GNT0006 Gene Therapy Trial in Patients With LGMDR9

A Phase 1-2 Multicenter Study (2-stages) to Evaluate the Safety and Efficacy of Intravenous GNT0006, Adeno-associated Viral Vector Carrying the FKRP Gene, in Patients With FKRP-related Limb-girdle Muscular Dystrophy (LGMDR9, Formerly LGMD2I)

Phase 1-2 study including a dose escalation safety and proof of concept phase (Stage 1, open label), followed by a double-blind, randomized, placebo-controlled confirmatory phase (Stage 2)

Multicenter, Phase 1-2 study evaluating safety, pharmacodynamic, efficacy, and immunogenicity of GNT0006, an Adeno-Associated Virus (AAV) vector carrying the human FKRP transgene. This study will consist of 2 phases: an open-label dose escalation phase (Stage 1) and a double-blind placebo controlled, randomized phase (Stage 2), both with long-term follow-up (LTFU) period. Stage 1 Two dose cohorts will be enrolled sequentially and enrollment. An initial cohort of three (3) patients will receive a potentially effective dose, followed by a 2nd higher dose cohort of 3 patients. Stage 2 After selection of the effective dose in Stage 1, thirty-three (33) ambulant patients will be randomized at the optimal selected dose and followed up to the primary efficacy timepoint, i.e., one year after investigational medicinal product (IMP) (or placebo) administration. At one-year post-IMP administration (timepoint of primary interest for efficacy), patients enrolled in placebo group will receive active IMP while patients randomized in the active IMP group will receive a placebo infusion. All subjects will be followed for up to 5 years after active IMP (GNT0006) administration.

Stage 1: single administration of GNT0006, open label Stage 2: randomized, placebo-controlled, double blind. One cohort will receive single administration of GNT0006 followed by a single administration of placebo one year after. The second cohort will receive single administration of placebo followed by a single administration of GNT0006 one year after

6 patients treated with GNT0006 in Stage 1 (open label) 2 dose cohorts : Cohort 1: single intravenous injection 9.0E+12 vg/Kg Cohort 2: single intravenous injection 2.7E+13 vg/Kg

22 patients randomized in single intravenous GNT0006 arm at selected dose in Stage 2 (double blind). The patients will receive placebo one year after to maintain the blind

11 patients randomized in placebo arm in Stage 2 (double blind). The patients will receive single intravenous GNT0006 at selected dose one year after to maintain the blind

Change from baseline in North Star Assessment for Neuromuscular Disorders (NSAD) scale (with a range from 0 to 54, the higher the score the better the ability)

Quality of Life in genetic Neuromuscular Disease (QoL-gNMD), with a range from 0 to 78, the higher the score the worse the quality of life

ACTIVLIM, scale measuring level of limitation in performing daily activities (total score ranging from 0 to 44, with the lower score the highest limitation)

Inclusion Criteria: 1. Female and male ambulant patients 2. Patients ≥ 16 years old 3. Documented LGMDR9 diagnosis based on clinical presentation and genotyping confirming the FKRP gene mutations 4. Moderate diaphragmatic muscle impairment Exclusion Criteria: 1. Detectable serum neutralizing antibodies against AAV9 2. Cardiomyopathy