General Information

Zynteglo (betibeglogene autotemcel) is an autologous hematopoietic stem cell-based gene therapy.

Zynteglo is specifically indicated for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell (RBC) transfusions.

Zynteglo is for autologous use only administered only as an intravenous infusion. Patients are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for Zynteglo manufacturing.

• Dosing of Zynteglo is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight.
• The minimum recommended dose is 5.0 × 106 CD34+ cells/kg.
• Full myeloablative conditioning must be administered before infusion of Zynteglo.
• Prophylaxis for hepatic veno-occlusive disease (VOD) is recommended. Prophylaxis for seizures should be considered.
• Verify that the patient’s identity matches the unique patient identification information on the Zynteglo infusion bag(s) prior to infusion. Do not sample, alter, or irradiate Zynteglo. 
• Do not use an in-line blood filter or an infusion pump.
• Administer each infusion bag of Zynteglo via intravenous infusion over a period of less than 30 minutes

Mechanism of Action

Zynteglo adds functional copies of a modified β-globin gene into patients’ hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 LVV. After Zynteglo infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce RBCs containing biologically active βA-T87Q-globin (a modified β-globin protein) that will combine with α-globin to produce functional adult Hb containing βA-T87Q-globin (HbAT87Q). βA-T87Q-globin can be quantified relative to other globin species in peripheral blood using high-performance liquid chromatography. βA-T87Q-globin expression is designed to correct the β/α-globin imbalance in erythroid cells of patients with β-thalassemia and has the potential to increase functional adult HbA and total Hb to normal levels and eliminate dependence on regular pRBC transfusions.

Side Effects

Adverse effects associated with the use of Zynteglo may include, but are not limited to, the following:

• mucositis
• febrile neutropenia
• vomiting
• pyrexia (fever)
• alopecia (hair loss)
• epistaxis (nose bleed)
• abdominal pain
• musculoskeletal pain
• cough
• headache
• diarrhea
• rash
• constipation
• nausea
• decreased appetite
• pigmentation disorder
• pruritus (itch)
• Grade 3 or 4 laboratory abnormalities (> 50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia

Clinical Trial Results

FDA approval of Zynteglo was based on data from Phase 3 studies HGB-207 (Northstar-2) and HGB-212 (Northstar-3) and the long-term follow-up study LTF-303. The single-arm, open-label, 24-month Phase 3 studies of Zynteglo included 41 patients aged 4 to 34 years with both non-β0/β0 and β0/β0 genotypes, with longest follow up out to 4 years. Eighty-nine percent (32/36) of evaluable patients across ages and genotypes achieved transfusion independence (TI), which is defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average total hemoglobin of at least 9 g/dL. Results in these patients were durable as of last follow-up. Across all studies, all patients who achieved transfusion independence have remained transfusion-free.