Gene Transfer Clinical Study in Crigler-Najjar Syndrome

This is a Phase 1/2, multinational, open-label, ascending-dose, delayed-treatment concurrent control clinical study to evaluate the safety and preliminary efficacy of AT342 in subjects with Crigler-Najjar aged ≥1 year. Subjects will receive a single dose of AT342 and will be followed for safety and efficacy for 5 years.

This study will evaluate safety and preliminary efficacy of gene transfer in Crigler Najjar Syndrome. Subjects will receive a single dose of AT342 delivered intravenously. A maximum of 3 dose levels of AT342 are planned for evaluation in this study. Up to four subjects will be enrolled at each dose level including up to 1 subject at each dose level randomized to control with delayed administration of the investigational product. Dose escalation to the next dose level will be considered after evaluation of at least 4 weeks of data from subjects dosed at the current dose level. One of the dose levels will be chosen for dose expansion, and the chosen dose will be administered to all delayed-treatment control subjects.

The primary efficacy endpoint measure of change in total serum bilirubin will be assessed at weeks 12 (whilst still on phototherapy) and week 18 (after phototherapy has been weaned) after administration of AT342; and the primary efficacy endpoint measure of change in number of hours of phototherapy will be assessed at week 18

This study will utilize an independent Data Monitoring Committee that will monitor subject safety and provide recommendations to Audentes regarding dose escalation, dose expansion, and safety matters.

At study termination, only one (1) pediatric participant was enrolled. This study was intended to be a Phase 1/2 trial but the study never moved forward to Phase 2.

Eligibility Criteria:
Key Inclusion Criteria:

* Subject has a diagnosis of Crigler-Najjar syndrome resulting from a confirmed mutation in the UGT1A1 gene as assessed by a Sponsor-approved testing facility.
* Subject is aged ≥1 year.
* Subject is prescribed daily phototherapy for a minimum of 6 hours within a 24-hour period (daily illumination time).

Key Exclusion Criteria:

* Subject is currently participating in an interventional study or has received gene or cell therapy.
* Subject has received a whole liver, partial liver, or hepatocyte transplant; or subject has a liver transplant scheduled within the treatment period of this study.
* Subject has significant cholestatic disease at screening.
* Subject is receiving phenobarbital or other known inducer of UGT1A1 within 30 days of screening.
* Subject tests positive for AAV8 neutralizing antibodies with titers above protocol specified threshold.
* Other than as required per protocol, subject has received immune-modulating agents within 3 months before dosing (use of inhaled corticosteroids to manage chronic respiratory conditions is allowed); use of other concomitant medications to manage chronic conditions must have been stable for at least 4 weeks before dosing.
* Subject has any clinically significant laboratory values, in the opinion of the investigator.
* Subject has clinically significant underlying liver disease (other than CN) at screening.
* Subject has a history of, or currently has, a clinically important condition other than CN, in the opinion of the investigator.