic confirmation of the disease, and specific physical capabilities. Following the screening, participants will undergo baseline assessments before randomization. Subsequent visits will be scheduled to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit will involve final assessments to evaluate the primary and secondary endpoints.

Inclusion criteria require participants to be between 18 and 70 years of age, with a confirmed diagnosis of Charcot-Marie-Tooth Disease Type 1 or 2. Participants must maintain stable doses of any medications for muscle cramps or pain and continue any existing physical or occupational therapy regimens. Exclusion criteria are not explicitly detailed in the provided data. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The study emphasizes the use of highly effective contraception methods for participants of childbearing potential, in accordance with local regulations.

Treatment

The clinical trial involves the administration of **NMD670**, an experimental medication formulated as a tablet. The active substance, also named **NMD670**, is a chemical entity developed by NMD PHARMA A/S. The medication is administered orally with a maximum daily dose of 800 mg, and the total dose over the treatment period should not exceed 16,800 mg. The treatment duration is set for a maximum of 21 days. The trial aims to evaluate the efficacy, safety, and tolerability of **NMD670** in ambulatory adult patients diagnosed with Charcot-Marie-Tooth Disease Type 1 and Type 2.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the experimental medication in appearance but contains no active substance. The use of a placebo allows for the assessment of the true efficacy of **NMD670** by providing a baseline for comparison. The administration route and frequency for the placebo are consistent with those of the experimental medication to maintain the study's integrity and ensure blinding.

Efficacy

The clinical trial aims to evaluate the efficacy of the investigational product, NMD670, in ambulatory adult patients with **Charcot-Marie-Tooth Disease** Type 1 and Type 2. Efficacy will be assessed through several primary endpoints, focusing on changes from baseline to day 21. These endpoints include the total distance walked during the 6-Minute Walk Test (6MWT), the time to complete the 10-Meter Walk/Run Test (10MW/RT), and the total time taken to perform the Timed Up and Go Test (TUG). These measures will be compared between the NMD670 and placebo groups.

The assessments will be conducted at baseline and on day 21 of the treatment period. The 6MWT, 10MW/RT, and TUG are standardized tests commonly used to evaluate functional mobility and endurance in patients with neuromuscular disorders. The data collected from these tests will be analyzed to determine the efficacy of NMD670 in improving physical performance in the study population. The trial is designed as a Phase 2a, randomized, double-blind, placebo-controlled study, ensuring rigorous evaluation of the investigational product's clinical efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female participants must be 18 to 70 years inclusive at the time of signing the ICF.
Diagnosis of CMT type 1 or 2 confirmed by genetic testing.
The following physical capabilities must be met without assistive devices such as AFOs (orthopaedic inserts are allowed) at screening (both must apply): a. 6MWT total distance within 1 standard deviation of the mean adjusted by age and sex from the provided CMT norm. b. Bilateral ankle dorsiflexion strength of 4 (inclusive) or less on the manual muscle testing scale.
Participants already receiving physical or occupational therapy or following a prescribed training regimen for more than 30 days prior to screening should continue their current treatment regimen throughout the study. Participants are not allowed to start physical or occupational therapy or a prescribed training regimen within 30 days of screening or during the study.
Participants taking medication for muscle cramps (e.g., magnesium) and/or pain (e.g., nonsteroidal anti-inflammatory drug [NSAID], neuropathic pain medication, or opiates) should be on a stable dose for at least 30 days prior to screening and should maintain a stable dose for the duration of the study.
Body mass index between 18 and 35 kg/m2 inclusive at screening and a minimum weight of 40 kg.
Female participants who are women of childbearing potential (WOCBP) and male participants with partners who are WOCBP must agree to use a highly effective contraception method during the study. Contraceptive use by men and women must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies (refer to Section 10.4, Appendix 4 for additional information).
Participant is capable of giving signed informed consent.
Participants willing and albe to comply with Syde(R)-related procedures (training on the device, daily use throughout from screening until the end of the study, and device return at the end of the study)

