Safety Study of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase to Treat Pompe Disease

NCT00976352 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: PGTC PD-AAV004-NP01HL059412-06
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Pompe disease is an inherited condition of acid alpha-glucosidase (GAA) deficiency resulting in lysosomal accumulation of glycogen in all tissues. Glycogen accumulation leads to muscle dysfunction and profound muscle weakness. A wide spectrum of disease is characteristic and the most severe patients have cardiorespiratory failure, often fatal in the first two years of life. Researchers have developed a way to introduce the normal GAA gene into muscle cells with the expectation that the GAA protein will be produced at levels sufficient to reduce glycogen accumulation. This study will evaluate the safety of the experimental gene transfer procedure in individuals with GAA deficiency. The study will also determine what dose may be required to achieve improvement in measures of respiratory function.

Conditions

Pompe Disease

Keywords

Gene Therapy; Pompe Disease; Glycogen Storage Disease

Outcome Measures

Primary Outcomes (1)

• Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration.

  Change in Adeno-associated virus (AAV) antibody level; Change in Alglucosidase alpha (GAA) Antibody level

  Change from baseline to 365 post study agent administration.

Secondary Outcomes (3)

• Maximal Inspiratory Pressure

  Baseline and 365 post study agent administration

• Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone.

  Screening, Baseline, and 365 post study agent administration.

• Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone.

  Screening, Baseline, and Day 365 post study agent administration

Study Arms (2)

rAAV1-CMV-GAA administration-cohort 1

EXPERIMENTAL

rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing.

Drug: rAAV1-CMV-GAA (study agent) Administration; Other: RMST

rAAV1-CMV-GAA administration-cohort 2

EXPERIMENTAL

rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing.

Drug: rAAV1-CMV-GAA (study agent) Administration; Other: RMST

Interventions

rAAV1-CMV-GAA (study agent) Administration DRUG

rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects.

Also known as: Gene transfer, study agent (rAAV1-CMV-GAA)

rAAV1-CMV-GAA administration-cohort 1; rAAV1-CMV-GAA administration-cohort 2

RMST OTHER

After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270.

Also known as: Respiratory Muscle Strength Training

rAAV1-CMV-GAA administration-cohort 1; rAAV1-CMV-GAA administration-cohort 2

Eligibility Criteria

• Age: 2 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Male or female subjects 2-18 years of age.
• Have a diagnosis of Pompe, as defined by protein assay, DNA sequence of the acid alpha-glucosidase gene and clinical symptoms of the disease.
• Using assisted ventilation at baseline. Mechanical Ventilation is defined as any use of ventilation support, (including but not limited to BiPAP, CPAP), a minimum of 1 hours per day.
• 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.

You may not qualify if:

• The subject must not:
• Have required acute, as distinguished from long-term, maintenance or chronic suppressive, oral or intravenous antibiotic therapy for a respiratory infection within 15 days prior to baseline screening.
• Have required oral or systemic corticosteroids within the last 15 days prior to baseline screening.
• Have a platelet count less than 75,000/ cu mm.
• Have an INR greater than 1.3.
• Serological evidence of hepatitis B, hepatitis C, or HIV positive.
• Be currently or within the past 30 days participating in any other research protocol involving investigational agents or therapies.
• Have received gene transfer agents within the past 6 months.
• 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 any other concurrent condition which, in the opinion of the investigator, would make the subject unsuitable for the study.

Sponsors & Collaborators

• University of Florida: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Shands at the University of Florida

Gainesville, Florida, 32610, United States

Location

Related Publications (9)

• Fraites TJ Jr, Schleissing MR, Shanely RA, Walter GA, Cloutier DA, Zolotukhin I, Pauly DF, Raben N, Plotz PH, Powers SK, Kessler PD, Byrne BJ. Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. Mol Ther. 2002 May;5(5 Pt 1):571-8. doi: 10.1006/mthe.2002.0580.

  PMID: 11991748 BACKGROUND

• Mah C, Cresawn KO, Fraites TJ Jr, Pacak CA, Lewis MA, Zolotukhin I, Byrne BJ. Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors. Gene Ther. 2005 Sep;12(18):1405-9. doi: 10.1038/sj.gt.3302550.

  PMID: 15920463 BACKGROUND

• Mah C, Pacak CA, Cresawn KO, Deruisseau LR, Germain S, Lewis MA, Cloutier DA, Fuller DD, Byrne BJ. Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors. Mol Ther. 2007 Mar;15(3):501-7. doi: 10.1038/sj.mt.6300100. Epub 2007 Jan 23.

  PMID: 17245350 BACKGROUND

• Pauly DF, Fraites TJ, Toma C, Bayes HS, Huie ML, Hirschhorn R, Plotz PH, Raben N, Kessler PD, Byrne BJ. Intercellular transfer of the virally derived precursor form of acid alpha-glucosidase corrects the enzyme deficiency in inherited cardioskeletal myopathy Pompe disease. Hum Gene Ther. 2001 Mar 20;12(5):527-38. doi: 10.1089/104303401300042447.

  PMID: 11268285 BACKGROUND

• Conlon TJ, Erger K, Porvasnik S, Cossette T, Roberts C, Combee L, Islam S, Kelley J, Cloutier D, Clement N, Abernathy CR, Byrne BJ. Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid alpha-glucosidase. Hum Gene Ther Clin Dev. 2013 Sep;24(3):127-33. doi: 10.1089/humc.2013.147.

  PMID: 24021025 BACKGROUND

• Byrne BJ. Pathway for approval of a gene therapy orphan product: treading new ground. Mol Ther. 2013 Aug;21(8):1465-6. doi: 10.1038/mt.2013.157. No abstract available.

  PMID: 23903569 BACKGROUND

• Corti M, Elder M, Falk D, Lawson L, Smith B, Nayak S, Conlon T, Clement N, Erger K, Lavassani E, Green M, Doerfler P, Herzog R, Byrne B. B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study. Mol Ther Methods Clin Dev. 2014;1:14033-. doi: 10.1038/mtm.2014.33.

  PMID: 25541616 BACKGROUND

• Smith BK, Collins SW, Conlon TJ, Mah CS, Lawson LA, Martin AD, Fuller DD, Cleaver BD, Clement N, Phillips D, Islam S, Dobjia N, Byrne BJ. Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Hum Gene Ther. 2013 Jun;24(6):630-40. doi: 10.1089/hum.2012.250.

  PMID: 23570273 RESULT

• Byrne BJ, Falk DJ, Clement N, Mah CS. Gene therapy approaches for lysosomal storage disease: next-generation treatment. Hum Gene Ther. 2012 Aug;23(8):808-15. doi: 10.1089/hum.2012.140.

  PMID: 22794786 DERIVED

MeSH Terms

Conditions

Glycogen Storage Disease Type II; Glycogen Storage Disease

Interventions

Pharmaceutical Preparations; Organization and Administration; Genetic Engineering

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; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Health Services Administration; Genetic Techniques; Investigative Techniques

Results Point of Contact

• Title: Dr. Barry Byrne, Professor and Associate Chair
• Organization: University of Florida

bbyrne@ufl.edu

352-273-6563

Study Officials

• Barry J Byrne, MD, PhD

  University of Florida

  PRINCIPAL INVESTIGATOR

• Shelley Collins, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Open label study
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2009
• First Posted: September 14, 2009
• Study Start: September 1, 2010
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: September 14, 2018
• Results First Posted: November 17, 2017

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)