Gene therapy for children with Ornithine Transcarbamylase deficiency

Phase I/II Open Label, Multicentre Clinical Trial to Assess Safety and Efficacy of AAVLK03hOTC for Paediatric Patients With Ornithine Transcarbamylase Deficiency.

This study is testing a new gene therapy for children with Ornithine Transcarbamylase deficiency to see if it can help their liver produce a missing enzyme and reduce dangerous ammonia levels in their blood.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 12 (estimated)
• Ages: 0 Days to 16 Years
• Sex: All
• Sponsor: University College, London (other)
• Locations: 1 site (London)
• Trial ID: NCT05092685 on ClinicalTrials.gov

What this trial studies

This clinical trial is investigating a new gene therapy called AAVLK03hOTC for children with Ornithine Transcarbamylase deficiency (OTCD), a rare genetic disorder that leads to dangerous levels of ammonia in the blood. The therapy aims to enable the liver to produce the enzyme ornithine transcarbamylase, which is deficient in these patients, thereby reducing the risk of life-threatening hyperammonaemic decompensations. The trial includes a dose escalation and expansion phase, targeting children aged 0-16 years who have severe disease and are currently on ammonia-scavenging drugs. The goal is to provide a potential 'bridge-to-transplant' solution, allowing children to maintain metabolic stability until a liver transplant can be performed.

Who should consider this trial

Good fit: Ideal candidates for this study are children aged 0-16 years with confirmed Ornithine Transcarbamylase deficiency and severe disease requiring ammonia-scavenging treatment.

Not a fit: Patients with mild forms of OTCD or those who do not meet the eligibility criteria, such as older patients or those without confirmed deficiency, may not benefit from this study.

Why it matters

Potential benefit: If successful, this gene therapy could significantly reduce the frequency of hyperammonaemic decompensations and improve the quality of life for children with OTCD.

How similar studies have performed: While gene therapy for metabolic disorders is a novel approach, similar studies have shown promise in treating other genetic conditions, indicating potential for success in this area.

Eligibility criteria

Inclusion Criteria:

1. Patient (male or female) aged ≤16 years at time of written informed consent. For the dose escalation phase patients must be aged 6-16, for the dose expansion phase patients must be aged 0-16 (at the time of written informed consent).
2. OTC deficiency confirmed via enzymatic or molecular analysis. This may include identification of pathogenic mutations or liver OTC activity that is \<20% of normal activity.
3. Patient has severe disease defined by reduced protein allowance and prescribed at least one ammonia scavenger drug.
4. Patient (if capable of signing) and parents or legal representative have signed a written informed consent form.
5. Females of childbearing potential must have a negative pregnancy test in serum or urine at the screening and Day 0 infusion visits, and use an adequate contraception method from the screening visit until 4 weeks after the first negative plasma sample monitoring vector genomes copies or the week 52 visit, whatever comes first.
6. Sexually active boys must use an adequate contraception method (abstinence or use of condom with spermicide) from at least 14 days prior to the infusion and until 4 weeks after the first negative plasma sample monitoring vector genomes copies or the week 52 visit, whatever comes first.
7. Patient's ammonia level at baseline visit (pre-gene therapy infusion) is \<100µmol/L and is within the range of historical ammonia levels obtained when the patient was clinically stable.
8. Patient has been on a stable dose of ammonia scavenger and stable protein allowance for the last 4 weeks at the baseline visit.
9. Patient is willing to commit to an additional 4 years of long-term safety follow-up.

Exclusion criteria:

1. Titres of the neutralising antibodies against AAV-LK03 \>1:5 serum dilution.
2. Significant hepatic inflammation as evidenced by the following laboratory abnormalities: alanine aminotransferase or aspartate aminotransferase or bilirubin \>2 x upper limit of normal (ULN), alkaline phosphatase \>3 x ULN.
3. Evidence of severe unexplained liver disease including but not limited to liver malignancy, liver cirrhosis, or acute liver failure.
4. Evidence of active hepatitis B or C virus (HBV and HCV respectively) documented by hepatitis B surface antigen (HBsAg) or HCV RNA positivity.
5. Positive PCR for human immunodeficiency virus (HIV).
6. Liver transplant including hepatocytes/cells infusion.
7. Current participation in another clinical trial of an investigational medicinal product or medical device, or participation within previous 12 months.
8. Patient has contraindication to immunosuppression.
9. Active infection (bacterial or viral).
10. Pregnant or breastfeeding females.
11. Patients with other serious underlying medical conditions including malignancy and severe (≥ grade 3) functional organ impairment (liver, kidney, respiratory) according to CTCAE v5.0. For neurological symptoms considered as sequelae of previous hyperammonaemic decompensation and which are considered as stable (i.e. not evolving), a grade 3 will be acceptable. Grade 4 and 5 will preclude inclusion.
12. Patients with any other significant condition or disability that, in the investigator opinion, may interfere with the patient's optimal participation in the study.

Where this trial is running

London

• Great Ormond Street Hospital — London, United Kingdom (RECRUITING)

Study contacts

• Study coordinator: Trial Manager

Conditions: Ornithine Transcarbamylase Deficiency