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

Document Type

Conference Proceeding

Publication Date

2-1-2025

Publication Title

Transplant Cell Ther

Keywords

adenine, busulfan, hemoglobin F, plerixafor, adult, anemia, autologous hematopoietic stem cell transplantation, clinical trial, conference abstract, controlled study, drug therapy, engraftment, female, follow up, hematopoietic stem cell, hemolysis, human, leukapheresis, material safety data sheet, mobilization, myeloablative conditioning, neutrophil, open study, promoter region, respiratory failure, sickle cell anemia, sickle cell crisis, upregulation

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 βS/βS, 1/6 βS/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.

Volume

31

Issue

2

First Page

S22

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