Phase 1/2a study of ATX-01 in participants with DM1

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Arthex Biotech S.L.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

12 Aug 2024 → ongoing

Decision date (initial)

2024-07-08

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Arthex Biotech, S.L.

External identifiers

EU CT number

2023-505363-37-00

WHO UTN

U1111-1298-2806

ClinicalTrials.gov

NCT06300307

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response

To evaluate the safety and tolerability of ATX-01 in adult participants with DM1

Secondary objectives 6

1. To further evaluate the safety and tolerability of ATX-01 in adult participants with DM1
2. To assess the pharmacokinetics (PK) of ATX-01 in plasma and urine
3. To assess the pharmacodynamics (PD) of ATX-01 in muscle tissue
4. To evaluate the efficacy of ATX-01 in participants with DM1 on myotonia
5. To evaluate the effects of ATX-01 in participants with DM1 on ankle dorsiflexion strength
6. To evaluate the impact of ATX-01 on activities of daily living (ADL) in participants with DM1 in terms of change in myotonia, mobility, upper extremity function, breathing, stamina, and gastrointestinal (GI) symptoms

Conditions and MedDRA coding

Myotonic dystrophy type 1 (DM1)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

The Spanish Agency Of Medicines And Medical Devices, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Participant must be 18 to 64 years of age inclusive, at the time of signing the informed consent.
2. 2. Participants with a documented clinical diagnosis of DM1 (a CTG expansion of >150 repeats in DMPK gene measured in peripheral blood mononuclear cells [PBMCs] would support the clinical diagnosis).
3. 3. Ambulatory, defined as able to complete a 10-meter walk/run test (10MWRT) at screening without the use of assistive devices such as canes, walkers, or orthoses, except for ankle-foot orthoses.
4. 4. Presence for >3 seconds of grip myotonia (long/middle finger on vHOT) as confirmed by a central reader.
5. 5. BMI <35 kg/m².
6. 6. Male and female participants.
7. 7. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
8. 8. The participant agrees not to post any personal medical data related to the study or information related to the study on any website or social media (e.g., Facebook, Twitter) or discuss the study publicly until the entire study has been completed.
9. 9. The participant is able to have muscle biopsies as per the Schedule of Activities.
10. 10. The participant is able to complete study assessments including all muscle testing assessments without use of assistive devices such as canes, walkers, or orthoses, except for ankle-foot orthoses, or the assistance of another person, at screening and baseline.

