Genethon and Hansa Biopharma Launch Trial for Gene Therapy and Antibody Cleaving Enzyme Therapy Combination Treatment in Crigler-Najjar Syndrome
The phase 2 trial will assess Hansa’s imlifidase as a pretreatment for Genethon’s GNT-0003.
Genethon and Hansa Biopharma have initiated a phase 2 clinical trial (GNT-018-IDES; NCT06518005) evaluating Hansa’s immunoglobulin G (IgG) antibody cleaving enzyme therapy imlifidase (marketed in Europe under the name Idefirix) as a pretreatment for Genethon’s GNT-0003, an investigational adeno-associated virus serotype 8 (AAV8) vector-based gene therapy intended to treat severe Crigler–Najjar syndrome.1
The single-arm GNT-018-IDES study, which will seek to enroll 3 adult patients with preformed antiAAV8 antibodies and Crigler-Najjar syndrome who need at least 6 hours per day of phototherapy, will include a 3 month observational period after screening. After the observational period, patients will be treated with imlifidase and subsequently receive GNT-0003. The companies anticipate reporting initial results from the study at some point next year.
Imlifidase is intended to allow for the treatment with AAV8 vector-based gene therapy of patients who would not normally be eligible for such therapies because of preexisting antibodies. It functions by cleaving IgG-antibodies in order to inhibit their activity. Imlifidase is currently available in Europe under a conditional marketing approval for desensitization treatment of highly sensitized patients who received adult kidney transplants and who have a positive crossmatch against an available deceased donor.
“We know that antiAAV antibodies prevent up to 1 in 3 people from benefitting from gene therapies using AAV-vectors,” Søren Tulstrup, MSc, the president and CEO of Hansa Biopharma, said in a statement.1 “That’s why our collaboration with Genethon and the initiation of the phase 2 clinical trial in Crigler-Najjar syndrome is so important. This collaboration with Genethon is the second of our 3 partnerships with leading gene therapy companies to have reached the clinical stage, marking an important milestone in our efforts to enable a much larger group of patients to benefit from potentially lifesaving gene therapies.”
Outside of GNT-018-IDES, GNT-0003 is also being evaluated as a monotherapy in a pivotal phase 1/2 clinical trial (NCT03466463). The gene therapy received PRIority MEdicines (PRIME) designation from the European Medicines Agency in March 2023.2
"This new clinical trial reflects Genethon’s commitment in pursuing innovative strategies to ensure and broaden access to gene therapies for patients suffering from rare diseases,” Frederic Revah, PhD, the chief executive officer of Genethon, added to the statement.1 “Patients with preexisting neutralizing antibodies against AAV vectors cannot today benefit from gene therapy. The initiation of this clinical trial and the collaboration with Hansa Biopharma is a crucial step for Genethon and highlights several years of pioneering research to understand and control the immune response to AAV in order to make gene therapy more effective and to increase the number of patients able to access it."
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.3 The lack of this enzyme leads to the build-up of unconjugated bilirubin. GNT-003 is delivered via intravenous injection and is intended to provide normal copies of UGT1A1.2
Results from an earlier portion of the monotherapy trial for GNT-0003 were reported in The New England Journal of Medicine in August 2023.4 The data showed that patients with the rare liver disease who received the trial’s higher dose (n = 3; 5×1012 vg/kg) experienced a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration.
“Although our study is small, among the patients who received the dose of 5×1012 vg/kg, GNT-0003 restored UGT1A1 activity to levels that permitted suspension of phototherapy, and the efficacy persisted at 18 months after the treatment,” study author Lorenzo D’Antiga, MD, of the Department of Pediatric Hepatology, Gastroenterology, and Transplantation at Hospital Papa Giovanni XXIII, in Bergamo, Italy, and colleagues wrote.4 “A test of replication in a larger, well-characterized cohort of patients will be important.”
