Lovo‐cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the <scp>HGB</scp>‐206 study

Abstract

Abstract lovo‐cel (bb1111; LentiGlobin for sickle cell disease [SCD]) gene therapy (GT) comprises autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β‐globin gene (β A‐T87Q ) to produce anti‐sickling hemoglobin (HbA T87Q ). The efficacy and safety of lovo‐cel for SCD are being evaluated in the ongoing phase 1/2 HGB‐206 study ( ClinicalTrials.gov : NCT02140554). The treatment process evolved over time, using learnings from outcomes in the initial patients to optimize lovo‐cel's benefit–risk profile. Following modest expression of HbA T87Q in the initial patients (Group A, n = 7), alterations were made to the treatment process for patients subsequently enrolled in Group B ( n = 2, patients B1 and B2), including improvements to cell collection and lovo‐cel manufacturing. After 6 months, median Group A peripheral blood vector copy number (≥0.08 c/dg) and HbA T87Q levels (≥0.46 g/dL) were inadequate for substantial clinical effect but stable and sustained over 5.5 years; both markedly improved in Group B (patient B1: ≥0.53 c/dg and ≥2.69 g/dL; patient B2: ≥2.14 c/dg and ≥6.40 g/dL, respectively) and generated improved biologic and clinical efficacy in Group B, including higher total hemoglobin and decreased hemolysis. The safety of the lovo‐cel for SCD treatment regimen largely reflected the known side effects of HSPC collection, busulfan conditioning regimen, and underlying SCD; acute myeloid leukemia was observed in two patients in Group A and deemed unlikely related to insertional oncogenesis. Changes made during development of the lovo‐cel treatment process were associated with improved outcomes and provide lessons for future SCD GT studies.