Overview
GNT0004 is a recombinant adeno-associated viral (AAV) vector gene therapy composed of an AAV8 serotype capsid containing a sequence-optimized gene for a human microdystrophin. Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by dystrophin gene mutations leading to absence of functional dystrophin, a key protein that prevents muscle cell damage during physiological contractions. To address the underlying cause of the disease, GNT0004 delivers an optimized dystrophin gene that is capable to produce a shortened but functional dystrophin protein in target tissues (heart and skeletal muscles) in DMD subjects. It is expected to significantly delay or slow disease progression. GNT0004 will be given as a one-time intravenous (IV) infusion to help it reach muscles throughout the body.
Description
The study includes 3 parts. Part 1: A dose-escalation part where two dose levels were studied in five DMD boys. Based on the review of the first 12 weeks of data, the higher dose (3×10¹³ vg/kg) was considered the most efficient dose of GNT0004 with an acceptable safety profile and was selected for Part 2. This part was completed. Part 2: A confirmatory part to evaluate the efficacy and side effects of GNT0004. Participants are randomly assigned to receive either GNT0004 or placebo in a blinded manner. This part lasts 18 months. After 18 months, participants initially receiving placebo will receive GNT0004, and those initially receiving GNT0004 will receive placebo. Part 3: A long-term follow-up part in which all participants who received GNT0004 in Parts 1 and 2 will be followed for a total of 5 years from dosing to monitor potential late-onset side effects and assess the duration of the treatment's beneficial effects. The five participants from Part 1 are currently being followed in Part 3.
Eligibility
Inclusion Criteria:
- Ambulant male.
- Being included in the GNT-014-MDYF study.
- 6 to 10 years (inclusive).
- For participants enrolled in Part 1: BMI scale ≤ 75th percentile. For participants enrolled in Part 2: Body weight ≤ 95th percentile of the BMI or body weight scale.
- Positive genetic testing with detailed genotyping confirmation of DMD.
- Able to achieve a score in the North Star Ambulatory Assessment (NSAA) scale ≥ 18 at the screening visit.
- Stable or descending evolution in the NSAA total score during the last assessment periods recorded in study GNT-014-MDYF.
- Gowers test (Time to Rise From Floor) ≤ 7 sec.
- Ongoing corticosteroid therapy according to standard of care: for at least 6 months before the screening.
- Up to date vaccination record.
- Willing and able to comply with all protocol requirements and procedures.
- Signed informed consents and assent as required by local law.
- Affiliated/beneficiary of an insurance health care scheme or National Health service (if required by local law).
Exclusion Criteria:
- DMD patients with any mutations affecting: exons 1 through 17, for Part 1 participants; affecting exons 8 and/or 9 for Part 2 participants.
- Presence of neutralizing antibodies against AAV8.
- Cardiomyopathy based on physical/cardiological examination and echocardiography (or cardiac MRI if available).
- Any respiratory assistance needed including non-invasive daytime or nocturnal ventilation.
- Inability to perform the planned respiratory functions tests.
- Any co-morbidity (ies) and/or previous or planned surgical event(s), which may interfere with DMD evolution /or evaluation of patient's safety or Investigational Medicinal Product (IMP)'s tolerability.
- Acute infection that is not expected to be fully resolved for a sufficient time before gene therapy administration.
- Clinically significant laboratory abnormality values as per protocol.
- Inability to cooperate with muscle strength and functional assessments.
- Nuclear Magnetic Resonance Imaging (MRI) contraindications: metal implants, or other contraindication for MRI such as severe phobia.
- Unwilling and/or unable to comply with all the study protocol requirements and/or procedures.
- Chronic hepatitis B or C, i.e., positive hepatitis B surface antigen or hepatitis C RNA viral load positive.
- Previous inclusion to another clinical trial with any non-gene therapy related.
- Previously treated with any drugs that may interfere with either natural diasease course and/or IMP evaluation (except for corticosteroid therapy), the last dose administration less than protocol defined washout period.
- Received any of the treatment designed to increase dystrophin expression (e.g., exon skipping or stop codon read-through agents for DMD) within protocol defined period prior to screening.
- Previous gene therapy for DMD.
