Bluebird Bio’s Lovo-Cel For Sickle Cell Disease Finally Under FDA Review

On 27th April 2023, Bluebird Bio1 submitted an application to FDA for its gene therapy lovotibeglogene autotemcel (lovo-cel) for approval to treat people aged 12 and older with sickle cell disease (SCD).

Understanding Sickle Cell Anaemia

SCD, or sickle cell anaemia, is a multisystem disorder and the most common genetic disease in the United States, affecting 1 in 500 African Americans2. Across the globe3, around 5% of the world’s population carries trait genes for haemoglobin disorders, mainly, sickle cell disease and thalassaemia. The genetic mutation in SCD causes polymerization of the haemoglobin molecule that alters the erythrocyte shape and its ability to deform2. People with SCD can remain asymptomatic for a prolonged period of time, but develop a range of symptoms later on, including vaso-occlusive crisis (VOC) such as stroke and acute chest syndrome (ACS), certain infections, pulmonary hypertension, chronic kidney disease, splenic sequestration and aplastic crisis2. 

Present Sickle Cell Anaemia Treatment Options

So far, the treatment options are conservative, focusing on complication or symptom management, and in some developed countries: blood transfusion. Management2 of complications is tailored to the type of complication. VOC management mainly consists of analgesia following the WHO pain ladder and rehydration. For most other complications like ACS, splenic sequestration and strokes, on top of the standard treatment protocols, transfusion therapy is usually needed. 

HGB-206 Trial: Gene Therapy for Sickle Cell Anaemia

Lovo-cel, developed by Bluebird Bio, is a gene therapy comprising of4 autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified beta-globin gene to produce anti-sicking haemoglobin. HGB-2064 is an ongoing phase 1/2, non‐randomized, open‐label, multi‐site, single‐dose clinical study of lovo‐cel for SCD and is the largest study of gene therapy in SCD to date. So far1 36 people with age between 12 and 50 have been enrolled in the trial. The gene therapy treatment process for lovo-cel for SCD was modified during the study, leading to three different cohorts, with the same study endpoints4: 

• Biological efficacy: functional βA-T87Q-globin expression, Hb proportions (HbS/HbAT78Q), and total non‐transfused Hb (HbS + HbF + HbA2 + HbAT87Q)
• Clinical efficacy: The frequency of severe VOC + ACS after lovo‐cel infusion was compared with the 24 months prior to treatment
• Safety: successful neutrophil engraftment, platelet engraftment, and evaluation of adverse events

The gene therapy treatment process of lovo‐cel for SCD was modified during the study. Due to variations in the time when patients were enrolled, cell collection and manufacturing improvements have been made along the process, leading to the retrospective designation of three sequential cohorts: Group A, B and C. All groups demonstrated great clinical efficacy with an 82.6% reduction in VOC+ACS incidents in Group A, a 79.1% reduction in the Group B1 patient, and a 100% reduction in the Group B2 patient. Overall, key markers of haemolysis were reduced after lovo‐cel infusion in Groups A and B with stable cardiac function. In terms of its safety, the most common were thrombocytopenia (85.7%), neutropenia (71.5%), and stomatitis (71.5%) in Group A, and leukopenia (100%), neutropenia (100%), and stomatitis (100%) in Group B. However, the CD4 level gradually stabilized 3 months after infusion without the need for immunomodulation. Two cases of acute myeloid leukaemia were unfortunately registered during the study, which is unclear whether the event is related to lovo-cel treatment or SCD. 

Concurrent Gene Therapy Trials for Sickle Cell Anaemia

So far, the HGB-206 study has been hailed as a major success in gene therapy on SCD and has been used as a launching platform for its FDA application. There are several other gene therapy trials currently running like CLIMB, PRECIZN-1 and MOMENTUM, all looking into a potential cure for people with SCD. More research is needed into monitoring the genotoxicity of gene therapy and its long-term clinical outcomes. 

References:

1. Maia M. Bluebird seeks FDA approval of lovo-cel as sickle cell gene therapy | Treatment targeted for patients over 12 with history of pain crises | Sickle Cell Disease News [Internet]. sicklecellanemianews.com. [cited 2023 May 2]. Available from: https://sicklecellanemianews.com/news/bluebird-seeks-fda-approval-sickle-cell-gene-therapy-lovo-cel/
2. Aziza Sedrak, Kondamudi NP. Sickle Cell Disease [Internet]. Nih.gov. StatPearls Publishing; 2021 [cited 2022 Mar 29]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482384/#:~:text=Sickle%20cell%20disease%20(SCD)%20is
3. Sickle Cell Disease [Internet]. WHO | Regional Office for Africa. Available from: https://www.afro.who.int/health-topics/sickle-cell-disease#:~:text=Sickle%2Dcell%20disease%20is%20characterized
4. Kanter J, Thompson AA, Pierciey FJ, Hsieh M, Uchida N, Leboulch P, et al. Lovo-cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the HGB-206 study. American Journal of Hematology [Internet]. 2023 Jan 1 [cited 2023 Jan 22];98(1):11–22. Available from: https://pubmed.ncbi.nlm.nih.gov/36161320/

‌5.Kanter J, Falcon C. Gene therapy for sickle cell disease: where we are now? Hematology [Internet]. 2021 Dec 10;2021(1):174–80. Available from: https://ashpublications.org/hematology/article/2021/1/174/482932/Gene-therapy-for-sickle-cell-disease-where-we-are

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