Safety and Dose-Finding Study of DTX401 (AAV8G6PC) in Adults With Glycogen Storage Disease Type Ia (GSDIa)

NCT03517085 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: 401GSDIA011706-16172016-003023-30
• Study Type: interventional
• Target: 12
• Locations: 4 countries
• Sites: 6

Brief Summary

The primary objective of the study is to determine the safety of single doses of DTX401, including the incidence of dose-limiting toxicities (DLTs) at each dose level.

Conditions

GSD1

Keywords

glycogen storage disorder Ia; AAV; gene therapy; von Gierke disease; glucose metabolism disorder

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Adverse Events (AEs) Treatment-Emergent AEs (TEAEs) Serious TEAEs, Discontinuations Due to TEAEs, and Dose-Limiting Toxicities (DLTs)

  An AE is defined as any untoward medical occurrence, regardless of its causal relationship to study product. An SAE is defined as any event that: results in death; is immediately life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; or an important medical event, in the opinion of the investigator. The relationship to study drug was categorized as unrelated, possible, probable or definite. A DLT is defined as any AE/SAE ≥ Grade 3 that is considered by the Investigator and/or Sponsor to be related to DTX401, based on the Nation Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 or later version. Per protocol, SAEs that occurred \> 30 days after EOS or Early withdrawal visit, did not need to be reported unless Investigator considered them related to study product.

  AEs Prior to Dosing: From signing the informed consent form (ICF) to first dose of study drug. TEAEs: From first dose of study drug through the End of Study (EOS)/Early Withdrawal visit (up to Week 52) plus 30 days.

Secondary Outcomes (1)

• Change From Baseline in Time to First Hypoglycemic Event Over Time

  Baseline, Weeks 12, 24, 52

Study Arms (4)

DTX401 Cohort 1

EXPERIMENTAL

Dose 1 (2.0 × 10\^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after alanine aminotransferase \[ALT\] elevation)

Genetic: DTX401; Drug: steroid regimen

DTX401 Cohort 2

EXPERIMENTAL

Dose 2 (6.0 × 10\^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation)

Genetic: DTX401; Drug: steroid regimen

DTX401 Cohort 3

EXPERIMENTAL

Dose 2 (6.0 × 10\^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation)

Genetic: DTX401; Drug: steroid regimen

DTX401 Cohort 4

EXPERIMENTAL

Dose 2 (6.0 × 10\^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)

Genetic: DTX401; Drug: steroid regimen

Interventions

DTX401 GENETIC

DTX401 administered as a single peripheral intravenous (IV) infusion

Also known as: AAV8G6PC, Pariglasgene brecaparvovec

DTX401 Cohort 1; DTX401 Cohort 2; DTX401 Cohort 3; DTX401 Cohort 4

steroid regimen DRUG

prednisone or prednisolone to manage alanine aminotransferase (ALT) elevation

DTX401 Cohort 1; DTX401 Cohort 2; DTX401 Cohort 3; DTX401 Cohort 4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females ≥18 years of age
• Documented GSDIa with confirmation by molecular testing
• Documented history of ≥1 hypoglycemic event with blood glucose \<60 mg/dL (\<3.33 mmol/L)
• Patient's GSDIa disease is stable as evidenced by no hospitalization for severe hypoglycemia during the 4-week period preceding the screening visit

You may not qualify if:

• Anti-AAV8 neutralizing antibody titer ≥1:5
• Screening or Baseline (Day 0) blood glucose level \<60 mg/dL (\<3.33 mmol/L)
• Liver transplant, including hepatocyte cell therapy/transplant
• Presence of liver adenoma \>5 cm in size
• Presence of liver adenoma \>3 cm and ≤5 cm in size that has a documented annual growth rate of ≥0.5 cm per year
• Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> upper limit of normal (ULN), total bilirubin \> 1.5 x ULN, or alkaline phosphatase \> 2.5 x ULN

Sponsors & Collaborators

• Ultragenyx Pharmaceutical Inc: lead

Study Sites (6)

UCONN Health

Farmington, Connecticut, 06030-3213, United States

Location

Michigan Medicine University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

UT Health - McGovern Medical School

Houston, Texas, 77030, United States

Location

Montreal Children Hospital, McGill University Health Centre

Montreal, Quebec, H4A3J1, Canada

Location

University Medical Center Groningen

Groningen, 9700RB, Netherlands

Location

Complejo Hospitalario Universitario de Santiago

Santiago de Compostela, A Coruna, 15706, Spain

Location

Related Publications (3)

• Weinstein DA, Derks TG, Rodriguez-Buritica DF, Ahmad A, Couce ML, Mitchell JJ, Riba-Wolman R, Mount M, Sallago JB, Ross KM, van der Klauw MM, de Boer F, van der Schaaf C, Saavedra H, Martinez-Olmos M, Atanga E, Hosseini A, Mitragotri D, Crombez E. Safety and Efficacy of DTX401, an AAV8-Mediated Liver-Directed Gene Therapy, in Adults With Glycogen Storage Disease Type I a (GSDIa). J Inherit Metab Dis. 2025 Mar;48(2):e70014. doi: 10.1002/jimd.70014.

  PMID: 40064185 DERIVED

• Zhang L, Lee C, Arnaoutova I, Anduaga J, Starost MF, Mansfield BC, Chou JY. Gene therapy using a novel G6PC-S298C variant enhances the long-term efficacy for treating glycogen storage disease type Ia. Biochem Biophys Res Commun. 2020 Jun 30;527(3):824-830. doi: 10.1016/j.bbrc.2020.04.124. Epub 2020 May 16.

  PMID: 32430177 DERIVED

• Zhang L, Cho JH, Arnaoutova I, Mansfield BC, Chou JY. An evolutionary approach to optimizing glucose-6-phosphatase-alpha enzymatic activity for gene therapy of glycogen storage disease type Ia. J Inherit Metab Dis. 2019 May;42(3):470-479. doi: 10.1002/jimd.12069. Epub 2019 Feb 22.

  PMID: 30714174 DERIVED

MeSH Terms

Conditions

Glycogen Storage Disease Type I; Glucose Metabolism Disorders

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Medical Information
• Organization: Ultragenyx Pharmaceutical Inc

medinfo@ultragenyx.com

1-888-756-8657

Study Officials

• Medical Director

  Ultragenyx Pharmaceutical Inc

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 24, 2018
• First Posted: May 7, 2018
• Study Start: May 18, 2018
• Primary Completion: November 2, 2021
• Study Completion: November 2, 2021
• Last Updated: November 18, 2022
• Results First Posted: November 18, 2022

Record last verified: 2022-10

Locations

NL (1); US (3); ES (1); CA (1)