Lovo-cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the HGB-206 study

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.

FIGURE 1

Overview of the lovo‐cel treatment process and HGB‐206 study design evolution. (A) Gene therapy treatment process of lovo‐cel for SCD. (B) Treatment process evolution. *The target TNC for BMH was ≥6 × 10⁸/kg per patient. The Group B1 patient received lovo‐cel produced using both the original and refined manufacturing process, and the Group B2 patient received lovo‐cel produced using only the refined manufacturing process. Both Group B patients received lovo‐cel manufactured from HSPCs collected using BMH; however, the Group B2 patient also underwent rescue HSPC collection by plerixafor mobilization/apheresis for the exploratory evaluation of its safety and enhancement of the lovo‐cel manufacturing process. The Group B2 patient did not receive lovo‐cel manufactured from HSPCs collected using plerixafor mobilization/apheresis. Figure adapted from N Engl J Med, Kanter, J. et al., Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease, 386, 617–628. Copyright © 2022 Massachusetts Medical Society. Reprinted with permission. AUC, area under the curve; BMH, bone marrow harvest; DP, drug product; HbA^T87Q, Hb with modified β‐globin gene (β^A‐T87Q); HbS, sickle Hb; HSPC, hematopoietic stem and progenitor cell; LVV, lentiviral vector; RBC, red blood cell; SCD, sickle cell disease; TNC, total nucleated cell count. [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Hb fractions over time and at last visit following lovo‐cel infusion. (A) PB VCN. (B) HbA^T87Q. (C) Hb fractions at last visit. (D) Total Hb. (E) HbF. Dashed lines indicate Group A patients 1 and 2 who, for an extended period post‐engraftment, were receiving regular transfusions and hydroxyurea; pRBC transfusion volume, day of transfusion, and transfusion type are reported in Table S3.*Patient diagnosed with AML in 2021. ^†Patient diagnosed with myelodysplastic syndrome/AML in 2018; data for efficacy endpoints are shown up to last visit prior to diagnosis of malignancy. ^‡Received regular transfusions and hydroxyurea for an extended period after lovo‐cel infusion, including the year prior to last visit; packed red blood cell transfusion volume, day of transfusion, and transfusion type are reported in Table S3. ^§Received a transfusion at last follow‐up. Total Hb baseline values (panel C) were defined as the average of the two most recent Hb assessments at/prior to screening; assessments were separated by >1 month, ≤24 months before informed consent, and excluded any patients who received a pRBC transfusion ≤3 months of each assessment; for patients receiving chronic transfusions, Hb values ≤24 months before the start of a regular transfusion program and separated by >1 month were used. AML, acute myeloid leukemia; c/dg, copies per diploid genome; Hb, hemoglobin; HbA, adult Hb; HbA^T87Q, Hb with modified β‐globin gene (β^A‐T87Q); HbF, fetal Hb; HbS, sickle Hb; M, month; pt, patient; PB, peripheral blood; pRBC, packed red blood cell; pt, patient; VCN, vector copy number. [Color figure can be viewed at wileyonlinelibrary.com]