Re-administration of Intramuscular AAV9 in Patients With Late-Onset Pompe Disease

NCT02240407 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: IRB20140013720182574
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

A recombinant AAV vector has been generated to carry the codon-optimized acid alpha-glucosidase (coGAA) gene expressed from a human desmin enhancer/promoter (DES). The proposed clinical trial is a within-participant, double-blind, randomized, phase I controlled study evaluating the toxicology, biodistribution and potential activity of re-administration of rAAV9-DES-hGAA injected intramuscularly into the TA. Nine participants (18 to 50-years old) who reside within the United States with Late-Onset Pompe Disease (LOPD) will be included. The goal of the immune modulation strategy is to ablate B-cells (Rituximab and Sirolimus) prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. At each study agent dosing, the contralateral leg will receive excipient. Patients will act as their own controls. Repeated measures, at baseline and during the following 3 months after each injection, will assess the safety, biochemical and functional impact of the vector.

Conditions

Pompe Disease

Keywords

Pompe Disease; Gene Therapy; Repeated dosing; Immune modulation

Outcome Measures

Primary Outcomes (1)

• Safety of rAAV9-DES-hGAA vector in LOPD by blood and urine test.

  Safety will be tested by clinical pathology tests, blood assay for vector genomes, antibodies against GAA and T-cell ELISPOT against GAA and AAV.

  520 days

Secondary Outcomes (5)

• Neurophysiological tests will be performed for neuro function of rAAV9-DES-hGAA vector.

  520 days

• Muscle biopsy will be performed for muscular function of rAAV9-DES-hGAA vector.

  520 days

• Clinical tests will be performed for function of rAAV9-DES-hGAA vector.

  520 days

• Magnetic Resonance Imaging will be performed for visualization of muscle with rAAV9-DES-hGAA vector.

  520 days

• Spectroscopy will be performed for function of rAAV9-DES-hGAA vector.

  520 days

Study Arms (2)

rAAV9-DES-hGAA vector

EXPERIMENTAL

Each subject will receive Rituxan and Rapamycin prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. Diphenhydramine and acetaminophen will be provided before each Rituxan dose. Immune Globulin will be administered to each subject every other month after first exposure to Rituxan and as clinical necessary. Lidocaine will be administered through percutaneous infiltration before injection of the study agent. Side of administration will be randomized at first Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase injection.

Genetic: Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase; Drug: Rapamycin; Drug: Rituxan; Drug: Diphenhydramine; Drug: Acetaminophen; Drug: Lidocaine; Drug: LMX 4 Topical Cream

Excipient

SHAM COMPARATOR

Each subject will receive Rituxan and Rapamycin prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. Diphenhydramine and acetaminophen will be provided before each Rituxan dose. Immune Globulin will be administered to each subject every other month after first exposure to Rituxan and as clinical necessary. Lidocaine will be administered through percutaneous infiltration before injection of the study agent. Side of administration will be randomized at first saline injection.

Drug: Rapamycin; Other: saline; Drug: Rituxan; Drug: Diphenhydramine; Drug: Acetaminophen; Drug: Lidocaine; Drug: LMX 4 Topical Cream

Interventions

Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase GENETIC

The dose selected for this study is a fixed dose of 4.6 x 10\^13 vg per TA muscle (range of 7.64 x 10\^11 vg/gm to 4.6 x 10\^11 vg/gm based on TA weight).

Also known as: rAAV9-DES-hGAA

rAAV9-DES-hGAA vector

Rapamycin DRUG

Patients will receive Rapamycin (dose 0.6-2 mg/m\^2/day, adjusted to maintain a trough serum sirolimus level of 2-4 ng/mL.) every day starting from 7 days before first injection of AAV9 until four months after second injection.

Also known as: Sirolimus

Excipient; rAAV9-DES-hGAA vector

saline OTHER

Same volume as rAAV9-DES-hGAA injection will be used.

