Crigler-Najjar Syndrome Gene Therapy Gets EMA PRIME Designation


Three patients treated with Genethon’s GNT-003 were able to cease treatment with standard of care phototherapy for at least 1 year.

Genethon’s GNT-003 (GNT0003), an investigational adeno-associated virus (AAV) vector-based gene therapy being evaluated for the treatment of Crigler-Najjar syndrome in a phase 1/2 clinical trial (NCT03466463), has received priority medicines (PRIME) designation from the European Medicines Agency (EMA).1

Crigler-Najjar syndrome, an autosomal recessive inherited disorder, is caused by mutations in the UGT1A1 gene, which lead to decreased or absent UDP-glucuronosyltransferase enzyme levels.2 The lack of this enzyme leads to the build-up of unconjugated bilirubin. Currently, some patients with Crigler-Najjar syndrome are required to receive phototherapy for up to 12 hours per day in order maintain non-toxic bilirubin levels.1

GNT-003 is intended to provide a functional copy of the UGT1A1 gene. It is administered via intravenous injection. The EMA gave GNT-003 the PRIME designation based on early positive findings from the clinical trial, which is being carried out in France, Italy, and the Netherlands. Genethon reported that GNT-003 was well-tolerated in the first 5 adult patients treated. Furthermore, the organization noted that 3 patients who received the highest dose of GNT-003 experienced reductions in bilirubin allowing them to cease treatment with phototherapy for at least 1 year. The study has now begun its pivotal phase, which will evaluate the highest dose for efficacy in adult and pediatric patients.

“We’re excited about the EMA’s PRIME recognition of GNT-0003,” Frederic Revah, chief executive officer, Genethon, said in a statement regarding the news.1 “If successful, GNT-0003 would be the first gene therapy for Crigler-Najjar syndrome. The PRIME status is similar to the US FDA’s fast track and breakthrough designations. The EMA’s program was started in 2016 and in the first 5 years, only 25% of eligible drug candidates received the PRIME designation.”

In addition to GNT-003, Genethon is contributing to the development of gene therapies for several other indications. GNT-004, an investigational gene therapy for Duchenne muscular dystrophy, is being developed in collaboration with Sarepta Therapeutics.3 A clinical trial for GNT-004 was initiated, but it was suspended in April 2021 in relation to a serious adverse event (AE). Following the AE, Genethon proposed an amended protocol for the trial, which was validated by the French National Agency for Medicines and Health Products Safety and the UK’s Medicines and Healthcare products Regulatory Agency in 2022. 

Genethon has also developed GNT 0006, GNT 0007, and GNT 0008, for the treatment of limb girdle muscular dystrophy with FKRP deficiency, gamma sarco-glycanopathy, and calpainopathy, respectively.4 Genethon carried out preclinical development of GNT 0006, which demonstrated efficacy in preclinical animal research. The organization also performed a substantial portion of the preclinical research for GN 0007. Both GNT 0006 and GNT 0007 were licensed to Atamyo Therapeutics for clinical development. The organization noted that Atamyo Therapeutics is anticipating the submission of a clinical trial application for GNT 0007 in the near future. GNT 0008 has also been licensed to Atamyo Therapeutics, which will carry out the remainder of its preclinical development.

1. Genethongiven PRIME status by EMA for gene therapy to treat Crigler-Najjar syndrome, a rare liver disease. News release. Genethon. March 6, 2023. Accessed March 7, 2023. 
2. Bhandari J, Thada PK, Yadav D. Crigler Najjar Syndrome. National Library of Medicine. Website Accessed January 10, 2023. 
3. Genethon. Duchenne muscular dystrophy. Website. Accessed March 7, 2023. 
4. Genethon. Limb girdle muscular dystrophies. Website. Accessed March 7, 2023. 
Related Videos
Jeffrey Chamberlain, PhD
Robert J. Hopkin, MD
Alan Beggs, PhD
Paul Harmatz, MD
Paul Harmatz, MD
Heather Lau, MD, MS, the executive director of global clinical development at Ultragenyx Pharmaceutical
Heather Lau, MD, MS, the executive director of global clinical development at Ultragenyx Pharmaceutical
Paul Harmatz, MD, on Challenges With Assessing Neurocognitive Outcomes
Paul Harmatz, MD, on Assessing D2S6 in Trials for MPS Type 2
© 2024 MJH Life Sciences

All rights reserved.