Gene Therapy for Ornithine Transcarbamylase Deficiency

Recruiting at 25 trial locations

Overseen By Patients Contact: Trial Recruitment

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Ultragenyx Pharmaceutical Inc

Must be taking: Ammonia scavengers

Must not be taking: Antivirals

Disqualifiers: Hepatic inflammation, Cirrhosis, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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: 64 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing DTX301, a treatment designed to help people with late-onset OTC deficiency, a condition that makes it hard for their bodies to process certain proteins. The treatment aims to improve the function of an enzyme that helps manage ammonia levels in the blood. Participants will be monitored for several years, with some continuing in a follow-up program for additional time.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are on daily ammonia scavenger therapy, you must be on a stable dose for at least 4 weeks before starting the trial.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, if you are on daily ammonia scavenger therapy, you need to be on a stable dose for at least 4 weeks before starting the trial.

What data supports the effectiveness of the treatment DTX301 for ornithine transcarbamylase deficiency?

Research using similar gene therapy approaches for ornithine transcarbamylase deficiency has shown that gene delivery can correct biochemical abnormalities and protect against high ammonia levels in animal models, suggesting potential effectiveness for DTX301. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment DTX301 for ornithine transcarbamylase deficiency?

Research using similar gene therapy approaches for ornithine transcarbamylase deficiency has shown that gene delivery can correct biochemical abnormalities and protect against high ammonia levels in animal models, suggesting potential effectiveness for DTX301. ^{1 2 3 4 5}

How does the treatment DTX301 differ from other treatments for ornithine transcarbamylase deficiency?

DTX301 is a gene therapy that uses a viral vector to deliver a healthy copy of the OTC gene directly to the liver, aiming to correct the underlying genetic defect, unlike traditional treatments that may involve dietary management or liver transplantation. ^{1 4 6 7 8}

How does the treatment DTX301 for ornithine transcarbamylase deficiency differ from other treatments?

DTX301 is a gene therapy that uses a viral vector to deliver a healthy copy of the OTC gene directly to the liver, aiming to restore normal enzyme function, which is a novel approach compared to traditional treatments like dietary management or liver transplantation. ^{1 4 6 7 9}

Research Team

Medical Director

Principal Investigator

Ultragenyx Pharmaceutical Inc

Eligibility Criteria

This trial is for people with late-onset OTC deficiency who are on a stable dose of ammonia scavenger therapy and diet, have safe plasma ammonia levels, and agree to use effective contraception. It's not for those in other gene studies, with active hepatitis or significant liver issues, infections, conditions that risk participation or skew results, or detectable antibodies against the AAV8 capsid.

Inclusion Criteria

From the time written informed consent through Week 128, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not father a child or donate sperm

Your ammonia level in the blood on the first day before taking the medication is less than or equal to 200 µmol/L.

If you are on a diet that limits protein, your daily protein intake should not change by more than 20% for at least 4 weeks before screening.

Exclusion Criteria

I am currently being treated for or have tested positive for hepatitis B or C.

I do not have any active infections.

I have severe liver inflammation or cirrhosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single peripheral IV infusion of DTX301 or placebo and are followed closely for 64 weeks

64 weeks

Crossover

Participants crossover to receive the alternate treatment (DTX301 or placebo) at week 64

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment, with an option to enroll in the Disease Monitoring Program for up to an additional 5 years

Up to 324 weeks

Treatment Details

Interventions

• DTX301

Trial Overview The study tests DTX301's ability to improve OTC function by maintaining safe ammonia levels without dietary protein restrictions or alternative meds. Participants will receive either DTX301 with oral corticosteroids or placebos for both and their efficacy will be compared.

Participant Groups

Group I: Placebo, Then DTX301 Experimental Treatment 5 Interventions

Participants receive single peripheral IV infusion of placebo. At week 64, participants receive single peripheral IV infusion of DTX301 in solution.

Group II: DTX301, Then Placebo Experimental Treatment 5 Interventions

Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. At week 64, participants receive single peripheral IV infusion of placebo.

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

Findings from Research

In a study using recombinant adeno-associated virus (rAAV) vectors to deliver mutant ornithine transcarbamylase (OTC) proteins to mice, no dominant-negative effects were observed, indicating that these mutants did not inhibit the activity of the wild-type OTC enzyme.

The findings suggest that gene therapy for OTC deficiency may be more effective than previously thought, as the mutant proteins did not negatively impact the therapeutic potential of the wild-type enzyme, allowing for further exploration of gene therapy strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo assessment of mutations in OTC for dominant-negative effects following rAAV2/8-mediated gene delivery to the mouse liver. Ginn, SL., Cunningham, SC., Zheng, M., et al.[2013]

The R141Q mutation in ornithine transcarbamylase completely abolishes enzymatic activity, while the R40H mutation reduces activity to only 26-35% of the wild-type enzyme, indicating significant differences in how these mutations affect protein function.

