Gene Therapy for Glycogen Storage Disease Type Ia

Not currently recruiting at 36 trial locations

Overseen By Grania Crowley

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Ultragenyx Pharmaceutical Inc

Must be taking: Cornstarch

Disqualifiers: Liver disease, Liver transplant, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 48 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a gene therapy called DTX401 for individuals with Glycogen Storage Disease Type Ia, a condition that impairs the body's ability to manage glucose levels. The trial aims to determine if DTX401 can reduce or eliminate the need for additional glucose treatments to stabilize blood sugar and improve overall glucose control. Participants may receive either a placebo or DTX401, with some initially receiving the placebo and later the treatment. Ideal candidates have confirmed Glycogen Storage Disease Type Ia and currently use cornstarch therapy to manage their condition. As a Phase 3 trial, this study is the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be on a stable regimen of cornstarch or equivalent for glucose control.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should be on a stable regimen of cornstarch or equivalent, so you may need to continue that treatment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that DTX401 has been safe in earlier studies. In trials with adults who have Glycogen Storage Disease Type Ia (GSDIa), participants generally tolerated DTX401 well. Most side effects were mild and expected, such as nausea and headache. Past trials did not directly link any serious side effects to the treatment. This suggests that DTX401 might be safe for humans, but ongoing studies will provide more information. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Glycogen Storage Disease Type Ia, which typically involve dietary management and enzyme replacement therapies, DTX401 offers a novel approach through gene therapy. DTX401 works differently by delivering a functional copy of the G6PC gene directly into the liver cells, potentially correcting the underlying genetic defect of the disease. This innovative mechanism targets the root cause rather than merely managing symptoms. Researchers are excited about DTX401 because it could offer longer-lasting benefits and possibly reduce the need for ongoing dietary restrictions and enzyme replacement, significantly improving patients' quality of life.

What evidence suggests that this trial's treatments could be effective for Glycogen Storage Disease Type Ia?

Research has shown that DTX401, a gene therapy, may help treat Glycogen Storage Disease Type Ia (GSDIa). In this trial, some participants will receive DTX401, which, in earlier studies, helped some patients reduce their reliance on extra glucose supplements needed to stabilize blood sugar levels. Patients who received this treatment also managed their blood sugar levels more effectively. The therapy uses a virus to deliver a healthy gene to liver cells, enhancing their ability to process glucose. Overall, these findings suggest that DTX401 could effectively improve glucose control in people with GSDIa. ^{1 2 3 6 7}

Who Is on the Research Team?

Medical Director

Principal Investigator

Ultragenyx Pharmaceutical Inc

Are You a Good Fit for This Trial?

This trial is for individuals with Glycogen Storage Disease Type Ia (GSDIa) who are on a stable regimen of cornstarch therapy. They must be willing to use effective contraception and not plan pregnancy. Excluded are those with liver disease, previous gene therapies, detectable AAV8 antibodies, or certain lab abnormalities.

Inclusion Criteria

I am on a stable cornstarch-based treatment plan for my condition.

I agree to use effective birth control during and after the study for the specified times.

My GSDIa diagnosis was confirmed by genetic testing or liver biopsy.

Exclusion Criteria

I have a liver tumor between 3 and 5 cm that's growing quickly.

You have antibodies to the AAV8 virus before starting the study.

I have had a liver transplant or received liver cell therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single peripheral IV infusion of DTX401 or placebo and are followed closely for 48 weeks

48 weeks

Crossover Treatment

Participants who received placebo are crossed over to receive DTX401, and vice versa, followed closely for an additional 96 weeks

96 weeks

Disease Monitoring Program (DMP)

Participants are followed for at least 10 years post DTX401 infusion

10 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• DTX401
• Oral corticosteroids
• Placebo
• Placebo for oral corticosteroids

Trial Overview The study tests DTX401's ability to reduce reliance on glucose replacement in GSDIa patients versus placebo. It aims to improve glucose control quality over a period of 144 weeks, comparing the effects of an oral corticosteroid treatment against a placebo.

How Is the Trial Designed?

Group I: DTX401, Then Placebo Experimental Treatment 4 Interventions

Participants receive single peripheral intravenous (IV) infusion of DTX401 in solution. At week 48 participants receive single peripheral IV infusion of Placebo.

Group II: DTX401 (Japan Only) Experimental Treatment 2 Interventions

Participants receive single peripheral intravenous (IV)infusion of DTX401 in solution.

