bluebird bio's Lovo-Cel Has Durable Effect in Sickle Cell Disease


Additional data on 2 patients who developed persistent anemia suggests a genetic cause may be behind the serious adverse event.

Additional data from bluebird bio's phase 1/2 clinical trial of lovotibeglogene autotemcel (lovo-cel; LentiGlobin) in sickle cell disease further demonstrated the gene therapy's efficacy, with 96% of patients treated in Group C experiencing complete resolution of severe vaso-occlusive events (sVOEs) through 24 months of follow-up.1

The findings were presented in an oral session at the 64th American Society of Hematology (ASH) Annual Meeting, December 10-12, 2022, in New Orleans, Louisiana.

The gene therapy is a transfusion of autologous hematopoietic stem and progenitor cells that are transduced with the BB305 lentiviral vector that encodes a modified β-globin gene that produces an anti-sickling hemoglobin, HbAT87Q. Patients undergo mobilization and apheresis followed by a myeloablative busulfan conditioning regimen before receiving the lovo-cel infusion.

The data are a critical positive update for the investigational therapy, as it had been placed on a partial clinical hold by the FDA in December 2021 barring it from enrolling patients under the age of 18 due to the development of persistent, nontransfusion-dependent anemia in a pediatric patient treated with the therapy. The case is 1 of 2 that have since been reported in relation to the drug, though presenting author Mark Walters, MD, of the University of California, San Francisco Benioff Children's Hospital provided an encouraging update during the session.

"An in-depth analysis of 2 cases of ineffective erythropoiesis with persistent anemia following lovo-cel treatment reassure that these cases do not have clonal evolution or an emerging malignancy," Walters said. "The working hypothesis is that the anemia is attributable to alpha-thalassemia trait with robust HbAT87Q production," noting that both patients have 2 α-globin gene deletions and entered the study with anemia, suggesting that the trait may contribute to anemia and dyserythropoiesis after treatment with lovo-cel.2

The initial reports caused concern about the development of myelodysplastic syndrome, but Walters confirmed that there has been no sign of malignancy in either patient and no hematologic malignancies in all of Group C thus far.

Overall, data through August 2022 were presented for 32 patients treated in Group C, with the median vector copy number in peripheral blood remaining stable in all patients at 1 c/dg or more 6 months post-infusion through last study follow-up, which resulted in median HbAT87Q levels of 5 g/dL or more. Baseline median total hemoglobin increased from 8.5 g/dL to 11 g/dL or more at 6 months through last visit, with no transfusions. Notably, HbAT87Q accounted for more than 40% of total hemoglobin.

Of the 32 patients treated, 96% (31/32) had complete resolution of sVOEs within the 24-month follow-up compared with 3.5 events per year in the 2 years prior to study enrollment. A single sVOE occurred in the adult patient with persistant anemia, and as of 24-month follow-up, that patient is transfusion-dependent and experiences intermittent chronic pain. Notably, the pediatric patient has not required transfusion and remains well. Both patients did experience a reduction or resolution of sVOEs following treatment with lovo-cel.

In terms of safety, the most frequently reported serious adverse events were pain, abdominal pain, anemia, drug withdrawal syndrome, nausea, suicidal ideation, and vomiting. No cases of veno-occlusive liver disease, graft failure, insertional oncogenesis or replication-competent lentivirus have been reported.

“Long-term results presented at ASH show... sustained treatment effect in patients with sickle cell disease treated with lovo-cel. Additionally, case studies from our lovo-cel clinical program have enhanced the field’s understanding of the mechanism of action of LVV gene therapy and its impact on clinical safety and efficacy," said Richard Colvin, MD, PhD, chief medical officer, bluebird bio, in a statement.2

bluebird said it remains on track to file its biologics license application for lovo-cel in the first quarter of 2023.

For more coverage of ASH 2022, click here.

1. Walters MC, Thompson AA, Kwiatkowski JL, et al. Lovo-cel (bb1111) Gene Therapy for Sickle Cell Disease: Updated Clinical Results and Investigations into Two Cases of Anemia from Group C of the Phase 1/2 HGB-206 Study. Presented at: ASH 2022 Annual Meeting. December 10-12, 2022; New Orleans, LA. Abstract 11.
2. New Data from bluebird bio’s Gene Therapies for Transfusion-Dependent Beta-Thalassemia and Sickle Cell Disease Presented at 64th ASH Annual Meeting. News release. bluebird bio. December 10, 2022.
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