In short
Currently, there are 2 ongoing clinical trials investigating gene therapy treatments for Crigler-Najjar syndrome, a rare genetic liver disorder that affects the body's ability to process bilirubin. These trials are testing new approaches that may reduce or eliminate the need for daily phototherapy in patients with severe forms of the condition. Trials are being conducted in France, Italy, and the Netherlands.
Clinical trial locations
- France
- Italy
- Netherlands
Study of GNT0003 and imlifidase in adults with Crigler-Najjar syndrome who require daily phototherapy and have pre-existing AAV8 antibodies
This trial is investigating a combination treatment for adults with severe Crigler-Najjar syndrome who require at least 6 hours of daily phototherapy and have antibodies against AAV8, a viral carrier used in gene therapy. The study is being conducted in France.
Main inclusion criteria: To participate, you must be at least 18 years old with confirmed severe Crigler-Najjar syndrome requiring daily phototherapy. You need genetic confirmation of a mutation in the UGT1A1 gene and must have detectable AAV8 antibodies in your blood. Acceptable blood test results are required, including normal or near-normal blood cell counts, blood clotting tests, kidney function, and liver function within specified limits. Participants must agree to use reliable birth control from the screening visit until at least 48 weeks after treatment and be willing to comply with all study requirements.
Main exclusion criteria: You cannot participate if you have a history of liver transplantation, are currently on the transplant waiting list, or have significant liver disease beyond Crigler-Najjar syndrome. Other exclusions include current participation in other clinical trials within 30 days, active infections or major illnesses, pregnancy or breastfeeding, significant kidney problems, recent major surgery within 3 months, history of cancer within the past 5 years, or alcohol or drug abuse within the past year. Conditions that could affect your ability to follow study procedures or comply with phototherapy requirements also exclude participation.
Focus and goals: The study aims to determine if the combination of GNT0003 gene therapy and imlifidase can help reduce bilirubin levels in adults who have existing antibodies against the viral carrier. The treatment process begins with imlifidase administered intravenously to prepare the body, followed by a single dose of GNT0003. Participants will continue their regular phototherapy during the first 16 weeks after treatment while being closely monitored with regular health checks, blood tests, and collection of various samples. If the condition improves, patients may be able to stop phototherapy after week 16, with bilirubin levels monitored to ensure they remain safe. The study includes long-term follow-up for up to 60 months to assess both effectiveness and safety.
Investigational drugs: GNT0003 is a gene therapy delivered through a single intravenous injection. It uses a modified virus to carry a working copy of the UGT1A1 gene into the body, aiming to help patients produce the enzyme needed to process bilirubin properly. Imlifidase is given before the gene therapy to reduce antibodies that might interfere with the treatment, specifically targeting patients with existing AAV8 antibodies. Additional medications including sirolimus, prednisolone, and methylprednisolone may be used to help manage the body's response to treatment.
Study on Gene Therapy GNT0003 for Patients with Severe Crigler-Najjar Syndrome Requiring Phototherapy
This clinical trial is evaluating GNT0003, a gene therapy treatment for patients with severe Crigler-Najjar syndrome who require daily phototherapy. The study is being conducted in France, Italy, and the Netherlands and is expected to continue until 2028.
Main inclusion criteria: Participants must have severe Crigler-Najjar syndrome requiring daily phototherapy for at least 6 hours per day. Molecular confirmation of mutations in the UGT1A1 gene through DNA sequencing is required. The study accepts participants of any gender and includes children, adolescents, and adults. The trial may also include individuals considered as a vulnerable population who might need special protection or care.
Main exclusion criteria: Patients who do not have severe Crigler-Najjar syndrome requiring phototherapy cannot participate. Those who fall outside the specified age range for the study are not eligible. Individuals who cannot safely receive the study treatment due to other health conditions or risks, or who are unable to follow study procedures or attend all required visits, are excluded from participation.
Focus and goals: The study is divided into two main phases. The first phase, called the dose escalation phase, focuses on determining the safest dose of GNT0003 by assessing safety and tolerability of a single intravenous dose. During this phase, participants are monitored for any side effects and changes in laboratory tests, vital signs, and physical examination up to week 17. The second phase, the confirmatory phase, evaluates how well the selected dose works in reducing bilirubin levels to 300 µmol/L or less by week 48, while observing patients for the absence of phototherapy need from week 16 onwards. Throughout the trial, regular assessments monitor the clearance of the GNT0003 vector from the body and measure changes in quality of life using specific questionnaires.
Investigational drug: GNT0003 is an experimental gene therapy administered as an intravenous injection. It uses an adeno-associated viral vector to carry the UGT1A1 gene into the patient's liver cells. The goal is to introduce a functional version of this gene, which may help the liver process bilirubin more effectively and reduce or eliminate the need for daily phototherapy. The therapy is designed to provide a one-time treatment that could offer long-term benefits for managing this condition.
Summary
Both ongoing clinical trials for Crigler-Najjar syndrome focus on the same investigational gene therapy, GNT0003, which aims to address the underlying genetic cause of the condition by delivering a functional copy of the UGT1A1 gene. A notable difference between the two studies is that one specifically targets adult patients with pre-existing AAV8 antibodies and combines GNT0003 with imlifidase to overcome this barrier, while the other trial includes a broader age range from children to adults without the antibody restriction.
The trials are concentrated in Western Europe, with France participating in both studies, while Italy and the Netherlands are involved in the broader trial. Both studies share the common goal of reducing or eliminating the need for daily phototherapy, which represents a significant burden for patients with this rare condition. The long follow-up periods, extending up to 60 months in one study and until 2037 in the other, demonstrate the commitment to understanding the long-term safety and effectiveness of this innovative gene therapy approach.
These trials represent important advances in treating Crigler-Najjar syndrome, as they investigate a potential one-time treatment that could fundamentally change disease management by addressing the genetic root cause rather than just managing symptoms with daily phototherapy.
