CareCN: A phase I/II, open-label, study to evaluate the safety and efficacy of an intravenous injection of GNT0003 (Adeno-associated Viral Vector expressing the UGT1A1 transgene) in patients with severe Crigler-Najjar syndrome requiring phototherapy

Adeno*associated virus (AAV) vector*mediated gene therapy has shown promising
results in preclinical animal models and, more recently, in humans ((Kaplitt et
al. 2007); (Maguire et al. 2008); (Nathwani et al. 2011); (Nathwani et al.
2014). Long*term correction of inherited diseases has been documented following
AAV vector mediated gene transfer (Mingozzi and High 2011) and, notably, long*
term transgene expression following liver gene transfer has been documented in
liver in dogs (Niemeyer et al. 2009), non*human primates (Nathwani et al.
2011), and humans (Nathwani et al. 2014). The investigational medicinal product
(rAAV8*hUGT1A1 - Product code GNT0003) is a genetically modified recombinant
viral vector composed by the viral capsid of the serotype 8 of the AAV and a
modified single stranded genome containing the cDNA sequence encoding for the
human UGT1A1 transgene. The rAAV8*UGT1A1 has high tropism for liver and
expresses the UGT1A1 transgene predominantly in hepatocytes following cell
transduction. This should allow for restoration of glucuronidation of bilirubin
and subsequent excretion into the bile, which will prevent its accumulation
into the blood. Overall, the good safety profile of recombinant AAV vectors
demonstrated in preclinical and clinical studies, the prospect for sustained
therapeutic effect thanks to the long*lived presence
of the viral vector genome, and the non*invasiveness of the administration
route proposed (peripheral vein infusion) make the intravenous administration
of the rAAV8*hUGT1A1 vector an attractive strategy for the treatment of CN
syndrome.

This study has been transitioned to CTIS with ID 2023-507007-60-00 check the CTIS register for the current data.

Primary objectives:

Dose escalation part:
- To assess the safety and tolerability of an intravenous single-dose
administration of GNT0003 in patients with severe Crigler-Najjar
syndrome requiring phototherapy

Confirmatory part:
- To assess the efficacy of the intravenous single-dose administration of
GNT0003 selected dose in patients with severe Crigler-Najjar syndrome
requiring phototherapy


Secondary objectives:
Dose escalation part:
- To assess the pharmacokinetics of GNT0003
- To assess the efficacy of the intravenous single-dose administration of
GNT0003 in patients with severe Crigler-Najjar syndrome requiring
phototherapy

Confirmatory part:
- To assess safety of the intravenous single dose administration of GNT0003
selected dose
- To evaluate the impact of GNT0003 selected dose in patients' Quality of
Life
- To assess pharmacokinetics of GNT0003 selected dose
- To assess pharmacodynamic effect of GNT0003 selected dose

A phase I/II, open-label, single-group, multi-center, dose escalation and
confirmatory study, followed by a long-term safety follow-up period. The study
will enroll approximately 17 CN patients and will be conducted in 3 parts:
- Part 1: the dose escalation study, to assess 2 doses of GNT0003. The dose
escalation part will include 2 cohorts of a maximum of 3 adult patients
- Part 2: the confirmatory study, to assess the efficacy and safety of the
selected dose from part 1. At the confirmatory part, 11 additional patients >=
10 years old will be enrolled
- Part 3: the long-term follow-up study, to monitor delayed adverse events of
all patients enrolled in part 1 and part 2 and to assess the sustainability of
GNT0003 efficacy

One intravenous infusion via peripheral vein of 200 mL of GNT0003 diluted in
saline and human serum albumin

This is the first time that GNT0003 will be taken by humans, however it is
thoughts that the risks associated are very low. In fact, GNT0003 has been
studied in rats, and no adverse effects have been reported.
In humans, in previous studies conducted with the same type of vector (rAAV8)
but in diseases other than Crigler-Najjar syndrome, an elevation of certain
liver enzymes, called transaminases, has been observed. This elevation has been
controlled by administering corticosteroids for a short period of time, which
was followed by a quick return of these enzymes to their normal values. For
this reason, in this study you will be asked to take oral corticosteroids
(prednisolone) starting from the day before the injection of the experimental
treatment and for the following four weeks to prevent this elevation
Blood samples for dosing liver enzymes will be taken regularly to check your
levels and maintain a safe level Therefore, if an elevation is observed, your
doctor can take the appropriate measures, such as resuming treatment with
corticosteroids
In addition to the effects described above, GNT0003 may have other risks that
at this point which are still unknown. Please also note that by receiving gene
therapy a person may no longer donate blood or an organ.