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

An Open-label, Phase 2 Trial to Evaluate the Efficacy and Safety of a Single Intravenous Administration of GNT0003 (an Adeno-associated Viral (AAV) Vector Expressing the UGT1A1 Transgene) Following Imlifidase Pre-treatment in Adult Participants With Severe Crigler-Najjar Syndrome (CNS) Requiring Daily Phototherapy and Presenting Pre-existing Anti-AAV8 Antibodies

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.

Study Overview

• Status: Recruiting
• Conditions: Crigler-Najjar Syndrome
• Intervention / Treatment: Drug: Imlifidase; Drug: GNT0003

• Study Type: Interventional
• Enrollment (Estimated): 3
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: GENETHON Clinical Development Department; Phone Number: +33 (0) 1 69 47 10 32; Email: clinicaldevelopment@genethon.fr

Study Locations

• France
  • Clamart, France, 92141
    • Recruiting
    • Hôpital Antoine Béclère
    • Contact: Phone Number: 00 33 (0)1 45 37 42 72; Email: philippe.labrune@abc.aphp.fr
    • Principal Investigator: Philippe LABRUNE, MD,PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment with imlifidase; Each participant will be treated with imlifidase	Drug: Imlifidase; Imlifidase: single administration (dose is confidential), Lyophilized powder for concentrate for solution for infusion
Experimental: Treatment with GNT0003; Each participant will be treated with GNT0003	Drug: GNT0003; GNT0003: single administration 5E+12 VG/kg, Sterile concentrate for solution for infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with serum total bilirubin ≤ 300 μmol/L, 48 weeks after GNT0003 infusion and without phototherapy from Week 16	Decrease of serum total bilirubin level after interruption of daily phototherapy; change in serum total bilirubin from baseline to week 48.	48 weeks post GNT0003 administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of significant clinical and/or laboratoy abnormalities, of all treatment-emergent adverse events, serious adverse events, adverse events of special interrests, adverse drug reactions, malignancies	Incidence and severity for each body system and laboratory parameter will be presented and summarized overall	48 weeks; 60 months
Change in Health-related quality of Life form baseline to week 48 post GNT0003 administration	Scale 36-Item Short From Survey (SF-36 Health Survey); from 0 (negative) to 100 (positive)	48 weks

Collaborators and Investigators

• Sponsor: Genethon
• Collaborators: Hansa Biopharma AB
• Investigators: Principal Investigator: Philippe LABRUNE, MD, PHD, APHP_Hopital Antoine BECLERE

Study record dates

Study Major Dates

• Study Start (Actual): November 8, 2024
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2030

Study Registration Dates

• First Submitted: July 18, 2024
• First Submitted That Met QC Criteria: July 23, 2024
• First Posted (Actual): July 24, 2024

Study Record Updates

• Last Update Posted (Actual): December 3, 2024
• Last Update Submitted That Met QC Criteria: November 28, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Disease; Hyperbilirubinemia, Hereditary; Syndrome; Cardiomyopathies; Crigler-Najjar Syndrome
• Other Study ID Numbers: GNT-018-IDES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No