Also known as: Excipient

Excipient

Rituxan DRUG

Patients will receive Rituxan (dose: 750 mg/m\^2 twice) 21 and 7 day prior first AAV9 injection, with a Rituxan dose 375 mg/m\^2 on the day of the injection. Rituxan will be repeated 7 days prior to the 2nd injection of the vector. The maintenance dose of Rituxan will be 375 mg/m\^2.

Also known as: Rituximab

Excipient; rAAV9-DES-hGAA vector

Diphenhydramine DRUG

25-50mg will be provided before each Rituximab dose.

Also known as: Benadryl

Excipient; rAAV9-DES-hGAA vector

Acetaminophen DRUG

We will provide 650 mg of tylenol before each dose of Rituximab.

Also known as: Tylenol

Excipient; rAAV9-DES-hGAA vector

Lidocaine DRUG

Lidocaine will be used based on standard of care: Percutaneous infiltration, concentration 0.5-1%, 1-10 mL, 5-300mg total dose.

Also known as: Xylocaine

Excipient; rAAV9-DES-hGAA vector

LMX 4 Topical Cream DRUG

Topical anesthesia cream will be used prior to gene therapy/saline injection.

Also known as: Lidocaine 4%

Excipient; rAAV9-DES-hGAA vector

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female subjects 18 to 50-years old
• Have a diagnosis of Pompe disease, as defined by protein assay AND/OR DNA sequence of the acid alpha-glucosidase gene, AND clinical symptoms of the disease
• Have residual ability to complete the 10 meter walk test
• Willing to discontinue aspirin, aspirin-containing products and other drugs that may alter platelet function, 7 days prior to dosing, resuming 24 hours after the dose has been administered
• Consistently taking enzyme replacement therapy (ERT) or remain off ERT from baseline until Day 520
• United States residents only.

You may not qualify if:

• Be pregnant or nursing, and if the subject is of child bearing potential they should use contraception until the end of the study
• Have required oral or systemic corticosteroids within the last 15 days prior to baseline screening
• Have a platelet count less than 75,000/mm\^3
• Have an INR greater than 1.3
• Have seronegative to AAV9 capsid protein (neutralizing Ab titers \<1:5 and total binding Ab titer \<50 U/ml)
• Have transaminases and alkaline phosphatase more than ten times the upper limit of normal at screening or Day-1
• Have bilirubin and gamma-glutamyl transpeptidase greater than 2 times the upper limit of normal at screening or Day -1
• Have any chronic liver disease (aside from hepatic dysfunction related to Pompe disease) such as hepatitis B and C and cirrhosis
• Be currently, or within the past 30 days, participating in any other research protocol involving investigational agents or therapies
• Have history of platelet dysfunction, evidence of abnormal platelet function at screening, or history of recent use of drugs that may alter platelet function, which the subject is unable/unwilling to discontinue for study agent administration
• Have received gene transfer agents within the past 6 months
• Have any medical condition or circumstance for which an MRI evaluation is contraindicated
• Have any other concurrent condition that, in the opinion of the investigator, would make the subject unsuitable for the study
• Inconsistent with use of ERT.

Sponsors & Collaborators

• University of Florida: lead
• Lacerta Therapeutics: collaborator

Study Sites (1)

Clinical and Translational Research Building (CTRB), University of Florida

Gainesville, Florida, 32610, United States

Location

Related Publications (29)

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MeSH Terms

Conditions

Glycogen Storage Disease Type II

Interventions

Sirolimus; Sodium Chloride; Excipients; Rituximab; Diphenhydramine; Acetaminophen; Lidocaine

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Glycogen Storage Disease; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Pharmaceutical Vehicles; Pharmaceutic Aids; Pharmaceutical Preparations; Specialty Uses of Chemicals; Chemical Actions and Uses; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Ethylamines; Amines; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Acetanilides; Anilides; Amides; Aniline Compounds

Study Officials

• Manuela Corti, P.T., PhD.

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 11, 2014
• First Posted: September 15, 2014
• Study Start: October 17, 2017
• Primary Completion: August 26, 2021
• Study Completion: August 26, 2021
• Last Updated: April 5, 2022

Record last verified: 2022-03

Locations

US (1)