Bluebird’s Beta-Thalassemia Gene Therapy Faces US Panel Scrutiny On Hematologic Malignancy Risk
Executive Summary
Although there were no cases of hematological malignancy reported and no evidence of insertional oncogenesis in patients treated with beti-cel, FDA raises a theoretical risk due to delayed platelet engraftment, as well as malignancies seen in other lentiviral vector programs.
A US Food and Drug Administration advisory committee will consider recommendations for pretreatment screening and postmarketing safety monitoring to address the potential risk of hematologic malignancies with bluebird bio’s betibeglogene autotemcel (beti-cel), a lentiviral vector-based gene therapy for beta-thalassemia.
In a briefing document released ahead of the Cellular, Tissue and Gene Therapies Advisory Committee meeting on 10 June, the FDA said beti-cel trials showed a clinically meaningful benefit in subjects with transfusion-dependent beta thalassemia (TDT), demonstrating transfusion independence that was durable.
However, the product’s benefit-risk profile for the proposed population has not been fully characterized “due to the pathologic latency of platelet recovery, along with marrow morphology abnormalities in subjects with TDT, and the hematologic malignancies in studies with other LVV-based products,” the agency said.
The beti-cel meeting is the second of bluebird’s gene therapy candidates that the committee will review in as many days. On 9 June, the panel will consider efficacy questions and malignancy concerns with elivaldogene autotemcel (eli-cel) in pediatric patients with early cerebral adrenoleukodystrophy (CALD). (Also see "Gene Therapy: Bluebird’s Eli-Cel Efficacy Uncertain, Malignancy Risk Concerning, US FDA Says" - Pink Sheet, 7 Jun, 2022.)
Both gene therapies are delivered through different lentiviral vectors, and presentations relevant to vector safety for both products, including integration and risk of insertional oncogenesis, are scheduled for the first day of the meeting. (Also see "Gene Therapy Reviews Return To US FDA Advisory Committee Schedule" - Pink Sheet, 19 Apr, 2022.)
Pivot To US After European Experience
TDT is a rare hemoglobinopathy associated with life-long anemia requiring frequent red blood cell transfusions. Disease-related complications include organ damage resulting from iron overload, reduced quality of life and shortened survival. Allogenic hematopoietic stem cell transplantation using HLA-matched related donors results in the best outcomes, but most patients lack such donors.
Despite supportive care with transfusions, iron chelators and Celgene Corporation’s erythroid maturation agent Reblozyl (luspatercept-aamt), there continues to be a significant unmet need for TDT patients, the agency said.
Bluebird is seeking approval of beti-cel, a one-time autologous gene therapy product, for treatment of patients with beta-thalassemia who require regular red blood cell transfusions.
The product, branded as Zynteglo, was conditionally approved in Europe in 2019. However, the marketing authorization was withdrawn at bluebird’s request after the company decided to wind down its gene therapy business in Europe following unsuccessful efforts to secure reimbursement for Zynteglo. (Also see "Bluebird Bio Decision in Europe Is A Wake-Up Call For Payers and Industry" - Pink Sheet, 30 Aug, 2021.)
Bluebird is banking on better chances for reaching reimbursement agreements in the US market. In a recently revised evidence report, the Institute for Clinical and Economic Review said that given the cost of standard care for TDT, with an anticipated price of $2.1m beti-cel met most commonly accepted value thresholds. This conclusion assumes an outcomes-based agreement with an 80% payback option if patients do not achieve and maintain transfusion independence over five years. (Also see "Bluebird Could Find US Tailwind For Zynteglo After ICER Report" - Scrip, 2 Jun, 2022.)
Transfusion Independence Achieved
Clinical data supporting the biologics license application come primarily from two Phase III, single-arm trials, HGB-207 and HGB-212. Study HGB-207 enrolled subjects with a non-β0/β0 genotype, while Study HGB-212 enrolled subjects with a β0/β0 genotype.
The agency also reviewed supportive safety data from a Phase I/II study, HGB-204, which allowed a lower dose of an earlier version of beti-cel made with a prior iteration of the manufacturing process.
The primary efficacy endpoint in the two Phase III studies was the proportion of subjects meeting the definition of transfusion independence (TI), which was defined as a weighted average hemoglobin (Hb) ≥9 g/dL without any RBC transfusions for a continuous period of ≥12 months at any time during the study after drug product infusion.
Among 36 subjects evaluable for the TI endpoint by data lock across the two trials, 32 (89%) reached TI at any time.
“FDA believes that TI represents a clinically meaningful benefit for patients with transfusion-dependent β-thalassemia, and could decrease the risks of iron overload, multi-system organ complications and early mortality,” the agency said.
“This clinical endpoint is supported by pharmacodynamics data which show rises in βA-T87Q-globin leading to the attainment of target levels of unsupported total Hb, regardless of age or genotype,” the agency said. “Ongoing Phase III and long-term follow-up studies suggest durability of beti-cel activity with subjects maintaining their Hb levels to time of last follow-up [median (range) 26 months (13-39)].”
Worries About Delayed Platelet Engraftment
There were no cases of hematological malignancy reported in the studies and no evidence of insertional oncogenesis in TDT patients treated with beti-cel.
However, the agency raises a theoretical risk of malignancy due to delayed platelet engraftment, followed by incomplete recovery of platelet counts toward normal, in beti-cel-treated subjects, as well as hematologic malignancies observed with LVV-based products for sickle cell disease and CALD.
In bluebird’s eli-cel CALD clinical program, there have been three reported cases of myelodysplastic syndrome (MDS). In addition, there have been two reports of acute myeloid leukemia with bluebird's lovo-cel (lovotibeglogene autotemcel) in clinical studies for sickle cell disease.
“FDA has not drawn definitive conclusions with respect to the role, if any, LVV integrations play in the delayed platelet engraftment experienced by subjects treated with beti-cel,” the agency said. “However, the hematologic malignancies observed after treatment with LVV-based products for SCD and CALD increase our concern that delayed platelet engraftment may represent MDS.”
The agency requests the advisory committee discuss recommendations for prescreening patients for potential germline and somatic mutations that would predispose them to hematologic malignancies. The panel also is asked to consider the adequacy of bluebird’s proposed safety monitoring measures, postmarketing pharmacovigilance program, long-term follow-up and registry studies.
Pharmacovigilance Plans
Patients treated with beti-cel in the clinical studies are being followed in a long-term study for a total of 15 years after infusion, with assessments performed every six months through the first five years and then annually for the next 10 years, bluebird’s briefing document states.
The company also plans to initiate an observational registry study in the US to characterize the safety and effectiveness of beti-cel in TDT patients. The registry study will record safety and effectiveness assessments taken during routine clinical care, including complete blood counts at least annually.
“Gene therapy-specific laboratory assessments such as integration site analysis (ISA) will be offered at least annually in the context of routine blood draws and more often if requested in the context of relevant clinical workup. For all enrolled patients, the registry study will collect and report information on all SAEs, AEs of interest, and beti-cel related AEs,” bluebird said.
“In addition, in the case of a newly diagnosed malignancy, bluebird bio will attempt to collect follow up samples including ISA as clinically feasible from patients regardless of enrollment” in the registry.
Product labeling and educational materials will recommend blood work at least annually for 15 years post-treatment to monitor for potential development of malignancies.