Phase 1-2 Multicenter Study on Safety and Efficacy of Intravenous GNT0006 in FKRP-Related Limb-Girdle Muscular Dystrophy (LGMDR9) Patients

The primary objective of this Phase 1-2 multicenter study is to evaluate the **safety** and **tolerability** of intravenous administration of GNT0006, an adeno-associated viral vector carrying the FKRP gene, in ambulant patients with FKRP-related limb-girdle muscular dystrophy (LGMDR9). In Stage 1, the study aims to assess these parameters at two different dosage levels to determine the recommended dose for Stage 2. In Stage 2, the focus shifts to demonstrating the efficacy of GNT0006 one year post administration. This is clinically relevant as it addresses both the immediate safety concerns and the long-term therapeutic potential of gene therapy in managing LGMDR9, a progressive muscular disorder.

Secondary objectives include:

• Stage 1: Collecting preliminary efficacy data.
• Stage 2: Assessing the safety and tolerability of GNT0006 in ambulant patients with LGMDR9.

The clinical trial involves a total of **20 participants** diagnosed with **FKRP-related limb-girdle muscular dystrophy (LGMD R9)**. The study population includes both male and female ambulant patients aged 16 years and older. Participants were selected based on a documented diagnosis of LGMDR9, confirmed through clinical presentation and genotyping for FKRP gene mutations. The trial includes individuals who can perform the 10-meter walk test within 30 seconds with assistance and can rise from a standard-height chair. Participants exhibit diaphragmatic muscle impairment, with a forced vital capacity between 40% and 80% of the expected value. The trial population is considered vulnerable, and effective contraception is required. The health status of participants is sufficiently stable to adhere to the study visit schedule and protocol requirements. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the safety and efficacy of the investigational product, GNT0006, in patients with **FKRP-related limb-girdle muscular dystrophy (LGMD R9)**. The trial is structured in two stages, with Stage 1 focusing on assessing the safety and tolerability of intravenous administration of GNT0006 at two different dosage levels in ambulant patients. Stage 2 aims to demonstrate the efficacy of the selected dose one year post-administration. The trial is expected to conclude by February 2029, with recruitment having commenced in February 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis, and specific functional capabilities. Following successful screening, participants will be randomized to receive either the investigational product or a placebo. Regular follow-up visits will be scheduled to monitor safety, tolerability, and efficacy endpoints, including changes in **forced vital capacity (FVC)**, muscular function tests, and muscle MRI parameters. The end-of-study visit will occur one year after the administration of the investigational product, where final assessments will be conducted.

The expected length of participant involvement is approximately one year from the time of administration. Conditions that may lead to early termination from the study include significant adverse events, inability to adhere to the study protocol, or withdrawal of consent. The trial's primary endpoint is the change from baseline in FVC% in a sitting position at one year post-administration, comparing the treated group to the placebo group. Secondary endpoints include changes in muscular function, muscle MRI parameters, respiratory assessments, muscle biomarkers, patient-reported outcomes, and quality-of-life assessments.

The clinical trial involves the administration of **rAAV9-hFKRPco_miR-208a**, a recombinant adeno-associated viral vector (rAAV) serotype 9. This vector is engineered to express the human Fukutin-Related Protein (FKRP) and includes a target sequence of the miR-208a. The pharmaceutical form of this experimental medication is a **solution for infusion**, and it is administered via the **intravenous route**. The trial is designed to evaluate the safety and efficacy of this gene therapy in patients with FKRP-related limb-girdle muscular dystrophy (LGMDR9). The dosing schedule involves two different dosage levels in Stage 1 to determine the recommended dose for Stage 2. Participant compliance is monitored through regular assessments and follow-ups.

In addition to the experimental treatment, the study includes the use of a **placebo** for **rAAV9-hFKRPco_miR-208a**. This placebo is utilized to maintain blinding and ensure the integrity of the trial results. The placebo is administered in a manner consistent with the experimental treatment to provide a valid comparison.

Another component of the trial is the administration of **Methylprednisolone**, which contains **lidocaine hydrochloride monohydrate** and **methylprednisolone acetate** as active substances. This medication is provided in a pharmaceutical form coded as PHF00243MIG and is administered intravenously. The role of this treatment is auxiliary, and it is used to manage potential inflammatory responses associated with the gene therapy.

The trial also includes the use of **Prednisolone placebo** and **Methylprednisolone placebo**. These placebos are employed to support the blinding process and ensure that any observed effects can be attributed to the active treatments rather than psychological or other non-specific effects.

Additionally, **Abiraterone acetate** is included in the trial as an auxiliary treatment. It is administered orally and is provided in a pharmaceutical form coded as PHF00082MIG. This treatment is used in conjunction with corticosteroids to manage specific conditions that may arise during the trial.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in forced vital capacity (FVC%) in a sitting position, expressed as a percentage of the expected value based on age, gender, weight, and height-adjusted norms, at one year post-investigational medicinal product (IMP) administration in the treated group compared to the placebo group. Secondary endpoints include changes from baseline in muscular function tests, such as the North Star Ambulatory Assessment (NSAD) score and the 10-meter walk test (10MWT), muscle MRI parameters including fat fraction and T2 water content, and other respiratory assessments like inspiratory capacity (IC), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and sniff nasal inspiratory pressure (SNIP). Additionally, changes in muscle biomarkers, including histological features, biodistribution, and transgene expression, will be evaluated. Patient-reported outcomes and quality-of-life assessments, such as the gNMD and Activlim, will also be measured, along with biomarkers like creatine kinase, myomesin-3, and circulating microRNA.

These efficacy parameters will be collected and analyzed at one year post-IMP administration. The trial involves the use of validated scales and laboratory tests to ensure accurate and reliable data collection. The comparison between the treated and placebo groups will provide insights into the efficacy of the intravenous administration of GNT0006, an adeno-associated viral vector carrying the FKRP gene, in patients with FKRP-related limb-girdle muscular dystrophy (LGMDR9). The assessments are designed to comprehensively evaluate the impact of the treatment on both physiological and patient-reported outcomes, providing a robust measure of efficacy.