Safety and Efficacy of Autologous CD34+ Base Edited Hematopoietic Stem Cells (BEAM-101) for the Treatment of Sickle Cell Disease with Severe Vaso-Occlusive Crises: Results from the Ongoing Phase 1/2 Beacon Study

Abstract

BEAM-101 is an investigational base edited autologous cell therapy for the treatment (tx) of SCD through upregulation of anti-sickling fetal hemoglobin (HbF). We present initial data from BEACON (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating the safety and efficacy of BEAM-101 in patients (pts) with SCD with severe vaso-occlusive crises (sVOCs).

Pts aged 18–35 with SCD and ≥4 sVOCs in the 2 years pre-screening were eligible per trial criteria. After plerixafor mobilization, autologous CD34+ HSPCs were collected by leukapheresis and edited with an adenine base editor. After myeloablative conditioning with busulfan, pts received a single infusion of BEAM-101 (≥3.0 × 10⁶ viable CD34+ cells/kg) and are monitored for 24 months (m).

As of July 2, 2024, 6 pts have been dosed. Demographics: 5/6 β^S/β^S, 1/6 β^S/β⁰, 50% female, 19–27 years. Half (n=3) required a single mobilization cycle and half required 2. Pts received a mean BEAM-101 dose of 11.9 × 10⁶ (5.2–23.4) viable CD34+ cells/kg.

Besides safety data that include all pts dosed (n=6), the following data are from pts dosed with ≥1m of follow up (n=4; 6, 5, 2, and 1m[s] post-tx, each). All 4 pts with ≥1m of follow up achieved neutrophil and platelet engraftment at a median of 17 (15–19) and 20 (11–34) days, respectively. One pt died due to respiratory failure, likely related to busulfan conditioning, 4m after infusion. In all pts dosed (n=6), there have been no ≥Grade 3 AEs or serious AEs related to BEAM-101.

Using central lab data, pts’ total Hb increased from baseline (mean 9.3 [7.9–10.9] g/dL) to 17.9, 18.2, 11.0, and 11.8 g/dL at last time point available (LTPA) for P1, P2, P3, and P4, respectively. No signs/symptoms or interventions were needed for high total Hb. All pts achieved >60% HbF of non-transfused (NT) Hb (total Hb − HbA) at Month (M) 1 and sustained this elevation to the LTPA. By M1, HbS% in NT blood dropped to ≤36% in all 4 pts and was sustained through LTPA. In total blood, % F-cells were 99.6% in P1 at M6, 94.4% in P2 at M4, 52.0% in P3 at M2, and 13.3% in P4 at M1 with all pts having >19 pg HbF/F-cell at LTPA. Peripheral blood editing in nucleated cells, measured in P1 (at M6) and P2 (at M3), was 69.9% and 76.1%, respectively. Markers of hemolysis have normalized or improved for all pts. No VOCs have been reported by investigators following BEAM-101 tx.

These initial data show a safety profile for BEAM-101 consistent with busulfan conditioning and autologous HSCT. Tx with BEAM-101 resulted in rapid engraftment and marked improvement of anemia in all 4 dosed pts. We observed rapid and robust HbF induction in NT blood in all post-tx assessments. No VOCs were reported by investigators post-tx. These initial data support base editing of the HBG1/2 promoters as an effective therapeutic modality for the tx of SCD and will continue to be investigated in the ongoing BEACON study. Updated data to be presented. © American Society of Hematology (2024). Reused with permission.