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

Phase 1

Recruiting

Conditions: Myotonic dystrophy type 1 (DM1)

Registration Number: 2023-505363-37-00

Lead Sponsor: Arthex Biotech S.L.

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

Detailed Description: Not available

Recruitment & Eligibility

Status: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 28

Inclusion Criteria

Participant must be 18 to 64 years of age inclusive, at the time of signing the informed consent.
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).
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.
Presence for >3 seconds of grip myotonia as confirmed by a central reader.
BMI <35 kg/m².
Male and female participants.
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.
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.
The participant is able to have muscle biopsies as per the Schedule of Activities.

Exclusion Criteria

Participants with congenital DM1.
Contraindication to a muscle biopsy defined as: use of an anticoagulant, platelet count < 50,000, or other bleeding disorder.
Use of mexiletine or other agent for myotonia within 5 half-lives, prior to screening.
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.
Exposure to another investigational drug within 3 months prior to start of study treatment.
Use of medications which are sensitive substrates of CCI, CCI, or CCI.
Medical Research Council Muscle Scale score of ≤ 3 on ankle dorsiflexion (either ankle) or significant tibialis anterior atrophy that prevents a muscle biopsy.
Active COVID-19 infection.
History of pacemaker or implantable cardioverter-defibrillator; atrial fibrillation or flutter; ventricular tachycardia; any other sustained atrial or ventricular arrhythmias; undiagnosed syncope in the last year; congestive heart failure; myocardial infarction; coronary artery disease; congenital heart disease; moderate or severe valvular heart disease. Participants with pacemakers or implantable cardioverter-defibrillators implanted for solely prophylactic reasons can be included after confirmation from the medical monitor.
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 family member that is not related to an underlying DM1 diagnosis.
Participants with serum electrolyte abnormalities that cannot be corrected.
Breast cancer within the past 10 years.
Participants receiving concomitant QTc prolonging medications unless on stable doses.
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.
Use of medications which are CCI, including regular use of CCI.
Participants with planned procedures requiring an CCI during the study.
Ongoing participation in any other interventional therapeutic clinical trial.
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.
Non-sinus rhythm, any second or third degree heart block, PR interval > 220 ms, QRS duration > 110 ms, QTcF > 450 ms (males and females), on a 12-lead ECG at screening. 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.
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.
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.
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.
ALT or AST > 3.0× upper limit of normal (ULN).
Total bilirubin > 1.5× ULN (Participants with Gilbert’s syndrome can be included with total bilirubin > 1.5× ULN as long as direct bilirubin is ≤ 1.5× ULN).
Known hepatic or biliary abnormalities (except for Gilbert’s syndrome or asymptomatic gallstones).
Chronic renal failure defined as calculated creatine clearance Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation < 60 mL/min/1.73 m².
Recent history (within the past 3 months before Screening) of acute kidney injury.
Proteinuria at screening defined as a urine protein-to-creatinine ratio (UPCR) ≥ 200 mg/g or a urine albumin-to-creatinine ratio (UACR) > 30 mg/g.
Untreated non-compensated hypothyroidism.

Study & Design

Study Type: INTERVENTIONAL

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Incidence of Serious Adverse Events (SAEs)		Incidence of Serious Adverse Events (SAEs)
Incidence of Adverse Events of Special Interest (AESIs)		Incidence of Adverse Events of Special Interest (AESIs)
Incidence of AEs leading to discontinuation of treatment		Incidence of AEs leading to discontinuation of treatment
Incidence of Treatment Emergent Adverse Events (TEAEs)		Incidence of Treatment Emergent Adverse Events (TEAEs)

Secondary Outcome Measures

Name	Time	Method
Absolute values and changes from baseline in clinical safety laboratory tests and electrocardiogram (ECG) parameters		Absolute values and changes from baseline in clinical safety laboratory tests and electrocardiogram (ECG) parameters
Absolute values and changes from baseline in urine kidney biomarkers (individual and Kidney Safety Composite Measure [KSCM])		Absolute values and changes from baseline in urine kidney biomarkers (individual and Kidney Safety Composite Measure [KSCM])
Absolute values and changes from baseline in vital signs		Absolute values and changes from baseline in vital signs
Suicidal ideation and behavior assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)		Suicidal ideation and behavior assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
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])		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])
PK parameters of ATX-01 in urine (including but not limited to amount excreted, CLR, excretion rate)		PK parameters of ATX-01 in urine (including but not limited to amount excreted, CLR, excretion rate)
PD biomarkers in the tibialis anterior: • Change from baseline in MBNL1 expression (target engagement) • Change from baseline in the RNA Splice Index		PD biomarkers in the tibialis anterior: • Change from baseline in MBNL1 expression (target engagement) • Change from baseline in the RNA Splice Index
Change from baseline in video hand opening time (vHOT)		Change from baseline in video hand opening time (vHOT)
Change from baseline in ankle dorsiflexion strength by quantitative myometry		Change from baseline in ankle dorsiflexion strength by quantitative myometry
Change from baseline in impact on ADL of myotonia, mobility, upper extremity function, breathing, stamina, GI symptoms (Impact on ADL questionnaire)		Change from baseline in impact on ADL of myotonia, mobility, upper extremity function, breathing, stamina, GI symptoms (Impact on ADL questionnaire)

Trial Locations

Locations (5): Hopital Universitaire Pitie Salpetriere
🇫🇷
Paris Cedex 13, France
Centro Clinico Nemo
🇮🇹
Milan, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹
Rome, Italy
Radboud universitair medisch centrum Stichting
🇳🇱
Nijmegen, Netherlands
Hospital Universitario Donostia
🇪🇸
Donostia, Spain
Hopital Universitaire Pitie Salpetriere
🇫🇷Paris Cedex 13, France
Guillaume Bassez
Site contact
0033142163791
guillaume.bassez@aphp.fr