A Study to Investigate the Safety, Tolerability, and Efficacy of SAR446268, an Adeno-associated Viral Vector-mediated Gene Therapy in Participants Aged 10 to 55 Years of Age With Non-congenital Myotonic Dystrophy Type 1

Official title

A Phase 1/Phase 2 Open-label Single Arm Study With Dose Escalation (Part A), and Dose Expansion (Part B) Parts to Evaluate the Safety, Tolerability, and Efficacy of SAR446268, an Adeno-associated Viral Vector-mediated Gene Therapy in Participants 10 to 55 Years Old With Non-congenital Myotonic Dystrophy Type 1

Overview

This is a Phase 1/Phase 2 open-label single arm, multicenter, and multinational study with SAR446268 for treatment of male and female participants 10 to 55 years old with non-congenital myotonic dystrophy (DM) type 1 (DM1). The purpose of this study is to evaluate the safety and efficacy of SAR446268 in knocking down dystrophia myotonica protein kinase (DMPK) messenger ribonucleic acid (mRNA) levels and improving neuromuscular function in DM1 participants receiving a single intravenous (IV) administration of SAR446268. The study consists of a dose escalation part (Part A) during which single ascending doses of SAR446268 will be evaluated in 3 distinct cohorts and an optional fourth dose cohort. Once a safe and effective dose is identified, additional participants will be treated in Part B, the dose expansion phase of the study. The study duration will be 112 weeks (approximately 2 years) for each participant in Parts A and B respectively and includes an optional pre-screening period, approximately 8-week screening phase and a 104-week follow-up period post-SAR446268 administration.

Detailed description

Each participant meeting the eligibility criteria for each of the study parts will receive a single dose administration of SAR446268.

Interventions

• Biological SAR446268
  Pharmaceutical form: Solution for infusion; Route of administration: IV infusion

Primary outcome measures

• Part A and Part B: Incidence of treatment-emergent adverse events (TEAEs) following SAR446268 administration [Time frame: Baseline to Week 52]
• Part B: Proportion of participants with at least 40% DMPK mRNA knockdown in muscle biopsy at Weeks 12 and 52 following SAR446268 administration [Time frame: Weeks 12 and 52]

Secondary outcome measures (12)

• Part A: Change in 10-meter walk-run test from baseline to Weeks 26 and 52 following SAR446268 administration [Time frame: Baseline to Week 26 and 52]
• Part A: Change in myotonia from baseline to Weeks 26 and 52 following SAR446268 administration as measured by the hand opening time (middle finger) [Time frame: Baseline to Week 26 and 52]
• Part A: Change in bilateral hand grip test from baseline to Weeks 26 and 52 following SAR446268 administration [Time frame: Baseline to Week 26 and 52]
• Part A: Proportion of participants with at least 40% DMPK mRNA knockdown in muscle biopsy at Weeks 12 and 52 following SAR446268 administration [Time frame: Weeks 12 and 52]
• Part A: Change in DMPK mRNA levels in muscle biopsy from baseline to Weeks 12 and 52 following SAR446268 administration [Time frame: Baseline to Week 12 and 52]
• Part A: Change in RNA splicing index in muscle biopsy from baseline to Weeks 12 and 52 following SAR446268 administration [Time frame: Baseline to Week 12 and 52]
• Part A: Assessment of the duration of AAV vector shedding of SAR446268 in sampling of urine, saliva, and semen at 4-week intervals following SAR446268 administration [Time frame: Baseline, Weeks 4, 8, and 12]
• Part B: Change in 10-meter walk-run test from baseline to Weeks 26 and 52 following SAR446268 administration [Time frame: Baseline to Week 26 and 52]
• Part B: Change in myotonia from baseline to Weeks 26 and 52 following SAR446268 administration as measured by the hand opening time (middle finger) [Time frame: Baseline to Week 26 and 52]
• Part B: Change in bilateral hand grip test from baseline to Weeks 26 and 52 following SAR446268 administration [Time frame: Baseline to Week 26 and 52]
• Part B: Change in DMPK mRNA knockdown in muscle biopsy from baseline to Weeks 12 and 52 following SAR446268 administration [Time frame: Baseline to Week 12 and 52]
• Part B: Change in RNA splicing index in muscle biopsy from baseline to Weeks 12 and 52 following SAR446268 administration [Time frame: Baseline to Week 12 and 52]

