Efficacy and Safety in Patients (Pts) with Sickle Cell Disease (SCD) Who Have Received Lovotibeglogene Autotemcel (Lovo-cel) Gene Therapy: Up to 60 Months of Follow-up

Introduction Lovo-cel gene therapy uses autologous transplantation of hematopoietic stem and progenitor cells (HSPCs) transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which produces an anti-sickling hemoglobin (Hb), HbAT87Q. Objective To report efficacy and safety from HGB-206 (phase 1/2; NCT02140554) and HGB-210 (phase 3; NCT04293185), including data from pediatric pts (age 12 to <18 y) in HGB-210. Methods HGB-206 Group C and HGB-210 pts who received lovo-cel using the current HSPC mobilization and manufacturing process were included. Pts with SCD and recurrent severe vaso-occlusive events (VOEs) or history of overt stroke underwent plerixafor mobilization and apheresis followed by myeloablative busulfan conditioning and lovo-cel infusion. Pts with 24 mo follow-up post infusion enrolled in the long-term LTF-307 study (NCT04628585). Lab evaluations, SCD-related outcomes (eg, resolution of independently adjudicated VOEs), globin response (composite endpoint evaluating HbAT87Q percentage and total Hb), and safety are reported. Results This analysis includes 47 pts (HGB-206 Group C, n=36; HGB-210, n=11; male, 59.6%; median [range] age, 23 y [12-38]) who received a lovo-cel infusion as of Feb 13, 2023. Median (range) follow-up was 35.5 mo (0.3-61.0). Median (range) total Hb increased from 8.7 g/dL (6.1-12.5) at relative baseline to 11.8 g/dL (8.4-15.0) at last visit; median percent HbAT87Q of nontransfused total Hb was ≈40% or more (Figure).Of 33 evaluable pts (ie, ≥18 mo follow-up and ≥4 VOEs in the 2 y before enrollment), 30 (90.9%) and 32 (97.0%) had complete resolution of VOEs and severe VOEs during the 6-18 mo post infusion vs a median (range) of 3.5 (1.5-16.5) and 3.0 (0.5-13.0) events/y in the 2 y before enrollment.Among pts who had globin response or who had ≥18 mo follow-up (n=38), 33 (86.8%) achieved globin response. Hemolysis markers approached normal levels.Among all 47 pts, 44 (93.6%) had a grade ≥3 adverse event (AE) post infusion, most commonly stomatitis (33 [70.2%]) and thrombocytopenia (28 [59.6%]). Serious AEs were reported for 26 (55.3%) pts, most commonly chronic pain/acute exacerbation of chronic pain (3 [6.4%]). One pt with α3.7/-α3.7 genotype diagnosed with myelodysplastic syndrome had stable complete blood counts 30 mo post infusion. No veno-occlusive liver disease, graft failure, replication-competent lentivirus, or vector-mediated insertional oncogenesis were observed. Lovo-cel regimen largely reflected known side effects of HSPC collection and busulfan conditioning. Conclusion One-time treatment with lovo-cel resulted in sustained HbAT87Q production and near-complete resolution of VOEs and severe VOEs up to 18 mo post treatment. AEs were consistent with underlying SCD and myeloablative conditioning. Ongoing long-term follow-up will provide important information on efficacy and safety post lovo-cel treatment.