Group III: Placebo, Then DTX401 Placebo Group 4 Interventions

Participants receive single peripheral IV infusion of Placebo. At week 48 eligible participants receive single peripheral IV infusion of DTX401 solution.

Who Is Running the Clinical Trial?

Ultragenyx Pharmaceutical Inc

Lead Sponsor

Trials

94

Recruited

104,000+

Dr. Emil D. Kakkis

Ultragenyx Pharmaceutical Inc

Chief Executive Officer since 2010

MD/PhD in Biological Chemistry from UCLA

Dr. Eric Crombez

Ultragenyx Pharmaceutical Inc

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Published Research Related to This Trial

A modified AAV2 vector with a bone-targeting peptide (D8) showed significantly higher affinity for hydroxyapatite (HA) and increased gene delivery to bone compared to the unmodified vector, as demonstrated in both in vitro and in vivo studies.

The modified vector maintained comparable physical properties and transduction efficiencies, while achieving 4.7-fold higher enzyme activity in bone three months post-infusion, suggesting a promising strategy for treating systemic bone diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tailoring the AAV2 capsid vector for bone-targeting. Alméciga-Díaz, CJ., Montaño, AM., Barrera, LA., et al.[2023]

A gene therapy using recombinant adeno-associated virus (rAAV) vectors showed promising results in treating a canine model of Glycogen storage disease type Ia (GSDIa), with significant improvements in blood glucose and lactate levels observed after treatment.

The rAAV2/1 vector delivered via the portal vein provided a more sustained correction of glucose homeostasis compared to the initial rAAV2/8 treatment, allowing the dog to thrive without dietary glucose supplementation for 18 months post-treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia. Weinstein, DA., Correia, CE., Conlon, T., et al.[2021]

The recombinant adeno-associated virus (AAV) vectors successfully delivered the human glucocerebrosidase (GC) and arylsulfatase A (ASA) genes into murine and patient fibroblasts, leading to significantly increased enzyme activity—15-fold for GC in Gaucher patient cells and up to 500-fold for ASA in metachromatic leukodystrophy cells.

The successful integration of 1-2 copies of the GC and ASA genes into the targeted cell genome demonstrates the potential of these AAV vectors for gene therapy applications in treating related genetic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of the human glucocerebrosidase and arylsulfatase A genes in murine and patient primary fibroblasts transduced by an adeno-associated virus vector. Wei, JF., Wei, FS., Samulski, RJ., et al.[2012]

The recombinant adeno-associated virus serotype 8 (AAV2/8) vector showed no significant short- or long-term toxicity in a preclinical study, indicating it is safe for use as an adjunctive therapy for Pompe disease.

The AAV2/8 vector effectively increased enzyme activity and reduced glycogen accumulation in tissues, with better efficacy observed in male subjects compared to females, suggesting potential for improved treatment outcomes when combined with enzyme replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. Wang, G., Young, SP., Bali, D., et al.[2020]

In a study of 38 individuals receiving systemic AAV9 gene therapy, those treated with corticosteroids experienced significant immune activation, including thrombotic microangiopathy (TMA) and complement pathway activation, indicating potential safety risks associated with this treatment.

In contrast, participants who received a combination of rituximab, sirolimus, and steroids showed minimal immune activation, suggesting that this immunomodulation regimen may enhance the safety of AAV gene therapy by reducing antibody formation and complement activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies. Salabarria, SM., Corti, M., Coleman, KE., et al.[2023]

In a study involving three dogs with glycogen storage disease type Ia (GSD Ia), gene therapy using adeno-associated virus (AAV) vectors led to a significant reduction in liver glycogen and improved metabolic parameters, including normalization of fasting glucose and other biochemical markers in one dog two months post-treatment.

The therapy resulted in sustained expression of the glucose-6-phosphatase (G6Pase) enzyme and improved liver histology, indicating the potential of AAV vector gene therapy as a promising treatment for GSD Ia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors. Beaty, RM., Jackson, M., Peterson, D., et al.[2013]

AAV2/8.TBG.hARSB gene therapy showed no significant toxicity in mice, indicating a favorable safety profile, with only minor transient effects observed.

The therapy effectively targets the liver for gene transfer, which is crucial for treating mucopolysaccharidosis type VI (MPS VI), and the results support moving forward to a phase I/II clinical trial in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI. Ferla, R., Alliegro, M., Marteau, JB., et al.[2020]

AAV2/8 vector-mediated gene therapy significantly improved survival and corrected liver G6Pase deficiency in GSD-Ia mice and dogs, with a 600-fold reduction in the required vector dose compared to previous methods.