Exclusion criteria 29

1. 1. Participants with congenital DM1.
2. 10. Breast cancer within the past 10 years.
3. 11. ALT or AST > 3.0× upper limit of normal (ULN) at screening.
4. 12. Total bilirubin > 1.5× ULN at screening (Participants with Gilbert’s syndrome can be included with total bilirubin > 1.5× ULN as long as direct bilirubin is ≤ 1.5× ULN).
5. 13. Known hepatic or biliary abnormalities (except for Gilbert’s syndrome or asymptomatic gallstones).
6. 14. Chronic renal failure defined as calculated creatine clearance Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation < 60 mL/min/1.73 m² at screening.
7. 15. Recent history (within the past 3 months before Screening) of acute kidney injury.
8. 16. Proteinuria at screening: a urine protein-to-creatinine ratio (UPCR) ≥ 200 mg/g or a urine albumin-to-creatinine ratio (UACR) > 30 mg/g at screening requires a 24-hour urine collection and measurement of protein excretion:• values of > 150 mg per 24 hours are exclusionary • values between 150 mg to 300 mg can trigger a repeat 24-hour urine measurement of protein excretion at the discretion of the investigator. If the repeat value is also >150 mg, the participant is excluded. Participants with a UPCR of < 200mg/g or a UACR ≤ 30mg/g at screening are eligible without the need for a 24-hour urine protein excretion measurement.
9. 17. Untreated non-compensated hypothyroidism.
10. 18. Contraindication to a muscle biopsy defined as: use of an anticoagulant (unless it can be temporarily stopped without undue consequence and 5 half-lives passed before the biopsy), platelet count < 50,000, or other bleeding disorder
11. 19. Use of mexiletine or other agent for myotonia within 5 half-lives, prior to screening.
12. 2. Prior or ongoing medical condition, medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
13. 20. Exposure to another investigational drug within 3 months prior to start of study treatment.
14. 21. Use of medications which are CCI may be restricted, any use must be discussed and confirmed acceptable with the Medical Monitor
15. 3. Medical Research Council Muscle Scale score of ≤ 3 on ankle dorsiflexion (either ankle) or significant tibialis anterior atrophy that prevents a muscle biopsy.
16. 4. Active COVID-19 infection.
17. 5. a. history of pacemaker or implantable cardioverter-defibrillator; participants with pacemakers or implantable cardioverter-defibrillators implanted for solely prophylactic reasons can be included after confirmation from the medical monitor. b. atrial fibrillation or flutter or any other sustained atrial arrhythmia with a resting heart rate (HR) ≥ 100bpm. If a participant is on stable therapy (per the investigator’s judgement), and the participant has a resting HR < 100bpm, the participant can be eligible. c. ventricular tachycardia d. any other sustained ventricular arrhythmia e. undiagnosed syncope in the last year f. congestive heart failure of New York Heart Association (NYHA) functional class IIIV. If a participant with class II-IV is on stable therapy (per investigator’s judgement), participant can be eligible. g. history of myocardial infarction h. congenital heart disease, unless on stable therapy i. moderate or severe valvular heart disease
18. 6. Participants with a family history of sudden cardiac death, unexplained death, long QT syndrome, or death from a primary dysrhythmia potentially associated with QT prolongation in any immediate family member (parents, siblings, children) that is not related to an underlying DM1 diagnosis.
19. 7. Participants with serum electrolyte abnormalities that cannot be corrected.
20. 8. Participants receiving concomitant QTc prolonging medications unless on stable doses.
21. 9. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years.
22. 22. Use of medications which are CCI, including regular use of CCI.
23. 23. Participants with planned procedures requiring an CCI during the study.
24. 24. Ongoing participation in any other interventional therapeutic clinical trial.
25. 25. Screening systolic blood pressure > 160 mmHg systolic and/or diastolic blood pressure > 100 mmHg. Blood pressure measurements may be repeated up to 3 times if anxiety is thought to be responsible for an elevation of blood pressure.
26. 26. Sustained non-sinus rhythm, any second or third degree heart block, PR interval > 240 ms, QRS duration > 120 ms, QTcF > 450 ms (males and females), on a 12-lead ECG at screening (mean or triplicate). Participants with an implantable cardioverter-defibrillators can be enrolled if their PR interval, QRS duration, or QTcF exceed these limits as long as their cardiac ejection fraction on echocardiogram does not meet criteria for exclusion #28.Participants with a PR interval >240ms may be considered eligible if: • they have had electrophysiological studies (EPS) within the 2 years prior to screening AND • their PR interval has remained stable since the EPS (in the opinion of the investigator) AND • their His-ventricular (HV) interval was ≤ 70ms in the EPS
27. 27. On a 24-hour ambulatory (Holter) ECG with at least 18 hours of interpretable recordings: any sustained (> 30 seconds) of atrial or ventricular arrhythmias, non- sustained ventricular tachycardia (3 or more beats at > 100 beats per minute [BPM]), Mobitz type II 2nd or 3rd-degree heart block, mean heart rate < 50 BPM in waking hours, any rate pauses > 3.0 seconds in waking hours. For entry into Part 2 (MAD), the 24-hour Holter ECG is required for treatment naïve participants, or if the participant was in the SAD and 6 months have elapsed from the SAD screening Holter assessment.
28. 28. Transthoracic Echocardiogram ejection fraction < 45% at Screening or if the participant has had an echocardiogram within the last 6 months. Any moderate or severe abnormality in chamber size, thickness, or valve function. For entry into Part 2 (MAD), if the participant was in the SAD and 6 months have elapsed from the SAD echocardiogram, the echocardiogram is required.
29. 29. Participant answers “yes” to C-SSRS suicidal ideation questions 4 or 5 within 1 year before Screening, or any suicidal behavior within 2 years before Screening.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Incidence of Serious Adverse Events (SAEs)
2. Incidence of Adverse Events of Special Interest (AESIs)
3. Incidence of AEs leading to discontinuation of treatment
4. Incidence of Treatment Emergent Adverse Events (TEAEs)

Secondary endpoints 10

1. Absolute values and changes from baseline in clinical safety laboratory tests and electrocardiogram (ECG) parameters
2. Absolute values and changes from baseline in urine kidney biomarkers (individual and Kidney Safety Composite Measure [KSCM])
3. Absolute values and changes from baseline in vital signs
4. Suicidal ideation and behavior assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
5. PK parameters of ATX-01 in plasma (including, but not limited to, area under the curve [AUC], maximum observed plasma concentration [Cmax], time from first dose at which Cmax was apparent [Tmax], apparent elimination half-life [t1/2])
6. PK parameters of ATX-01 in urine (including but not limited to amount excreted, CLR, excretion rate)
7. PD biomarkers in the tibialis anterior: • Change from baseline in MBNL1 expression (target engagement) • Change from baseline in the RNA Splice Index
8. Change from baseline in video hand opening time (vHOT)
9. Change from baseline in ankle dorsiflexion strength by quantitative myometry
10. Change from baseline in impact on ADL of myotonia, mobility, upper extremity function, breathing, stamina, GI symptoms (Impact on ADL questionnaire)

Investigational products

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

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Arthex Biotech S.L.

Sponsor organisation

Arthex Biotech S.L.

Address

Calle De San Agustin 9

City

Paterna

Postcode

46980

Country

Spain

Scientific contact point

Organisation

Arthex Biotech S.L.

Contact name

Judith Walker

Public contact point

Organisation

Arthex Biotech S.L.

Contact name

Matilda Wyatt

Third parties 17

Locations

4 EU/EEA countries · 5 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 125 files

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

Application history

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