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Exclusion Criteria

Participants with other significant disease that may interfere with the interpretation of study data (e.g., other neuromuscular diseases) and/or ability to complete the tests, in the opinion of the Investigator.
Participants unable to undergo the ophthalmologic evaluation at screening.
Participants who require prohibited medication within 30 days of screening (or 5 half-lives of the medication, whichever is shorter) and/or are likely to require them during the study; prohibited medications include drugs showing relevant effects on NMJ transmission and drugs where the effect might be affected by potential metabolic drug-drug interactions with NMD670. Other current and recent (within 1 month prior to screening) treatments will be allowed if judged by the Investigator to be of no relevance for the study.
Use of daily assistive devices such as AFOs (orthopaedic inserts are allowed) for 4 weeks prior to screening and for the entire duration of the study. Daily AFO use is defined as individuals with CMT disesas who rely on assistive devices such as AFOs for regular functional support in daily activities. Patients who use an AFO but do not rely on it for regular activities and home activities or who use it only in specific situations, such as during outdoor activities, travelling, or work-related tasks, are not considered daily AFO users.
Participants who have received treatment with another IMP within 30 days (or 5 half-lives of the medication, whichever is longer) prior to day 1.
Participants with history of poor compliance with relevant therapy in the opinion of the Investigator.
Female participants who plan to become pregnant during the study or are currently pregnant or breastfeeding.
Severe deformity or ankle contracture that in the opinion of the Investigator would limit passive range of motion to interfere with performance of the tests.
Ankle surgery or other limb-surgery procedures related to CMT within 9 months of screening.
Moderate-to-severe neuropathic or inflammatory/musculoskeletal pain that in the opinion of the Investigator would interfere with performance of the tests.
Participants with a clinical diagnosis of gout or with serum uric acid greater than the upper limit of normal (ULN) at screening.
Participants with breast cancer, lymphoma, leukaemia, or any malignancy within the past 5 years. An exception of this 5-year requirement is basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease.
Study participants with a centrally read 12-lead ECG with findings considered to be clinically significant upon medical review. The clinical significance of the findings needs to be assessed by the Investigator to determine eligibility.
Participants with any of the following: a. Abnormal liver function test result defined as total bilirubin >1.5×ULN (participants with Gilbert’s syndrome can be included with total bilirubin >1.5×ULN if direct bilirubin is ≤1.5×ULN and ≤35% of total bilirubin). b. Abnormal liver transaminase levels at baseline and confirmed current or chronic history of liver disease including (but not limited to) hepatitis virus infections, drug- or alcohol-related liver disease, non-alcoholic steatohepatitis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, α-1 antitrypsin deficiency, primary biliary cholangitis, primary sclerosing cholangitis, or any other liver disease considered clinically significant by the Investigator. c. Known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones). d. Abnormal renal function with estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiaology Collaboration (CKD-EPI) equation based on cystatin C24: <40 years: eGFR <75mL/min/1.73m2 40 to 65 years: eGFR <60mL/min/1.73m2 >65 years: eGFR <45mL/min/1.73m2, provided there is no proteinuria
Participants with laboratory test result abnormalities at screening considered clinically significant by the Investigator.
Participants with an ongoing significant psychiatric disorder (e.g., unstable and newly diagnosed major depressive disorder or unstable and newly diagnosed anxiety disorders).
Participants with alcohol abuse as judged by the Investigator or with positive drug screen results (cocaine, heroin, opiates, or marijuana) at screening. a. If positive for marijuana, criteria for drug abuse (as determined by the Investigator) is also needed to meet this exclusion criterion. b. If positive for opiates, the exclusion criterion is not met if opiates have been medically prescribed for the treatment of pain in CMT.
Participants with a positive HIV antibody test result.
Participants with positive serology test results for hepatitis B (unless due to vaccination, resolved natural infection, or passive immunisation, as confirmed with the Medical Monitor).
Participants positive for hepatitis C antibody.
Participants with a clinically significant history of allergic conditions (including drug allergies and anaphylactic reactions) or hypersensitivity to any component of the IMP.
Participant with myotonic disorders or those on drugs that induce or mask myotonia.
Paticipants with any of the following abnormalities at screening QT interval corrected for heart rate using Fridericias's correction (QTcF) a . greater than 450 msec for males and 460 msec for females b. PR interval greater than 220 msec c. Complete bundle branch block (QRS interval ≥120 msec) NOTE: This exclusion criterion is assessed by a central reader