This study's expression system allows for the investigation of specific mutations related to ornithine transcarbamylase deficiency, which could help in understanding their effects and evaluating potential gene therapy treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of wild-type and mutant human ornithine transcarbamylase genes in Chinese hamster ovary cells and lack of dominant negative effect of R141Q and R40H mutants. Augustin, L., Mavinakere, M., Morizono, H., et al.[2009]

A novel missense mutation, E122G, was identified in the OTC gene of a Chinese family, which may be responsible for late onset ornithine transcarbamylase (OTC) deficiency.

The study utilized polymerase chain reaction and direct sequencing methods to confirm the mutation, highlighting the importance of genetic analysis in understanding metabolic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Molecular characterization of a new mutation E122G of human ornithine transcarbamylase gene]. Gao, H., Li, W., Yan, ZH., et al.[2006]

A novel splice site mutation (c.78-1G[A) in the ornithine transcarbamylase (OTC) gene was identified in a young girl with OTC deficiency, leading to a significant frameshift mutation that affects protein function.

The same mutation was found in a mosaic state in her asymptomatic father, highlighting the variable expression of OTC deficiency and the potential for asymptomatic carriers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel splice site mutation in OTC gene of a female with ornithine transcarbamylase deficiency and her asymptomatic mosaic father. Olga, S., Natalia, S., Igor, B., et al.[2022]

Gene therapy using an adenoviral vector has shown promise for treating ornithine transcarbamylase (OTC) deficiency, with successful transduction and expression in a mouse model leading to biochemical corrections for 2-3 months.

A modified adenoviral vector with improved safety and efficacy is set to be tested in a phase I trial for adults with partial OTC deficiency, demonstrating rapid protection against acute hyperammonaemia within 24 hours.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developing adenoviral-mediated in vivo gene therapy for ornithine transcarbamylase deficiency. Raper, SE., Wilson, JM., Yudkoff, M., et al.[2019]

Three children with ornithine transcarbamylase (OTC) deficiency successfully underwent living-related liver transplantation, with all patients surviving and thriving without the need for protein restriction.

The study suggests that auxiliary partial orthotopic transplantation (APOLT) is a safer method for treating OTC, as it allows for the retention of the native liver, which can recover function and serve as a backup in case of graft failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ornithine transcarbamylase deficiency in girls by auxiliary liver transplantation: conceptual changes in a living-donor program. Kasahara, M., Kiuchi, T., Uryuhara, K., et al.[2019]

The study successfully used a defective recombinant retrovirus to transduce primary hepatocytes from mice with ornithine transcarbamylase (OTC) deficiency, achieving high efficiency with an average of 0.5-2 proviral copies per cell.

Transduced hepatocytes produced human OTC mRNA levels comparable to normal human liver and showed partial biochemical correction of the OTC deficiency, indicating potential for future somatic gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retroviral-mediated gene transfer of human ornithine transcarbamylase into primary hepatocytes of spf and spf-ash mice. Grompe, M., Jones, SN., Loulseged, H., et al.[2012]

A new genetic mutation (G > T substitution) in the OTC gene has been identified, which contributes to the understanding of ornithine transcarbamylase deficiency (OTCD), a condition that can arise from various genetic changes.

The discovery of a novel single nucleotide polymorphism (SNP) in intron 8 (IVS8 + 35 nt: G > T) provides a useful diagnostic tool for detecting OTCD, especially in cases where gene deletions are suspected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ornithine transcarbamylase deficiency: a novel splice site mutation in a family with meiotic recombination and a new useful SNP for diagnosis. Azevedo, L., Vilarinho, L., Teles, EL., et al.[2019]

A gene therapy trial using an adenovirus vector to deliver human OTC cDNA in adults with partial ornithine transcarbamylase deficiency (OTCD) showed limited success, with only modest increases in urea cycle activity in some subjects.

Despite some transgene expression in liver cells, the overall low levels of gene transfer and the occurrence of adverse effects, including flu-like symptoms and transient liver enzyme elevations, indicate that the doses tested did not achieve significant metabolic correction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. Raper, SE., Yudkoff, M., Chirmule, N., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

In vivo assessment of mutations in OTC for dominant-negative effects following rAAV2/8-mediated gene delivery to the mouse liver. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Expression of wild-type and mutant human ornithine transcarbamylase genes in Chinese hamster ovary cells and lack of dominant negative effect of R141Q and R40H mutants. [2009]

3. China pubmed.ncbi.nlm.nih.gov

[Molecular characterization of a new mutation E122G of human ornithine transcarbamylase gene]. [2006]

4. India pubmed.ncbi.nlm.nih.gov

A novel splice site mutation in OTC gene of a female with ornithine transcarbamylase deficiency and her asymptomatic mosaic father. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Developing adenoviral-mediated in vivo gene therapy for ornithine transcarbamylase deficiency. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Treatment of ornithine transcarbamylase deficiency in girls by auxiliary liver transplantation: conceptual changes in a living-donor program. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Retroviral-mediated gene transfer of human ornithine transcarbamylase into primary hepatocytes of spf and spf-ash mice. [2012]

8. United States pubmed.ncbi.nlm.nih.gov

Ornithine transcarbamylase deficiency: a novel splice site mutation in a family with meiotic recombination and a new useful SNP for diagnosis. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency. [2013]