Sickle Cell Disease (SCD)


Lovo-cel (also known as bb1111 or LentiGlobin™ for sickle cell disease [SCD]) is an investigational gene therapy in development by Bluebird Bio for patients with SCD. This experimental treatment is envisioned as a one-time therapy for patients with SCD.1

Sickle cell disease is a debilitating genetic disease caused by a single point mutation in the β-globin gene (HBB).2,3 This mutation results in the formation of sickle hemoglobin (HbS) and sickling red blood cells following the polymerization of HbS.3 Patients with SCD have an increased risk of early death as they experience vaso-occlusive events, progressive vasculopathy, and chronic hemolytic anemia due to the presence of sickling red blood cells.2,3

Therapeutic options for SCD include disease-modifying therapies for the control of symptoms.2 There is also the potentially curative human leukocyte antigen (HLA)-matched sibling allogeneic hematopoietic stem cell transplantation. This treatment approach, however, is recommended for young patients and carries risks of graft-vs-host disease, graft rejection, and transplantation-related death. Additionally, an HLA-matched donor is required, which is found for only 14% to 20% of the patients.2,3 

The development of new strategies for managing SCD, such as gene therapies based on autologous stem cells, may offer advantages when considering the challenge of reducing transplantation-related death.3

Mode of Action of Lovo-Cel

Lovo-cel is a gene therapy involving the autologous transplantation of hematopoietic stem and progenitor cells (HSPCs). These cells are first transduced with the lentiviral vector BB305, which encodes a modified β-globin gene (βA-T87Q). The administration of lovo-cel aims to promote the production of an antisickling hemoglobin, HbAT87Q. This hemoglobin is a modified protein in which an amino acid substitution helps to sterically block the polymerization of HbS, reducing hemolysis and other complications.3 

The advantages of lovo-cel in patients with SCD include the potential elimination of the risk of graft-vs-host disease, the similar morphology and function (oxygen-binding affinity and oxygen-hemoglobin dissociation curve) that HbAT87Q maintains with adult hemoglobin, and the absence of the need for a well-matched donor.2,3

Lovo-Cel in Preclinical and Clinical Studies 

Lovo-cel-mediated βA-T87Q expression has been shown to decrease HbS expression and polymerization in preclinical studies.2 Data from these studies guided the clinical development program for lovo-cel, including the HGB-206 study.2 HGB-206 (NCT02140554) is an ongoing nonrandomized, open-label, multisite, single-dose, phase 1/2 study designed to evaluate both the safety and efficacy of lovo-cel in about 50 adults and adolescents with severe SCD.3,4 In this study, patients will be followed up for 24 months before joining a 13-year follow-up observational study (NCT04628585) to assess the long-term safety and efficacy of the investigational therapy.5

Results deriving from the HGB-206 trial have shown a sustained production of HbAT87Q, with reduced hemolysis as well as a complete resolution of severe vaso-occlusive events. No reports of graft-vs-host disease or failure have been reported.3

The clinical development program sponsored by Bluebird Bio also includes a phase 3 clinical trial that is currently recruiting participants, the HGB-210 study (NCT04293185).6 HGB-210 is a nonrandomized, open-label, multisite, single-dose study that will enroll about 35 adult and pediatric patients with SCD to further study lovo-cel.6 

After the first clinical hold, which was lifted by July 2021, the lovo-cel clinical program was placed under a partial clinical hold for pediatric patients by the FDA due to an observed case of an adolescent patient with persistent, non-transfusion-dependent anemia.1,6,7

References

1. Bluebird Bio announces the lifting of FDA clinical hold for sickle cell disease and β-thalassemia studies. News release. Bluebird Bio, Inc; June 7, 2021.

2. Kanter J, Thompson AA, Pierciey FJ Jr, et al. Lovo-cel gene therapy for sickle cell disease: treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. Published online September 25, 2022. doi:10.1002/ajh.26741

3. Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 2022;386(7):617-628. doi:10.1056/NEJMoa2117175

4. A study evaluating the safety and efficacy of bb1111 in severe sickle cell disease. ClinicalTrials.gov. May 16, 2014. Updated July 19, 2022. Accessed December 19, 2022.

5. Long-term follow-up of subjects with sickle cell disease treated with ex vivo gene therapy. ClinicalTrials.gov. November 13, 2020. Updated November 1, 2022. Accessed December 19, 2022.

6. A study evaluating gene therapy with BB305 lentiviral vector in sickle cell disease. ClinicalTrials.gov. March 3, 2020. Updated July 19, 2022. Accessed December 19, 2022.

7. Pipeline. Bluebird Bio. Accessed December 19, 2022.

Reviewed by Harshi Dhingra, MD, on 12/16/2022.

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