This therapy effectively prevented hypoglycemia during fasting and reduced liver glycogen accumulation to near-normal levels, demonstrating its potential as a safe and effective treatment for GSD-Ia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia. Koeberl, DD., Pinto, C., Sun, B., et al.[2017]

Gene therapy using a novel adeno-associated virus (AAV) vector successfully prevented mortality and corrected liver glycogen storage in animal models of glycogen storage disease type Ia (GSD-Ia), demonstrating its potential as a new treatment option.

Despite initial success, the therapy faced challenges with the gradual loss of transgene expression, indicating the need for further development and possibly different AAV vector types to maintain long-term efficacy in treating GSD-Ia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In search of proof-of-concept: gene therapy for glycogen storage disease type Ia. Koeberl, DD.[2021]

Recombinant adeno-associated virus (AAV) vectors are effective for gene delivery in muscle research, showing potential to treat inherited muscle diseases in animal models and yielding promising results in early clinical trials.

AAV vectors provide robust and long-lasting gene expression in various animal models, and researchers have developed multiple AAV variants to tailor their use for specific muscle gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant adeno-associated viral vector production and purification. Shin, JH., Yue, Y., Duan, D.[2021]

Adeno-associated viral (AAV) vectors are generally safe and effective for gene therapy, but their limited cargo capacity of less than 5 kb restricts their use for diseases requiring larger gene transfers.

To address this limitation, researchers are exploring dual vector strategies, where a larger gene is split between two AAV vectors, and various mechanisms to restore full-length gene expression, highlighting ongoing efforts to enhance AAV's therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can Adeno-Associated Viral Vectors Deliver Effectively Large Genes? Tornabene, P., Trapani, I.[2021]

Adeno-associated virus (AAV) is a safe and effective vector for gene therapy, as it integrates stably into human chromosome 19 and can efficiently transduce various cell types, including blood and nerve cells.

A new method for producing high titer AAV vectors using packaging cell lines and sulfonated cellulose column chromatography could enhance the development and application of AAV-based gene therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gene transfer using adeno-associated virus (AAV) vectors]. Shimada, T.[2012]

AAVrh.10hARSA, a gene therapy vector for treating metachromatic leukodystrophy, was administered safely at a low dose in nonhuman primates, showing no significant adverse effects.

At a high dose, while localized CNS abnormalities were observed, they did not lead to clinical consequences, indicating a need to understand dose limits for safe administration of AAV vectors in the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Direct Intraparenchymal AAVrh.10-Mediated Central Nervous System Gene Therapy for Metachromatic Leukodystrophy. Rosenberg, JB., Chen, A., De, BP., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40064185/

Safety and Efficacy of DTX401, an AAV8-Mediated Liver ... This open-label, phase 1/2, dose-escalation, 52-week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa.

2. ir.ultragenyx.com ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-longer-term-data-phase-3-study

Ultragenyx Announces Positive Longer-term Data from ... Ultragenyx Announces Positive Longer-term Data from Phase 3 Study of DTX401 AAV Gene Therapy for the Treatment of Glycogen Storage Disease Type ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03517085

Safety and Dose-Finding Study of DTX401 (AAV8G6PC) in ... Gene therapy using a novel G6PC-S298C variant enhances the long-term efficacy for treating glycogen storage disease type Ia. Biochem Biophys Res Commun ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11893205/

Safety and Efficacy of DTX401, an AAV8‐Mediated Liver‐ ... Safety and efficacy of DTX401, an AAV8‐Mediated Liver‐Directed Gene Therapy, in Adults With Glycogen Storage Disease Type I a (GSDIa)

5. ultragenyx.com ultragenyx.com/our-research/pipeline/dtx401-for-gsdia/

DTX401 for GSDIa DTX401 (pariglasgene brecaparvovec) is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase-α using a single ...

6. ir.ultragenyx.com ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-24-week-data-first-cohort-phase-12

Release details Ultragenyx Announces Positive 24-week Data from First Cohort of Phase 1/2 Study of DTX401 Gene Therapy in Glycogen Storage Disease Type Ia. February 21, 2019.

7. cgtlive.com cgtlive.com/view/ultragenyx-glycogen-storage-disease-gene-therapy-dtx401-continues-enable-decreases-reductions-daily-cornstarch-intake-96-weeks

Ultragenyx's Glycogen Storage Disease Gene Therapy ... With regard to safety, DTX401's safety profile was characterized as “acceptable and expected.”