Crigler-Najjar Syndrome Gene Therapy Trial Enters Pivotal Portion


Some patients previously treated with GNT-003 were able to maintain the stoppage of phototherapy for at least 1 year.

Genethon’s GNT-003 (GNT0003), an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat Crigler-Najjar syndrome, has entered the pivotal part of its phase 1/2 clinical trial (NCT03466463).1

Crigler-Najjar syndrome, an autosomal recessive inherited disorder, is caused by mutations in the UGT1A1 gene, which leads to decreased or absent UDP-glucuronosyltransferase enzyme levels.2 The lack of this enzyme leads to the build-up of unconjugated bilirubin. Current standards of care include intensive phototherapy and plasmaspheresis, which can help reduce bilirubin levels. The only curative option currently available is liver transplant.

GNT-003 is delivered via intravenous injection and is intended to provide normal copies of UGT1A1. The clinical trial originally began in 2017 and initially treated 6 adult patients. Preliminary results from the trial, which were announced in 2021, indicated that GNT-003 was well-tolerated in the first 5 patients treated.3 In terms of efficacy, it was noted that patients in cohort 1, treated at the trial’s lowest dose, showed a temporary therapeutic effect which was not sufficient for the patients to stop phototherapy for a prolonged period by 16 weeks after treatment. However, the first 2 patients treated in cohort 2, who received a higher dose than those in cohort 1, achieved a major reduction in bilirubin levels allowing for the stoppage of phototherapy. It was later reported that patients in cohort 2 were able to maintain the stoppage of phototherapy for at least 1 year.1

“These initial observations indicate that gene therapy could become an alternative treatment for this severe liver disease,” Frederic Revah, chief executive officer, Genethon, said at the time the data was announced in 2021.2 “We need to remain cautious, as the trial is ongoing and will allow us to evaluate these initial encouraging results in other patients and over a longer period.”

The open-label clinical trial is enrolling patients aged 10 years and older with severe Crigler-Najjar syndrome who require phototherapy.1 Patients who have undergone liver transplantation, patients who are currently participating in another investigational trial, and patients with chronic hepatitis B or C, HIV infection, significant underlying liver disease, or significant encephalopathy will be excluded from the study. The trial’s primary end points include the incidence of adverse events and serious adverse events and the decrease in total serum bilirubin level 7 days after the stoppage of daily phototherapy at 16 weeks post-treatment. The trial's secondary end point will assess quality of life with the Scale 36-Item Short Form Survey (SF-36 Health Survey for adults) or the Scale 10-Item Short Form Survey (SF-10 Health Survey for children). The trial is being carried out in a collaboration with the European consortium CureCN, and the pivotal part will take place at 4 sites in France, Italy, and the Netherlands.

"We are very pleased with this new step because if the results of the pivotal part confirm the efficacy of GNT-003, we will be able to move forward towards a registration application and the availability of the treatment for patients,” Revah said in a statement regarding the news of the trial entering its pivotal portion.1 “This new step demonstrates once again the excellence of the research conducted at Genethon, which is today one of the major players in gene therapy at the international level."

Several other treatments for Crigler-Najjar syndrome are also currently in development. LogicBio Therapeutics’ and Takeda’s LB-301, an investigational AAV vector-based gene-editing candidate, is currently in preclinical development.4 In addition, Moderna and the Institute for Life Changing Medicines are collaborating on mRNA-3351, an investigational mRNA therapeutic intended to treat Crigler-Najjar syndrome.5

1. Genethon launches pivotal clinical trial of gene therapy for Crigler-Najjar syndrome, a rare liver disease. News release. Genethon. January 10, 2022.
2. Bhandari J, Thada PK, Yadav D. Crigler Najjar Syndrome. National Library of Medicine. Website Accessed January 10, 2023.
3. Preliminary results of clinical trial for rare liver disease Crigler-Najjar syndrome presented at ESGCT congress. News release. Genethon. June 28, 2021. 
4. Logicbio Therapeutics announces collaboration with Takeda to develop new genome editing candidate LB-301 for the treatment of Crigler-Najjar syndrome. News release. LogicBio Therapeutics Inc. January 10, 2020.
5. Moderna and the Institute for Life Changing Medicines announce a new collaboration to develop an mRNA therapeutic for ultra-rare disease, Crigler-Najjar syndrome type 1. News release. Moderna, Inc. September 7, 2021.
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