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

NCT ID: NCT06518005

Last Updated: 2024-12-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-11-08
• Study Completion Date: 2030-09-30

Brief 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.

Conditions

Crigler-Najjar Syndrome

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment with imlifidase

Each participant will be treated with imlifidase

Group Type: EXPERIMENTAL

Imlifidase

Intervention Type: DRUG

Imlifidase: single administration (dose is confidential), Lyophilized powder for concentrate for solution for infusion

Treatment with GNT0003

Each participant will be treated with GNT0003

Group Type: EXPERIMENTAL

GNT0003

Intervention Type: DRUG

GNT0003: single administration 5E+12 VG/kg, Sterile concentrate for solution for infusion

Interventions

Imlifidase

Imlifidase: single administration (dose is confidential), Lyophilized powder for concentrate for solution for infusion

Intervention Type: DRUG

GNT0003

GNT0003: single administration 5E+12 VG/kg, Sterile concentrate for solution for infusion

Intervention Type: DRUG

Eligibility Criteria

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 Criteria

1. Participation in another interventional trial within 6 months prior to start of clinical 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 with Human immunodeficiency virus

5. Any other clinically significant illness

6. Uncontrolled hyperlipidemia.

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

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hansa Biopharma AB

INDUSTRY

Sponsor Role: collaborator

Genethon

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Philippe LABRUNE, MD, PHD

Role: PRINCIPAL_INVESTIGATOR

APHP_Hopital Antoine BECLERE

Locations

Hopital Antoine BECLERE

Clamart, , France

Site Status: RECRUITING

Countries

France

Central Contacts

GENETHON Clinical Development Department

Role: CONTACT

clinicaldevelopment@genethon.fr

+33 (0) 1 69 47 10 32

Facility Contacts

Role: primary

philippe.labrune@abc.aphp.fr

00 33 (0)1 45 37 42 72

Other Identifiers

GNT-018-IDES

Identifier Type: -

Identifier Source: org_study_id