Gene Transfer Study in Patients With Late Onset Pompe Disease (FORTIS)

• ClinicalTrials.gov Identifier: NCT04174105
• Recruitment Status: Recruiting
• First Posted: November 22, 2019
• Last Update Posted: February 10, 2023
• Sponsor: Astellas Gene Therapies
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Gene Therapies )

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Pompe Disease (Late-onset)	Genetic: AT845	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention 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)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 27, 2020
• Estimated Primary Completion Date: December 31, 2024
• Estimated Study Completion Date: November 30, 2028

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Safety and Tolerability over time [ Time Frame: Change from baseline through Week 48 ]
   Frequency of adverse events (AEs), serious adverse events (SAEs), and changes from baseline in relevant clinical laboratory tests
2. GAA enzymatic activity [ Time Frame: Baseline and Week 12 ]
   Change from baseline in GAA enzymatic activity in muscle biopsies at week 12
3. GAA protein expression [ Time Frame: Baseline and Week 12 ]
   Change from baseline in GAA protein expression in muscle biopsies at week 12.

Secondary Outcome Measures :

1. Vector Copy Number [ Time Frame: Baseline and Week 12 ]
   Change from baseline in vector copy number (VCN) in muscle biopsies at week 12
2. Thigh Fat Fraction [ Time Frame: Baseline and Month 18 ]
   Change from baseline in thigh fat fraction by MRI
3. 6-Minute Walk Test (for ambulatory patients) [ Time Frame: Baseline, Week 24 and Week 48 ]
   Change from baseline in the distance walked in the six 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
4. The Gait, Stairs, Gower Maneuver, Chair (GSGC) [ Time Frame: Baseline, Week 24 and Week 48 ]
   The GSGC is a composite test that evaluates both the time to perform different motor activities and qualitatively measures motor function.
5. Patient-Reported Outcomes Measurement Information System (PROMIS) [ Time Frame: Baseline and Week 48 ]
   Change from baseline in scores of PROMIS short forms
6. Forced Vital Capacity (FVC) [ Time Frame: Baseline, Week 24 and Week 48 ]
   Change from baseline in percentage of predicted FVC measured by pulmonary function testing
7. Maximum Inspiratory Pressure (MIP) [ Time Frame: Baseline, Week 24 and Week 48 ]
   Change from baseline in MIP measured by pulmonary function testing
8. Maximum Expiratory Pressure (MEP) [ Time Frame: Baseline, Week 24 and Week 48 ]
   Change from baseline in MEP measured by pulmonary function testing
9. EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Questionnaire [ Time Frame: Baseline and Week 48 ]
   Change from baseline in health profiles and overall health status as assessed by the EQ-5D-5L
10. Rasch-built Pompe-specific Activity (R-PAct) scale [ Time Frame: Baseline and Week 48 ]
    Change from baseline in the R-PAct scale, which was developed to measure Pompe patients' ability carry out daily life activities and social participation

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Key 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 must agree to use appropriate contraception following consent through 6 months post AT845 administration.

Key Exclusion Criteria:

• Subject is currently participating in an interventional study or has received gene or cell therapy.
• Subject tests positive for AAV8 neutralizing antibodies with titers above protocol specified threshold.
• Subject has received immune-modulating agents within 90 days before dosing (use of inhaled corticosteroids is allowed).
• Subject tests positive for GAA total antibodies with titers above protocol specified threshold.
• 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 in the opinion of the Investigator suggests a high risk for an allergic reaction to ERT).
• Subject has an active viral infection based on clinical observation.
• 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 in the opinion of the Investigator precludes enrollment.
• Subject has a clinically significant underlying liver disease.
• Subject has a contraindication to study drug or ingredients or to corticosteroids.

Contacts and Locations

Contacts

Contact: Astellas Pharma Global Development, Inc.; 800-888-7704; Astellas.registration@astellas.com

Locations

United States, California

University of California Irvine, Department of Neurology; Recruiting

Orange, California, United States, 92868

Contact: Jennifer Scott 714-456-5956 stemcell@uci.edu

Principal Investigator: Tahseen Mozaffar, MD

Stanford University; Recruiting

Palo Alto, California, United States, 94304

Contact 650-725-4341 NeuromuscularResearch@stanford.edu

Principal Investigator: John Day, MD, PhD

United States, Utah

University of Utah, Division of Medical Genetics; Recruiting

Salt Lake City, Utah, United States, 84108

Contact: Kenzie Fait 801-585-7160 kenzie.fait@hsc.utah.edu

Principal Investigator: Nicola Longo, MD

United Kingdom

Newcastle Upon Tyne Hospitals Foundation Trust Clinical Research Facility; Recruiting

Newcastle upon Tyne, United Kingdom, NE1 4LP

Contact: Ellie Drummond 0191 241 8601

Contact Ellie.Drummond@newcastle.ac.uk

Principal Investigator: Jordi Diaz-Manera, MD, PhD

Sponsors and Collaborators

Astellas Gene Therapies

Investigators

• Study Director: Medical Director; Astellas Pharma Global Development, Inc.

More Information

• Responsible Party: Astellas Gene Therapies
• ClinicalTrials.gov Identifier: NCT04174105
• Other Study ID Numbers: AT845-01; 2019-003595-38 ( EudraCT Number )
• First Posted: November 22, 2019
• Last Update Posted: February 10, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: Access to anonymized individual participant level data will not be provided for this trial as it meets one or more of the exceptions described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc ( Astellas Gene Therapies ):

LOPD

Additional relevant MeSH terms:

Glycogen Storage Disease Type II; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Glycogen Storage Disease; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases