Gene Transfer Study in Patients With Late Onset Pompe Disease

Study Overview
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Brief Summary
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This is a phase 1/2 open-label, ascending dose, multicenter clinical study to evaluate the safety and efficacy of AT845 in adult (aged ≥ 18 years) subjects, ambulatory or nonambulatory, with Late Onset Pompe Disease (LOPD).

Detailed Description
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This study (FORTIS) will evaluate the safety and efficacy of an investigational gene replacement therapy, AT845, in adult subjects with LOPD. Subjects will receive a single dose of AT845 delivered via intravenous (IV) infusion. Up to 3 nominal dose levels of AT845 are planned to be evaluated in this study. A single AT845 administration via IV infusion is planned for each subject. The initial dosing cohort received a single dose of 3x10^13 vg/kg of AT845. The second dose cohort will receive a single dose of 6×10^13 vg/kg. The third dose cohort will receive a single dose of 1×10^14 vg/kg. Dose escalation between cohorts will be based on evaluations of safety and in consultation with the independent DMC. There will be a core observation period of 48 weeks with scheduled visits and assessments. Following the conclusion of the core observation period, subjects will be seen every 6 months for a safety follow-up visit for up to 5 years postdose.

Official Title
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A Phase 1/2, Open-Label, Ascending-Dose Clinical Study to Evaluate the Safety and Preliminary Efficacy of AT845, an AAV8-Delivered Gene Transfer Therapy in Patients With Late Onset Pompe Disease

Conditions
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Pompe Disease (Late-onset)

Intervention / Treatment
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* Genetic: AT845


