Enhanced CD34+ cell mobilizations, collections, and comparable safety profile with fixed-dose versus weight-based plerixafor dosing in patients with sickle cell disease receiving autologous CD34+ base-edited hematopoietic stem cells (BEAM-101) in the ongoing BEACON study Free

Introduction Autologous transplantation with genetically modified hematopoietic stem and progenitor cells (HSPCs) for sickle cell disease (SCD) often requires multiple stem cell mobilization and collection cycles. Plerixafor, a CXCR4 inhibitor, enhances HSPC mobilization into peripheral blood. Dose optimization can improve mobilization and shorten collection cycles, which can reduce transfusions, hospital stay, central venous access days, and apheresis-associated complications. In adults and children (bodyweight ≤83kg), a tiered fixed-dose approach in combination with G-CSF has been shown to increase plerixafor exposure and HSPC mobilization (see plerixafor prescribing information).

BEAM-101 is an investigational cell therapy comprising autologous CD34+ HSPCs collected after plerixafor mobilization. Cells are base edited ex vivo to introduce naturally occurring A-to-G substitutions into the HBG1/2 promoters that encode γ-globin, leading to increased fetal hemoglobin production. BEACON (NCT05456880) is an ongoing Phase 1/2, single-arm, open-label study evaluating a single dose of BEAM-101 in individuals with SCD and severe vaso-occlusive crises (sVOCs).

PKPD modeling compared plerixafor exposure and mobilization profiles in patients (pts) categorized by weight, using weight-based (WB) and fixed-dose (FD) approaches. A modeling and simulation approach was used to extend FD beyond plerixafor's label for adult and pediatric pts with SCD weighing ≥10kg without use of G-CSF.

We compare HSPC mobilization and collection efficacy and evaluate the safety profile of WB vs FD plerixafor in the BEACON study.

Methods Key inclusion criteria included pts aged 12–35 years with SCD and ≥4 sVOCs in the 2 years before informed consent. Plerixafor PKPD modeling showed that a tiered FD approach in pts ≤83kg had the potential to increase plerixafor plasma concentrations without exceeding observed exposures in pts >83kg, thereby enhancing HSPC mobilization. Based on modeling and extensive literature evaluation supporting plerixafor's wide therapeutic window, an FD approach was incorporated into the BEACON protocol. HSPCs were collected by leukapheresis/isolation after mobilization with plerixafor administered to pts at the following doses for up to 4 consecutive days of each cycle: WB (>83kg: 0.24mg/kg); FD tiers (40–83kg [20mg], 20–39kg [12.5mg], 10–19kg [10mg]).

Results As of June 16, 2025, 46 pts have initiated, and 36 pts have completed mobilization. Of the 36 pts, 29 were ≤83kg (22 FD, 7 WB). In pts ≤83kg, FD plerixafor resulted in higher CD34+ cell collection vs WB per cycle, resulting in fewer total days of apheresis, with a median (range) of 4 (2–12) vs 6 (4–11) days, respectively. Median mobilization cycles were 1 vs 2 in pts receiving FD vs WB, respectively, with lower median days from mobilization start to completion with FD (4 vs 30 days).

After Cycle 1 of apheresis in pts ≤83kg, a median (range) of 22.7 (7.8–43.5) 10⁶/kg CD34+ cells were collected in the FD group vs 18.0 (10.3–46.5) 10⁶/kg CD34+ cells in the WB group. The higher CD34+ cell collection over each mobilization cycle was consistent with higher collection on Day 1 of each cycle (7.6 [2.4–20.3] vs 4.3 [1.6–12.0] 10⁶/kg in FD vs WB, respectively). Higher collection of CD34+ cells was also consistent with higher pre-apheresis blood CD34+ levels, which were 71.7 (17.0–207.0) and 37.2 (11.0–96.0) 10⁶/L following FD and WB plerixafor, respectively. CD34+ levels were 7.0 (0.1–36.5) vs 5.0 (3.5–7.0) 10⁶/L for FD vs WB at screening.

Safety data are available for the 46 pts (26 FD, 20 WB) who initiated and completed at least Cycle 1 of mobilization. Within 7 days post-plerixafor in all mobilization cycles, 16 (61.5%) FD and 13 (65%) WB pts experienced adverse events (AEs), of which 2 (7.7%) FD and 3 (15%) WB pts had serious AEs. A greater incidence of plerixafor-related AEs was experienced by WB (n=8 [40%]) vs FD (n=4 [15.4%]) pts. A higher number of sickle cell crises was observed during the mobilization period in WB (3 AEs in 2 pts) vs FD (1 AE in 1 pt).

Conclusion In the BEACON study, pts receiving plerixafor using an FD regimen required fewer days and cycles of apheresis than pts on the traditional WB dose regimen. More CD34+ cells were apheresed in pts receiving FD due to the greater number of CD34+ cells mobilized in the peripheral blood, particularly on Day 1. Pre-dose CD34+ levels were similar, with a generally comparable AE profile between WB and FD groups.