Efficacy and Safety of GNT0003 Following Imlifidase Pre-treatment in Severe Crigler-Najjar Syndrome

Last updated: November 28, 2024
Sponsor: Genethon
Overall Status: Active - Recruiting

Phase

2

Condition

Circulation Disorders

Treatment

Imlifidase

Imlifidase and GNT0003

GNT0003

Clinical Study ID

NCT06518005
GNT-018-IDES
  • Ages > 18
  • All Genders

Study Summary

Clinical trial rationale:

CNS is an ultra-rare (<1/1 million newborns), autosomal recessive disorder of bilirubin conjugation caused by mutation in the gene coding for uridine 5'-diphosphate glucuronosyltransferase (UGT1A1), that causes the accumulation of neurotoxic unconjugated bilirubin (UCB).

Reduction of UCB is managed with phenobarbital in mild CNS, and daily phototherapy in severe CNS.

There is no authorized curative medical treatment for CNS. Liver transplantation is currently the only curative treatment for severe CNS.

GNT0003 is a genetically modified recombinant (r) viral vector composed of the AAV8 viral capsid carrying the UGT1A1 transgene which aims to correct the dysfunction of the mutated gene by achieving durable expression of a functional copy of the affected gene.

Imlifidase (IgG-degrading enzyme) has demonstrated its efficacy in highly sensitized adult kidney transplant patients.

To give participants with pre-existing anti-AAV8 antibodies access to gene therapy treatments, this trial aims to demonstrate the safety and efficacy of GNT0003 following imlifidase pre-treatment in adult participants with severe CNS requiring daily phototherapy and presenting with pre-existing anti-AAV8 antibodies.

Primary objective: to assess efficacy of a single intravenous administration of GNT0003 following imlifidase pre-treatment in participants with severe CNS requiring phototherapy and pre-existing AAV8 antibodies

Secondary objective: to collect data on safety and tolerability of GNT0003 and imlifidase, efficacy of imlifidase, pharmacokinetic and pharmacodynamic profile of GNT0003, and Quality of Life.

The trial will include 3 parts:

  • A baseline period for at least 3 months

  • A treatment period

  • A follow-up period:

    • Initial post-treatment follow-up over 48 weeks

    • Long-term follow-up for 4 additional years

This trial will be conducted in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice and the Declaration of Helsinki. Participants must be consented using the approved Informed Consent Form before any procedures specified in the protocol are performed.

Eligibility Criteria

Inclusion

Main Inclusion Criteria:

  1. Severe Crigler-Najjar syndrome requiring ≥ 6 hours/ day of phototherapy

  2. Molecular confirmation of mutation in the UGT1A1gene by DNA sequencing

  3. Detectable serum neutralizing antibodies against AAV8

  4. Laboratory parameters value not clinically significant

  5. Highly effective method of contraception

  6. Affiliated to or a beneficiary of a health care system

Exclusion

Exclusion Criteria:

  1. Participation in another interventional trial within 6 months prior to start ofclinical trial intervention and during the whole clinical trial

  2. Fibrosis score ≥ 3 (METAVIR) or 10 kPa (FibroScan®)

  3. Liver transplantation

  4. Significant underlying liver disease, chronic hepatitis B, C and/or infected withHuman immunodeficiency virus

  5. Any other clinically significant illness

  6. Uncontrolled hyperlipidemia.

  7. History of major thrombotic events, active peripheral vascular disease, provenhypercoagulable conditions,

  8. History or presence of thrombotic thrombocytopenic purpura (TTP) or known familialhistory of TTP

  9. Prior or current treatment with Gene therapy, cell based therapy, CRISPR/Cas9 or anyother form of gene editing, imlifidase

Study Design

Total Participants: 3
Treatment Group(s): 3
Primary Treatment: Imlifidase
Phase: 2
Study Start date:
November 08, 2024
Estimated Completion Date:
September 30, 2030

Connect with a study center

  • Hopital Antoine BECLERE

    Clamart, 92141
    France

    Active - Recruiting

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