bluebird bio announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending conditional marketing authorization for ZYNTEGLO™ (autologous CD34+ cells encoding β A-T87Q-globin gene), a gene therapy for patients 12 years and older with transfusion-dependent β-thalassemia (TDT) who do not have a β0/β0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate but a human leukocyte antigen (HLA)-matched related HSC donor is not available. If approved, ZYNTEGLO, formerly referred to as LentiGlobin™ for TDT, will be the first gene therapy to treat TDT.
The CHMP’s positive opinion will now be reviewed by the European Commission (EC), which has the authority to grant marketing authorization for ZYNTEGLO in the European Union (EU). A CHMP positive opinion is one of the final steps before the EC decides on whether to authorize a new medicine. A final decision by the EC for ZYNTEGLO is anticipated in the second quarter of 2019.
TDT is a severe genetic disease caused by mutations in the β-globin gene that result in reduced or absent hemoglobin. In order to survive, people with TDT maintain hemoglobin levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.
“The goal of treatment with ZYNTEGLO is to enable patients with transfusion-dependent β-thalassemia to produce hemoglobin at sufficient levels to allow lifelong independence from blood transfusions,” said David Davidson, M.D., chief medical officer, bluebird bio. “The positive CHMP opinion for ZYNTEGLO is a crucial step toward providing what would be the first one-time gene therapy for people living with TDT. We share this achievement with the TDT community, patients and clinical investigators whose dedication made it possible. We look forward to the upcoming decision from the European Commission.”
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from American Pharmaceutical Review – all delivered right to your inbox! Sign up now!
“For many of my patients, living with TDT means a lifetime of chronic blood transfusions, iron chelation therapy and supportive treatments to manage anemia and other serious complications of this disease,” said Professor Franco Locatelli, M.D., Ph.D., Professor of Pediatrics, Sapienza University of Rome, Italy and Director, Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy. “The burden placed on these patients and their families is significant. It extends beyond immediate health implications to their daily lives, which are affected by the symptoms, hospitalizations and necessary chronic care required for TDT.”
“The present management of TDT, including regular blood transfusions every two to four weeks and daily iron chelation therapy has many psychological and social consequences, including marginalization and isolation. And in many patients TDT-related morbidities can lead to a shortened life span. Therefore, it is with great anticipation and eagerness that the international patient community has closely followed the dynamic rejuvenation of scientific interest and research of gene therapy in TDT over the last few years,” said Dr. Androulla Eleftheriou, Thalassaemia International Federation Executive Director. “Thus, the potential approval of a gene therapy brings hope that we can dramatically change the course of this disease and the health and quality of lives of patients with TDT.”
ZYNTEGLO adds functional copies of a modified form of the β-globin gene (β A-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells (HSCs). This means there is no need for donor HSCs from another person as is required for allogeneic HSC transplantation (allo-HSCT). A patient’s HSCs are collected and removed from the body through a process called apheresis. These HSCs are taken to a lab where a lentiviral vector is used to insert the β A-T87Q-globin gene into the patient’s HSCs. This step is called transduction. Before their modified HSCs are returned, the patient receives chemotherapy to prepare their bone marrow for the modified HSCs, which are returned through an infusion. Once a patient has the β A-T87Q-globin gene they have the potential to produce HbAT87Q, which is gene therapy- derived-hemoglobin, at levels that significantly reduce or eliminate the need for transfusions.
“The EMA’s collaborative approach and innovative programs have been instrumental in improving timely access of new medicines to patients with significant unmet needs, like those who are living with TDT,” said Anne-Virginie Eggimann, senior vice president of regulatory science at bluebird bio.
ZYNTEGLO was reviewed under an accelerated assessment timeline as part of the EMA’s Priority Medicines (PRIME) and Adaptive Pathways programs, which support medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.
The positive CHMP opinion is supported by efficacy, safety and durability data from the Phase 1/2 HGB-205 study and the completed Phase 1/2 Northstar (HGB-204) study as well as available data from the ongoing Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies, and the long-term follow-up study LTF-303.
As of September 14, 2018, data from Phase 1/2 Northstar showed that 80 percent (n=8/10) of patients who do not have a β0/β0 genotype achieved transfusion independence, meaning they had not received a transfusion for at least 12 months and maintained hemoglobin ≥9 g/dL. These eight patients had maintained transfusion independence for a median duration of 38 months (21 – 44 months) at the time of data cut off.
In the Phase 3 Northstar-2 and Northstar-3 studies, a refined manufacturing process was used to produce ZYNTEGLO and was intended to further improve the clinical results observed in the Northstar study. As of September 14, 2018, the median (min – max) total hemoglobin for patients six months after ZYNTEGLO infusion in the Northstar-2 study (n=10) was 11.9 (8.4, 13.3) g/dL.
Non-serious adverse events (AEs) observed during clinical trials that were attributed to ZYNTEGLO were hot flush, dyspnoea, abdominal pain, pain in extremities and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to ZYNTEGLO.
Additional AEs observed in clinical studies were consistent with the known side effects of HSC and bone marrow ablation with busulfan including SAEs of veno-occlusive disease.
ZYNTEGLO continues to be evaluated in the ongoing Phase 3 Northstar-2 and Northstar-3 studies and the long-term follow-up study LTF-303.