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is aged ≥ 18 years (ambulatory or nonambulatory). Subject has a documented clinical diagnosis of Pompe disease by genetic testing. Subject has received enzyme replacement therapy (ERT) with rhGAA for the previous ≥ 2 years. Subject has been on a stable standard dose (at least 20 mg/kg every 2 weeks) of ERT with rhGAA for at least the previous 6 months. Subject has upright FVC ≥ 30% of predicted normal value. Subject or legally authorized representative(s) (LAR) (if applicable) provides written informed consent. Subject and LAR(s) are willing and able to comply with study visits and study procedures. Subject must agree to refrain from blood or blood products donation and sperm or egg donation from the time of AT845 administration until the later of 90 days or 3 consecutive negative viral shedding samples Exclusion Criteria: Subject is currently participating in an interventional study or has received gene or cell therapy. Subject tests positive for AAV8 antibodies with titers >1:20 neutralizing. Subject has received immune-modulating agents within 90 days before dosing (use of inhaled corticosteroids is allowed); use of other concomitant medications to manage chronic conditions must have been stable for at least 30 days before dosing. Concomitant medications that may predispose the subject to peripheral neuropathy will be evaluated. Subject has any clinically significant laboratory values (other than those directly associated with LOPD [e.g., GAA, serum creatine kinase (CK)]) that would preclude participation in the study. Subject has clinically significant underlying liver disease at Screening, or has any of the following: Gamma glutamyl transferase (GGT) > 5.0 x upper limit of normal (ULN) Active hepatitis B or C, and hepatitis B surface antigen (HBsAg), HB core antibody (HBcAb), HBV-DNA positivity or HCV-RNA viral load positivity, respectively. Negative viral load assays in 2 samples, collected at least 6 months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible. Currently on antiviral therapy for hepatitis B or C Subject has serological or viral load evidence of HIV-1 or HIV-2. Subject has received drugs for treatment of myopathy or neuropathy with immunosuppressive therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab) within 3 months prior to starting the study Subject has a high risk for a severe allergic reaction to rhGAA (ie, previous moderate to severe anaphylactic reaction to alglucosidase alfa or and/or a history of sustained high immunoglobulin G [IgG] antibody titers to alglucosidase alfa that suggests a high risk for an allergic reaction to ERT). Subject has a history of hypersensitivity to β2 agonist drugs such as albuterol, levalbuterol, bitolterol, pirbuterol, terbutaline, salmeterol, which contraindicates pulmonary function testing. Subject has an active viral infection based on clinical observation. Subject has a history of or concurrent medical condition other than Pompe disease that could jeopardize safety of the subject or impact study results. Subject has a history of, or currently has, a clinically important cardiac condition, such as an echocardiogram (ECHO) with ejection fraction below 40% or has symptoms or signs of cardiomyopathy that precludes enrollment. Subject has a contraindication to study drug or to corticosteroids, or has demonstrated hypersensitivity to any of the components of the study drug. Subject tests positive for GAA antibodies with titers > 1:50,000 total Subject has a history of hypersensitivity to MRI contrast agents including gadolinium. Subject has a known hypersensitivity to local anesthetics such as lidocaine. Subject has a bleeding diathesis, e.g., due to anti-coagulation or anti-platelet treatments. Subject has a concurrent medical condition (including uncontrolled diabetes, alcohol use disorder, certain autoimmune conditions, Lyme disease, active malignancy requiring chemotherapy and/or radiation, uremic nephropathy, known exposure to heavy metals) commonly associated with peripheral neuropathy. Other concurrent medical conditions that may predispose to peripheral neuropathy will be evaluated and action taken on a case-by-case basis, following discussion between the Investigator and Medical Monitor. Subject has a history of diagnosed peripheral neuropathy or an abnormal NCS and/or mISS that is consistent with peripheral neuropathy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Interventional Model Description: Up to 3 nominal dose levels of AT845 are planned to be evaluated in this study. A single AT845 administration via IV infusion is planned for each subject. The initial dosing cohort received a single dose of 3×10^13 vg/kg. The second dose cohort will receive a single dose of 6×10^13 vg/kg. The third dose cohort will receive a single dose of 1×10^14 vg/kg. Dose escalation between cohorts will be based on evaluations of safety and in consultation with the independent DMC.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Initial Dose Cohort<br>3x10^13 vg/kg of AT845 administered via intravenous infusion | Genetic: AT845<br>* AT845 is an AAV8 vector delivering a functional copy of the human GAA gene, under the control of a muscle-specific promoter<br>|
| Experimental: Second Dose Cohort<br>6x10^13 vg/kg of AT845 administered via intravenous infusion | Genetic: AT845<br>* AT845 is an AAV8 vector delivering a functional copy of the human GAA gene, under the control of a muscle-specific promoter<br>|
| Experimental: Third Dose Cohort<br>1x10^14 vg/kg of AT845 administered via intravenous infusion | Genetic: AT845<br>* AT845 is an AAV8 vector delivering a functional copy of the human GAA gene, under the control of a muscle-specific promoter<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability over time | Frequency of adverse events (AEs), serious adverse events (SAEs), and changes from baseline in relevant clinical laboratory tests | Change from baseline and up to month 60 | 
| GAA enzymatic activity | Change from baseline in GAA enzymatic activity in muscle biopsies at week 12 | Baseline and Week 12 | 
| GAA protein expression | Change from baseline in GAA protein expression in muscle biopsies at week 12. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vector Copy Number | Change from baseline in vector copy number (VCN) in muscle biopsies at week 12 | Baseline and Week 12 | 
| Thigh Fat Fraction | Change from baseline in thigh fat fraction by MRI | Baseline and Month 18 | 
| 6-Minute Walk Test (for ambulatory patients) | Change from baseline in the distance walked in the 6 minute walk test (6MWT), which is a standardized assessment of how far an individual can walk on a hard, flat surface in a period of 6 minutes | Baseline, Week 24 and Week 48 | 
| Forced Vital Capacity (FVC) | Change from baseline in percentage of predicted FVC measured by pulmonary function testing | Baseline, Week 24 and Week 48 | 
| Maximum Inspiratory Pressure (MIP) | Change from baseline in MIP measured by pulmonary function testing | Baseline, Week 24 and Week 48 | 
| Maximum Expiratory Pressure (MEP) | Change from baseline in MEP measured by pulmonary function testing | Baseline, Week 24 and Week 48 | 
| The Gait, Stairs, Gower Maneuver, Chair (GSGC) | The GSGC is a composite test that evaluates both the time to perform different motor activities and qualitatively measures motor function. | Baseline, Week 24 and Week 48 | 
| Rasch-built Pompe-specific Activity (R-PAct) scale | Change from baseline in the R-PAct scale, which was developed to measure Pompe patients' ability carry out daily life activities and social participation | Baseline and Week 48 | 
| EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Questionnaire | Change from baseline in health profiles and overall health status as assessed by the EQ-5D-5L | Baseline and Week 48 | 
| Patient-Reported Outcomes Measurement Information System (PROMIS) | Change from baseline in scores of PROMIS short forms for fatigue, physical function, social participation and sleep disturbance | Baseline and Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LOPD