Safety and efficacy of NMD670 in ambulatory adult patients with Type 3 spinal muscular atrophy (SYNAPSE-SMA)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

NMD Pharma A/S

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

7 Jul 2023 → 17 Feb 2026

Decision date (initial)

2024-10-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516321-31-00

EudraCT number

2022-002301-24

ClinicalTrials.gov

NCT05794139

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacokinetic

To assess changes in muscle strength and function after NMD670 400 mg bid for 21 days, compared with placebo, in participants with SMA

Secondary objectives 1

1. - To assess changes in muscle strength after NMD670 400 mg bid for 21 days, compared with placebo, in participants with SMA. - To further assess changes in muscle strength and function after NMD670 400 mg bid for 21 days, compared with placebo, in participants with SMA. - To assess changes in neuromuscular junction transmission after NDM670 400 mg bid for 21 days, compared with placebo, in participants with SMA. - To assess the safety and tolerability of NMD670, compared with placebo, over 21-day dosing, in participants with SMA.

Conditions and MedDRA coding

Type 3 spinal muscular atrophy

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, Danish Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Participant must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
2. Participants who are with a clinical diagnosis of Type 3 SMA.
3. Participants who are ambulatory, defined as being able to walk at least 50 metres without walking aids at screening during the 6-minute walk test.
4. Participant with genetic confirmation of diagnosis (e.g., homozygous deletion or compound heterozygous deletion and mutation of survival of motor neuron 1 gene [SMN1]).
5. Participant with 2 to 5 copies of survival of motor neuron 2 gene [SMN2].
6. Participants with an MFM-32 dimension 1 (D1) score <80% at screening.
7. Participants with ≥7% CMAP amplitude decrement at screening during repeated nerve stimulation [RNS].
8. Participant has a body mass index (BMI) within the range 19-35 kg/m2 (inclusive).
9. Participant is male or female.
10. Contraceptive use by men and women must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male Participants: - A male participant must agree to use a highly effective contraception as detailed in Appendix 4 of this protocol during the intervention period and until the follow-up visit (corresponding to time needed to eliminate study intervention) and refrain from donating sperm during this period. Female Participants: - A female participant is eligible to participate if she is not pregnant (see Appendix 4), not breastfeeding, and at least one of the following conditions applies: - Not a woman of childbearing potential (WOCBP) as defined in Appendix 4. OR - A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during the intervention period and until the follow-up visit (corresponding to time needed to eliminate study intervention).
11. Participant is capable of giving signed informed consent as described in Appendix 1, Section 10.1.3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion criteria 20

1. Participants with prior surgery or fixed deformity (scoliosis, contractures) which would restrict ability to perform study-related tasks.
2. Participants with positive drug screen (cocaine, heroin, opiates, and ketamine) at screening. Participants will not be excluded from the study if they showed a positive drug screen due to medically prescribed opiates or ketamine.
3. Participants with positive human immunodeficiency virus (HIV) antibody test.
4. Participants with presence of hepatitis B surface antigen (HBsAg) [or hepatitis B core antibody (HBcAb)] at screening or within 3 months prior to first dose of investigational intervention.
5. Participants with positive hepatitis C antibody or ribonucleic acid (RNA) test result at screening or within 3 months prior to Day 1. NOTE: Participants with hepatitis C with positive hepatitis C antibody could be enrolled, if a negative hepatitis C RNA test is obtained.
6. Participants with a clinically significant history of allergic conditions (including drug allergies and anaphylactic reactions) or hypersensitivity to any component of the study intervention.
7. Participants unable to undergo the ophthalmologic evaluation, at screening.
8. Participants who have received any prohibited medication within 5 half-lives of the medication, prior to day 1 or are likely to require treatment with prohibited medications during the study. Prohibited medications are listed in Section 6.9 and include drugs affecting neuromuscular transmission (such as anticholinergic drugs), drugs showing relevant effect on ClC-1 channel, drugs with potential drug-drug interactions with NMD670. Other current and recent (within 1 month prior to the screening) treatments will be allowed, if judged by the Investigator to have no clinical relevance.
9. Participants received treatment with an investigational medicinal product (IMP) within 30 days (or 5 half-lives of the medication, whichever is longer) prior to Day 1.
10. Participants unable to perform or tolerate electromyography (EMG), according to medical history or at screening.
11. Participants with history of poor compliance with relevant SMA therapy.
12. Participants with other significant disease that may interfere with the interpretation of study data (e.g., other neuromuscular or muscular diseases).
13. Participant with a clinical diagnosis of gout, or with serum uric acid >ULN at screening.
14. Participant with clinically significant electrocardiogram (ECG) abnormalities at screening including PR interval ≥220 msec, irregular rhythms (other than sinus arrhythmia or occasional, rare supraventricular or rare ventricular ectopic beats) in the judgement of the Investigator, or T-wave configurations are not of sufficient quality for assessing QT interval duration.
15. Participant with any of the following abnormalities in QT interval corrected for heart rate using Fridericia’s correction (QTcF) at screening: a.QTcF interval greater than 450 msec at baseline for males and 460 msec for females; b. PR interval greater than 220 msec; c. complete bundle branch block (QRS ≥120 msec)
16. Participant with any of the following: a. Abnormal liver function test 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 or 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 Epidemiology Collaboration (CKD-EPI) equation based on cystatin C: < 40 years: eGFR < 75 mL/min/1.73 m². 40-65 years: eGFR < 60 mL/min/1.73 m². >65 years: eGFR < 45 mL/min/1.73 m², provided there is no proteinuria.
17. Participant with clinically significant laboratory test abnormalities at screening.
18. Participant with breast cancer within the past 10 years or 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.
19. Participants with ongoing significant psychiatric disorder (e.g., uncontrolled depression, anxiety).
20. Participants with Myotonic disorders or those on drugs that induce or mask myotonia.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline in 6MWT (total distance) after 21-day dosing

Secondary endpoints 1

1. Change from baseline in individual muscle groups maximum strength (measured with a dynamometer) after 21-day dosing. Change from baseline after 21-day dosing in: -6MWT (fatigue index), -revised Hammersmith scale score. Change from baseline in jitter and blocking measured via sfEMG after 21- day dosing. AEs, physical examinations, clinical laboratory parameters, vital signs, ECG, C-SSRS.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

NMD Pharma A/S

Sponsor organisation

NMD Pharma A/S

Address

Palle Juul-Jensens Boulevard 82

City

Aarhus N

Postcode

8200

Country

Denmark

Scientific contact point

Organisation

NMD Pharma A/S

Contact name

Parexel ServiceDesk

Public contact point

Organisation

NMD Pharma A/S

Contact name

Parexel ServiceDesk

Third parties 2

Locations

6 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 50 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications