An Update on Lovotibeglogene Autotemcel (Lovo-cel) Clinical Trials for Sickle Cell Disease (SCD) and Analysis of Early Predictors of Response to Lovo-Cel

Lovo-cel, which consists of transplantation of autologous hematopoietic stem and progenitor cells encoding a functional anti-sickling β-globin gene, is approved for patients aged ≥12 y with SCD and a history of vaso-occlusive events (VOEs). We report updated outcomes for participants treated with lovo-cel from HGB-206 Group C (NCT02140554; phase 1/2) and HGB-210 (NCT04293185; phase 3) and examine how early pharmacodynamic (PD) parameters predict long-term clinical responses to lovo-cel. Data shown are from lovo-cel trial participants (HGB-206 completed and HGB-210 ongoing) treated as of Feb 2024; updated data will be presented. A post hoc, exploratory analysis utilized univariate logistic regression to estimate the association between post–lovo-cel PD parameters and clinical outcomes. A receiver operating characteristic curve determined the optimal HbA T87Q cutoff value, maximizing predictive power for complete resolution of VOEs (VOE-CR)/severe VOEs (sVOE-CR). As of Feb 2024, 55 participants (n=55; male, 61.8%; median [range] age, 21 [9-38] y) received lovo-cel per the current manufacturing process, including 14 participants <18 y. Median (range) time to last follow-up was 41.9 (0.9-72.3) months. Of 34 VOE-evaluable participants, 30 (88.2%) and 32 (94.1%) achieved VOE-CR and sVOE-CR in the 6-18 months post infusion. Among 46 evaluable participants, 41 (89.1%) achieved globin response (GR). Median (range) % peripheral blood (PB) HbA T87Q 6 months post infusion was 49% (26%-63%). Results were similar for adult (≥18 y) and pediatric (<18 y) subgroups. The lovo-cel safety profile reflects the known effects of underlying SCD and myeloablative conditioning . Analyses of HGB-206 (all groups) and HGB-210 data showed long-term PD and biologic responses can be predicted as early as 6 months post infusion (Fig. 1). PD parameters are highly predictive of clinical outcomes, including achieving GR and resolution of VOEs 6-18 months post infusion (Fig. 2). Increased HbA T87Q is associated with VOE-CR and sVOE-CR, with high confidence of achieving clinical outcomes above 33% PB HbA T87Q (Fig. 3). In HGB-206 Group C and HGB-210, the median HbA T87Q was 49% at ≥6 months. The HbA T87Q level is established by the drug product (DP), as PD response is significantly correlated with the DP % lentiviral vector (LVV)+ cells ( r =0.86, P <0.001). In participants from HGB-206 Group C and HGB-210, the median (range) % LVV+ cells is 83% (63%-93%). Among participants who are not VOE evaluable (<18 months follow-up; n=12), the median (range) % PB HbA T87Q is 53% (46%-59%) at 6 months. One-time lovo-cel treatment results in sustained HbA T87Q production and eliminated VOEs and sVOEs in a majority of participants. Models developed in this post hoc analysis enable prediction of the likelihood of VOE-CR and sVOE-CR using measurements as early as 6 months post lovo-cel infusion.