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

ConditionCrigler-Najjar Syndrome
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorGenethon

About this trial

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

This trial does not accept healthy volunteers

Qualifiers

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

Molecular confirmation of mutation in the UGT1A1gene by DNA sequencing

Detectable serum neutralizing antibodies against AAV8

Laboratory parameters value not clinically significant

Disqualifiers

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

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

Liver transplantation

Significant underlying liver disease, chronic hepatitis B, C and/or infected with Human immunodeficiency virus

Trial design

Design model

Single group

Treatments tested in this trial

  • Imlifidase

    Drug

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

  • GNT0003

    Drug

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

Treatment groups

3 Participants
are divided into 2 treatment groups
Group A: Treatment with imlifidaseExperimental treatment 1 intervention
Group B: Treatment with GNT0003Experimental treatment 1 intervention

Trial outcomes

Primary outcomes

1

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.

Time frame
48 weeks post GNT0003 administration

Secondary outcomes

1

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

Time frame
48 weeks; 60 months
2

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)

Time frame
48 weks

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Genethon

Lead sponsor

Hansa Biopharma AB

Collaborator

Source ClinicalTrials.gov
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