A Study to Evaluate the Safety of LION-101 in Subjects With Genetic Confirmation of LGMD2I/R9 (Part1)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety and tolerability of a single intravenous infusion of LION-101 in adults diagnosed with limb girdle muscular dystrophy type 2I/R9 (LGMD2I/R9). Participants will be treated in sequential, dose-level cohorts. (Part 1)

Official Title
-----------------
A Phase 1/2, Double-blind, Randomized, Placebo-controlled, Dose-escalation Study to Evaluate the Safety of LION-101 Gene Therapy in Adult Subjects (18-65 Years) With Genetic Confirmation of Limb Girdle Muscular Dystrophy Type 2I/R9 (LGMD2I/R9) - Part 1

Conditions
-----------------
Limb Girdle Muscular Dystrophy, Limb-Girdle Muscular Dystrophy Type 2, LGMD2I, Muscular Dystrophy, LGMD2, LGMD, FKRP, FKRP Mutation, Fukutin Related Protein

Intervention / Treatment
-----------------
* Genetic: LION-101 dose level 1
* Genetic: LION-101 dose level 2
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female subjects between the ages 18 and 65 years with clinical diagnosis of LGMD2I/R9 and confirmation of FKRP gene mutation. Ability to ascend 4 stairs between 2.5 and 10 seconds. Ability to walk/run 10 meters in < 30 seconds. Able to understand and comply with all study procedures. Sexually active females of childbearing potential and female and male partners of male subjects receiving LION-101 must use a barrier method of contraception for the first 6 months after dosing. Exclusion Criteria: Significant cardiomyopathy as defined by echocardiogram (left ventricular ejection fraction <40%), evidence of conduction defect (increased PR and RR intervals, left bundle branch block and QTcF >480m/sec), NYHA Class 3 or 4 heart failure, or MRI gadolinium enhancement evidence of clinically important myocardial fibrosis. Contraindication to MRI or hypersensitivity to contrast dyes, shellfish or iodine. Implanted spinal rods, cardiac pacemaker or other implantation that would distort cardiac MRI images. History of chronic liver disease (e.g. hepatitis, HIV, steatosis) or abnormal liver function (abnormal GGT and/or abnormal total/direct bilirubin and/or AST and ALT >2 ULN). Abnormal renal function (GFR < 60 ml/min, using the MDRD equation). Any life-threatening disease, including malignant neoplasms and medical history or malignant neoplasms within the past 5 years prior to screening (except basal and squamous cell skin cancer). In the opinion of the investigator, a pre-existing medical condition that predisposes the subject to risks that outweighs the potential benefits. Requirement for daytime ventilatory support. Change in glucocorticosteroid treatment within 3 months prior to baseline visit. Exposure to another investigational drug within 3 months prior to study treatment or any previous treatment with gene therapy. Ongoing participation in any other therapeutic clinical trial. Neutralizing antibody titer to AAV9 ≥ 1:5. Female subjects who are pregnant, plan to become pregnant in the next 12 months, or breastfeeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LION-101 Cohort 1<br> | Genetic: LION-101 dose level 1<br>* Single intravenous infusion of LION-101 gene therapy at dose level 1<br>|
| Experimental: LION-101 Cohort 2<br> | Genetic: LION-101 dose level 2<br>* Single intravenous infusion of LION-101 gene therapy at dose level 2<br>|
| Placebo Comparator: Placebo (Cohorts 1 and 2)<br> | Other: Placebo<br>* Single intravenous infusion of Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Treatment Emergent Adverse Events, Serious Adverse Events, Dose Limiting Toxicity | 0-52 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
gene therapy, LGMD2I, LGMD2I/R9, gene augmentation therapy, FKRP, fukutin related protein, FKRP mutation