Preliminary results of clinical trial for rare liver disease Crigler-Najjar syndrome presented at ESGCT congress

After a first presentation at the International Liver Congress last June, new preliminary results have just been presented at the European Society of Geneand Cell Therapy (ESGCT) congress by Dr d’Antiga, one of the investigators of the trial (Bergamo, Italy). Based on initial observations, the drug candidate is well tolerated and the first therapeutic effects have been demonstrated, to be confirmed as the trial continues.

Preliminary results from the European gene therapy trial for Crigler-Najjar syndrome, conducted by Généthon in collaboration with European network CureCN, were presented at the EASL (European Association for the Study of the Liver) annual International Liver Congress on June 26. Based on initial observations, the drug candidate is well tolerated and the first therapeutic effects have been demonstrated, to be confirmed as the trial continues.

Crigler-Najjar syndrome is a rare genetic liver disease characterized by abnormally high levels of bilirubin in the blood (hyperbilirubinemia). This accumulation of bilirubin is caused by a deficiency of the UGT1A1 enzyme, responsible for transforming bilirubin into a substance that can be eliminated by the body, and can result in significant neurological damage and death if not treated quickly. At present, patients must undergo phototherapy for up to 12 hours a day to keep their bilirubin levels below the toxicity threshold.

Dr. Lorenzo D’Antiga (Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy), one of the investigators working on the gene therapy trial being conducted into Crigler-Najjar syndrome by Généthon, presented the results from the first treated patients. The treatment involves providing the liver cells with a copy of the UGT1A1 gene that encodes an enzyme designed to facilitate bilirubin elimination. Based on initial observations, the results are encouraging.

Specifically, the first two cohorts reveal that:

• The product is safe and well tolerated in the five patients undergoing treatment

• There appears to be a dose-response relationship (to be confirmed):
  • In cohort 1, treated at the lowest dose, the clinicians observed a temporary therapeutic effect but that was insufficient to allow prolonged stopping the phototherapy at the sixteenth week post-injection (the product efficacy endpoint)
  • In cohort 2, treated at a higher dose, a major reduction in bilirubin levels was demonstrated in the first two patient, enabling them to stop phototherapy a few weeks ago.

“Our work on the immunomodulation protocol is now focused on maintaining a durable effect in the long term. This innovative strategy may replace liver transplantation in patients with a genetic liver disease”, Dr. Lorenzo D’Antiga, who treated the last three patients, explained.

The trial uses a technology developed by Généthon’s Immunology and Liver Diseases team, headed up by Dr. Giuseppe Ronzitti, who says: “The team has worked incredibly hard on this project, from designing and developing the approach right through to the trial. We designed the drug candidate, undertook the preclinical efficacy testing, then designed the product for the clinical trial. We are continuing our work to develop new approaches for other liver diseases.”

“These initial observations indicate that gene therapy could become an alternative treatment for this severe liver disease. 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”, Frédéric Revah, CEO of Généthon, says.

About the trial

This European trial aims to assess the product’s safety, identify the optimal dose, and evaluate the therapeutic efficacy of the drug candidate. The clinical trial is being conducted at four European study sites: in France (Prof. Labrune – Hôpital Béclère, Clamart), Italy (Prof. Brunetti-Pierri – Hôpital Federico II; Prof. d’Antiga – Azienda Ospedaliera Papa Giovanni XXIII, Bergamo) and the Netherlands (Prof. Beuers – Academic Medical Center, Amsterdam). The project is supported by European consortium CureCN, which brings together 11 European partners, and has received funding from the European Unionʼs Horizon 2020 research and innovation program.