AAV2/8-LSPhGAA (ACTUS-101) in Late-Onset Pompe Disease

Study Overview
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Brief Summary
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Open-label, ascending dose trial of ACTUS-101 administered intravenously.

Detailed Description
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This study will be a prospective, open-label trial designed to objectively assess the safety and bioactivity of ACTUS-101 in subjects diagnosed with Pompe disease, which is caused by a defect in acid α-glucosidase (GAA) gene. ACTUS-101 is intended to enable expression of a functional copy of the GAA gene in subject's hepatocytes.

Official Title
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A Phase 1 Study of the Safety of AAV2/8-LSPhGAA (ACTUS-101) in Late-onset Pompe Disease

Conditions
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Pompe Disease

Intervention / Treatment
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* Biological: ACTUS-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Pompe disease by blood or skin fibroblast GAA assay and two pathogenic variants in the GAA gene, Age: Greater than or equal to 18 years at enrollment. Subjects are capable of giving written informed consent. Able to walk at least 100 meters on the 6MWT (with assistive devices permitted). FVC within the range of 30% to less 90% (inclusive) of predicted in the upright position. Subjects with a confirmed diagnosis of LOPD who have been treated with ERT for at least 104 weeks (inclusive) immediately preceding screening and receiving a stable dose of ERT for the 52-week period immediately preceding dosing. Exclusion Criteria: Invasive ventilation required or noninvasive ventilation required while awake and upright. FVC <20% of predicted (supine). Received any live vaccination 2 months prior to study Day 1. Pregnant or nursing mothers. Serology consistent with exposure to HIV, or serology consistent with active hepatitis A, B or C infection. Any active liver disease. Active infection based upon clinical symptoms. Having started respiratory muscle strength training in the last 6 months prior to study day 1 or having discontinued respiratory muscle strength training in the 6-month period preceding study day 1, or having started respiratory strength training greater than 6 months prior to study day 1 and unwilling to continue for the first year of study participation. Received an investigational drug or participated in another interventional study within 90 days prior to Study Day 1. Additionally, subjects cannot participate in any other interventional clinical trial throughout the first 78 weeks after receiving ACTUS-101.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>A one-time intravenous infusion of ACTUS-101 (dose level 1) | Biological: ACTUS-101<br>* Adeno-associated virus serotype 8 carrying the human GAA gene under the control of the LSP promoter.<br>|
| Experimental: Cohort 2<br>A one-time intravenous infusion of ACTUS-101 (dose level 2) | Biological: ACTUS-101<br>* Adeno-associated virus serotype 8 carrying the human GAA gene under the control of the LSP promoter.<br>|
| Experimental: Cohort 3<br>A one-time intravenous infusion of ACTUS-101 (dose level 3) | Biological: ACTUS-101<br>* Adeno-associated virus serotype 8 carrying the human GAA gene under the control of the LSP promoter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of patient reported Treatment Emergent Adverse Events (TEAEs) (safety and tolerability) | The incidence of patient reported TEAEs will be measured according to protocol specifications. | 78 weeks | 
| Incidence of patient reported Serious Adverse Events (SAEs) (safety and tolerability) | The incidence of patient reported SAEs will be measured according to protocol specifications. | 78 weeks | 
| Number of Participants With Abnormal Laboratory Values | Laboratory assessments will be performed (CBC, Chemistry, urinalysis, serology, anti-GAA antibody, T-cell response, GAA activity) and compared to baseline values. | 78 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle GAA Bioactivity | Muscle GAA activity will be compared to baseline by muscle biopsy | 78 weeks | 
| Serum GAA Bioactivity | Serum GAA activity will be compared to baseline by blood screening | 78 weeks | 
| Glycogen content in muscle | Muscle glycogen level compared to baseline by muscle biopsy | 78 weeks | 
| Anti-rhGAA antibody formation | Anti-rhGAA antibodies monitored by ELISA | 78 weeks | 
| Muscle Status Testing - 6 minute walk test | The 6-minute walk test will be performed and results compared to baseline. | 78 weeks | 
| Muscle Status Testing - Gross Motor Function Measure | The gross motor function measure (GMFM88) will be performed and the results compared to baseline. | 78 weeks | 
| Muscle Status Testing - Quick Motor Function Test (QMFT) Measure | Measurement of functional motor abilities using the Quick Motor Function Test (QMFT) will be performed and the results compared with baseline. | 78 weeks | 
| Muscle Status Testing - Gait, Stairs, Gower, Chair | The Gait, Stairs, Gower, Chair (GSGC) test will be performed and results compared to baseline. | 78 weeks | 
| Pulmonary Function Testing | Pulmonary function (forced vital capacity, FVC in liters of air) measured by spirometer in comparison to baseline. | 78 weeks | 
| Muscle Status Testing - Timed up and Go (TUG) | Measurement of functional motor abilities using the Timed up and Go (TUG) test will be performed and the results compared with baseline. | 78 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene Therapy