Eligibility criteria

Inclusion criteria

Participants are eligible to be included in the study only if all of the following criteria apply:

• For Part A, participants must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
• For Part B, participants must be as follows:

• 10 to 17 years of age inclusive, at the time of signing the informed consent or,
• 18 to 55 years of age inclusive, at the time of signing the informed consent.
• Participants with non-congenital onset DM1
• Participants presenting with signs of DM1 including myotonia and muscle weakness, as diagnosed previously by a clinician based on medical history.
• Participants with genetic diagnosis of DM1 \[cytosine-thymine-guanine (CTG) repeat length ≥50 in one allele from medical history\]
• Participants who can walk independently for at least 10 meters at screening (orthoses and ankle braces allowed).

Exclusion criteria

Participants are excluded from the study if any of the following criteria apply:

• Participants with neutralizing antibodies against the AAV.SAN011 capsid
• Participants with left ventricular ejection fraction <50%
• Participants with liver or biliary disease defined as having at least one of the following:

• ALT >3 x ULN and AST >3 x ULN
• Alkaline phosphatase >3 x ULN
• Total bilirubin >1.5 x ULN (unless has a genetically confirmed diagnosis of Gilbert's syndrome)
• Direct bilirubin ≥1.5 x ULN
• Participants with International normalized ratio >1.5
• Participants with renal disease defined as:

• Serum creatinine >1.5 x ULN and/or estimated glomerular filtration rate <60 mL/min/1.73 m2 as determined by Chronic Kidney Disease Epidemiology Collaboration (2021) for those age ≥18 years and Bedside Schwartz Equation for those <18 years
• Participants with chronic respiratory insufficiency and on long term/hull-time ventilatory assistance requiring at least 6 hours per day for at least 21 consecutive days.
• Participants with contraindication to corticosteroid or with conditions that could worsen in the presence of corticosteroids, as determined by the Investigator.
• Participants with active hepatitis B or C infection; HBsAg (+), or HCV RNA (+), or current antiviral therapy for either.
• Participants with HBcAb (+) who are not amenable for prophylactic anti-HBV therapy or pre-emptive therapy guided by serial HBV DNA monitoring during the corticosteroids therapy.
• Participants at high risk for tuberculosis reactivation during the corticosteroids therapy as determined by the Investigator.
• Participants with a known HIV infection
• Participants with serious intercurrent illness that, in the opinion of the Investigator, would preclude participation in the study or potentially decrease survival.
• Participants with recent history of or current drug or alcohol abuse in the past 12 months prior to screening.
• Participants with history of tibialis anterior biopsy within 12 weeks from Day 1 or planning to undergo tibialis anterior biopsies during the duration of this clinical trial.
• Participants with significant developmental delay, intellectual disability, or behavioral neuropsychiatric manifestations as determined by the Investigator.
• Participants with previous systemic corticosteroids treatment at doses of >5 mg/day within 15 days of Day 1
• Participants with previous treatment with anti-myotonic medication within 15 days of Day 1
• Participants not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures.
• Participants who have been classified as severe cardiac risk by the Investigator.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• University of Florida, 2004 Mowry Road - Site Number: 8400005 — Gainesville
• University of South Florida - Neuromuscular Research, 13330 USF Laurel Drive - Site Number — Tampa
• Columbia University Medical Center - Neurological Institute, 710 W. 168th, 2nd floor, suit — New York
• Virginia Commonwealth University Medical Center- Site Number : 8400006 — Richmond

Argentina · 1 center

• Hospital Italiano de Buenos Aires, Juan Domingo Peron 4190 - Site Number: 0320001 — Buenos Aires

Australia · 1 center

• Investigational Site Number : 0360001 — Brisbane

Canada · 1 center

• The Montreal Neurological Institute and Hospital, 3801 rue University - Site Number: 12400 — Montreal

Israel · 1 center

• Investigational Site Number : 3760002 — Ramat Gan

United Kingdom · 1 center

• Investigational Site Number : 8260002 — Newcastle upon Tyne

Identifiers

NCT: NCT06844214 · DFI17808 · U1111-1290-9594

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