Gene Therapy for Ornithine Transcarbamylase Deficiency

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a gene therapy called DTX301 for individuals with ornithine transcarbamylase (OTC) deficiency, a genetic disorder affecting ammonia processing in the body. The main goal is to determine if DTX301 can maintain safe ammonia levels in the blood. Initially, participants will receive either the DTX301 treatment or a placebo (a harmless solution), and eventually, both groups will receive DTX301. Those with a confirmed OTC deficiency diagnosis, stable on their current treatment, and without recent serious ammonia issues might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

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

Research has shown that DTX301 has been studied for safety in people with late-onset ornithine transcarbamylase (OTC) deficiency. In earlier studies involving 11 adults monitored over time, DTX301 was generally well-tolerated. Participants received a single IV infusion, and most side effects were mild to moderate, with no serious side effects directly linked to the treatment. These findings suggest that DTX301 could be a promising option for improving OTC function with manageable side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about DTX301 for treating Ornithine Transcarbamylase Deficiency because it offers a new approach through gene therapy. Unlike traditional treatments that focus on dietary management and ammonia-lowering medications, DTX301 aims to address the root cause by delivering a functional copy of the defective gene directly into the liver. This could potentially provide a long-term solution by enabling the body to produce the necessary enzyme on its own. Additionally, the treatment is administered as a single intravenous infusion, which could reduce the need for ongoing medication and dietary restrictions.

What evidence suggests that DTX301 might be an effective treatment for ornithine transcarbamylase deficiency?

Research has shown that DTX301, a gene therapy, could help treat ornithine transcarbamylase (OTC) deficiency. In earlier studies, patients who received just one dose of DTX301 experienced lasting improvements in their condition. Specifically, it helped maintain safe ammonia levels in the blood, a major concern for those with OTC deficiency. Long-term follow-up of 11 adults demonstrated that the treatment was both effective and safe. In this trial, participants will receive either a single peripheral IV infusion of DTX301 or a placebo followed by DTX301. This suggests that DTX301 could be a strong option for managing this rare genetic disorder. ^{1 2 3 4 6}

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 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 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 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Placebo, Then DTX301 Experimental Treatment 5 Interventions

Participants receive single peripheral IV infusion of placebo. Between Week 36 and Week 64, participants receive single peripheral IV infusion of DTX301 in solution.

Group II: DTX301 Experimental Treatment 5 Interventions

Participants receive single peripheral intravenous (IV) infusion of DTX301 in solution. Between Week 36 and Week 64, participants may 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

Published Research Related to This Trial

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]

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]

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]

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 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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S294977442500175X

Durable efficacy and safety of DTX301: Long-term follow ... We report the long-term follow up (LTFU) of 11 adults with late-onset OTC deficiency who received a single IV infusion of DTX301 in the Phase 1/2 trial.

2. ir.ultragenyx.com ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-completion-patient-dosing-first-cohort

Release details Patients in the first cohort received a single dose of 2.0 × 10^12 GC/kg. To evaluate therapeutic response of DTX301, the study measures the change in the rate ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05345171

NCT05345171 | Clinical Study of DTX301 AAV-Mediated ... This study is a Phase 3, randomized, double-blind, placebo-controlled study of DTX301 in patients with late-onset OTC deficiency 12 years of age and older.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10452060/

Genetic Therapy Approaches for Ornithine Transcarbamylase ... Long-term outcomes in Ornithine Transcarbamylase deficiency: A series of 90 patients. Orphanet J. Rare Dis. 2015;10:58. doi: 10.1186/s13023 ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02991144

NCT02991144 | Safety and Dose-Finding Study of DTX301 ... This is a Phase 1/2, open-label, single arm, multicenter, safety and dose finding study of DTX301 in adults with late-onset OTC deficiency.

6. ultraclinicaltrials.com ultraclinicaltrials.com/otc/

Ornithine Transcarbamylase (OTC) Deficiency The purpose of this study is to determine the efficacy and confirm the safety of DTX301 in patients 12 years of age and older with late-onset OTC deficiency.