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Partial Hold Lifted on bluebird bio's Sickle Cell Disease Gene Therapy

The hold was originally placed in December 2021 and was related to a case of persistent, non-transfusion-dependent anemia in a pediatric patient.

The FDA’s partial clinical hold suspending enrollment, cell collection, conditioning, and infusion of patients under the age of 18 in bluebird bio's phase 3 HGB-210 clinical trial (NCT04293185) of lovotibeglogene autotemcel (lovo-cel; bb1111), an investigational gene therapy intended to treat sickle cell disease (SCD), has been lifted.1

Lovo-cel is intended to deliver modified functional copies of βA-T87Q-globin, the disease-targeted gene, to patients’ hematopoietic stem cells (HSCs). The cells are collected from patients’ via plerixafor mobilization and apheresis, modified ex-vivo, and re-administered as a 1-time autologous HSC transplantation. The trial’s hold was originally placed in December of 2021 and was related to a case of persistent, non-transfusion-dependent anemia in an adolescent patient which occurred 18 months after the patient received the therapy.2 The hold did not affect continued enrollment and treatment of adult patients in the trial, which is open to patients aged 2 years to 50 years.

“We are very pleased to have addressed the FDA’s questions and resolved the partial clinical hold,” Richard Colvin, MD, PhD, chief medical officer, bluebird bio, said in a statement regarding the news.1 “We are working closely with study investigators and clinical trial sites to resume enrollment and treatment of pediatric and adolescent patients in the first quarter of next year.”

Data related to the case, as well as another case of persistent anemia in an adult patient treated with the therapy, were presented at the 64th American Society of Hematology (ASH) Annual Meeting, held December 10-12, 2022, in New Orleans, Louisiana. It was determined that the 2 patients were the only patients involved in the trial that had the alpha-thalassemia trait, which consists of 2 α-globin gene deletions (−α3.7/−α3.7). As such, the genotype has been added to the exclusion criteria for all current studies of lovo-cel.

"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 Mark Walters, MD, of the University of California, San Francisco Benioff Children's Hospital, said during the presentation at ASH.3 "The working hypothesis is that the anemia is attributable to alpha-thalassemia trait with robust HbAT87Q production.” Walters additionally noted that both patients entered the trial with anemia.

bluebird bio has announced intention to continue enrollment and treatment of pediatric patients in the trial now that the hold has been lifted.1 The company also intends to submit a biologics license application (BLA) for lovo-cel in the first quarter of next year. Lovo-cel has previously been evaluated in the phase 1/2 HGB-205 clinical trial (NCT02151526), and is additionally being examined in the ongoing phase 1/2 HGB-206 (NCT02140554) clinical trial and the long-term follow-up study LTF-307 (NCT04628585). Lovo-cel has previously received orphan drug, fast track, regenerative medicine advanced therapy, and rare pediatric disease designations from the FDA.

REFERENCES
1. FDA lifts partial clinical hold for bluebird bio’s sickle cell disease (SCD) studies for patients under the age of 18. News release. bluebird bio, Inc. December 19, 2022. https://investor.bluebirdbio.com/news-releases/news-release-details/fda-lifts-partial-clinical-hold-bluebird-bios-sickle-cell
2. bluebird bio Announces Partial Clinical Hold for Patients Under 18 in Sickle Cell Gene Therapy Clinical Program. News release. bluebird bio. December 20, 2021. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-partial-clinical-hold-patients-under-18
3. 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.