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LentiGlobin for Sickle Cell Disease: 24-Month Follow-Up Yields Sustained QOL Outcomes

The greatest improvements were seen in the Pain, Fatigue, and Physical Functioning domains.

Building on previously reported 12-month follow-up data from Group C of the HGB-206 study (NCT02140554) of lovotibeglogene autotemcel (bb1111; lovo-cel; LentiGlobin) for the treatment of sickle cell disease (SCD), investigators shared additional 24-month post-treatment data in a poster presented at the Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR (2022 Tandem Meetings), held in Salt Lake City, Utah, and virtually April 23-26, 2022.1

A lovo-cel infusion resulted in clinically meaningful health-related quality of life (HRQoL) benefits that sustained up to 2 years after administration, including near-complete resolution of the painful vaso-occlusive events (VOEs) that characterize SCD, investigators reported.

Lovo-cel comprises the autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which generates an antisickling hemoglobin, HbAT87Q. The ongoing phase 1/2 HGB-206 study is evaluating the efficacy and safety of lovo-cel for patients with SCD, as well as its effect on incidence of VOEs, frequent hospitalizations, and patient-reported quality of life (QoL) outcomes.

Patients included in Group C were ≥ 12 – ≤ 50 years with a genotype of either βSβS, βSβ0, or βSβ+. All individuals reported a history of severe VOEs, defined as ≥ 4 severe VOEs in 2 years before informed consent, as well as failure of or intolerance to hydroxyurea.

Study investigators gathered patient-reported outcomes at baseline using PRO Measurement Information System (PROMIS)-57, and then every 6 months through month 24. QOL categories spanned physical, mental, and social, and included 7 domains: Depression, Anxiety, Pain Interference, Fatigue, Sleep Disturbance, Physical Function, and Satisfaction with Participation in Social Roles. Additionally, patients were asked to rate their pain intensity on a scale of 1-10.

Baseline PROMIS-57 data were available for 25 of the 35 patients in Group C. Of these 25, the median age was 25 year (range, 19–38) and 60% were male. Patients in the overall population (n = 25) were divided into 2 subgroups per each domain depending on whether their baseline assessment was “better or near” or “worse” than what is considered the US population norm, which measured a standardized T-score of 50 for all 7 domains and a rating of 2.6 for Pain Intensity.

“Meaningful within-patient change was calculated as a function of change in group means and defined as ≥ 5-point change for all domains and ≥ 2-point change for Pain Intensity,” investigators reported.

Patients reported meaningful change in mean difference for all 7 PROMIS-57 domains except Anxiety, as well as in the Pain Intensity score. The QoL benefits kicked in early and sustained through month 24 post-infusion. Patients who reported “worse” baselines scores compared with the population norm related improvements in all 7 domains 6 to 24 months post-infusion. The greatest improvements were seen in the Pain, Fatigue, and Physical Functioning domains.

Overall, investigators concluded that “these findings may reflect the resolution of severe VOEs in all patients up to and beyond 24 months, with improvements to patient QoL not yet observed in the SCD treatment landscape to-date.”

The development of bluebird bio’s lovo-cel has been turbulent, as the company hit another bump in the road in December 2021 when the FDA placed the program on partial clinical hold following a report of persistent anemia in an adolescent patient. The pause marked the second clinical hold for the program, the first of which was lifted in June 2021 after the company demonstrated that its lentiviral vector was not associated with patients developing acute myeloid leukemia and myelodysplastic syndrome. Under the FDA directive, the company is able to continue conducting follow-up of previously treated patients, which comprises the Tandem Meetings data presented here.

“While the partial hold is in place, we intend to continue planned follow-up on previously treated patients from HGB-206 and HGB-210 and plan to enroll and treat new adult patients with lovo-cel through study HGB-210 to further characterize the efficacy and safety of lovo-cel for patients with SCD and to continue to advance the field of gene therapy,” bluebird bio’s chief medical officer Richard Colvin, MD, said in a statement at the time.2

Lovo-cel is currently being evaluated in the phase 3 HGB-210 study (NCT04293185) and previous positive efficacy data has been presented from the phase 1/2 HGB-206 study (NCT02140554).3 The FDA has granted the gene therapy orphan drug, fast track, regenerative medicine, and rare pediatric disease designations.

1. Walters M, Tisdale J, Mapara M, et al. Sustained improvements in patient reported quality of life up to 24 months post-treatment with lentiglobin for sickle cell disease (bb1111) gene therapy. Presented at: Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City, UT. Accessed April 21, 2022. https://tandem.confex.com/tandem/2022/meetingapp.cgi/Paper/19113 
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. Resolution of Serious Vaso-Occlusive Pain Crises: Results from the ongoing phase 1/2 HGB-206 group C study of lentiglobin for sickle cell disease (SCD; bb1111) gene therapy. Presented at: 2021 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; Held virtually February 8-12, 2021. Abstract 13.