Initial Results from the BEACON Clinical Study: A Phase 1/2 Study Evaluating the Safety and Efficacy of a Single Dose of Autologous CD34+ Base Edited Hematopoietic Stem Cells (BEAM-101) in Patients with Sickle Cell Disease with Severe Vaso-Occlusive Crises

Fetal hemoglobin (HbF) is anti-sickling and elevated HbF ameliorates sickle cell disease (SCD) manifestations. BEAM-101 is an investigational cell therapy comprised of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that are base edited ex vivo to introduce naturally occurring A-to-G substitutions into the promoters of the HBG1/2 genes that encode γ-globin to disrupt BCL11A transcriptional repressor binding sites, leading to increased HbF production. We previously demonstrated in pre-clinical studies that base editing potently induced HbF (>60%) and proportionately reduced sickle hemoglobin (HbS) (<40%) without relying on double-stranded DNA breaks. We present initial data from BEACON (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating the safety and efficacy of a single dose of BEAM-101 in patients with SCD with severe vaso-occlusive crises (VOCs).

Patients 18–35 years diagnosed with SCD and ≥4 severe VOCs in the 2-year period prior to screening per trial criteria were eligible. After plerixafor mobilization, autologous CD34+ HSPCs were collected by leukapheresis/isolation and genetically modified with an adenine base editor. After myeloablative conditioning with pharmacokinetically adjusted busulfan, patients received a single infusion of BEAM-101 (≥3.0 × 10⁶ viable CD34+ cells/kg) and are monitored for neutrophil and platelet engraftment, adverse events (AEs), total hemoglobin (Hb), Hb fractions, % F-cells, hemolysis markers, peripheral blood editing, and VOCs for 24 months.

As of July 2, 2024, >20 patients are enrolled and BEAM-101 has been manufactured for 8 patients, of whom 6 patients have been dosed. One patient not included in this analysis discontinued during the mobilization/collection period prior to BEAM-101 treatment for non-medical reasons. Baseline demographics were as follows: 5/6 patients β^S/β^S, 1/6 patients β^S/β⁰, all self-reported Black/African American, 50% female, aged 19–27 years. Of the 6 patients, half (n=3) required only a single mobilization cycle and the other half required 2. Patients received a mean BEAM-101 dose of 11.9 × 10⁶ (5.2–23.4) viable CD34+ cells/kg.

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

Using the central laboratory data, patients’ 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 (LTP) available for P1, P2, P3, and P4, respectively. No signs/symptoms or interventions were undertaken for high total Hb. All patients achieved >60% HbF of non-transfused Hb (total Hb − HbA) at Month (M) 1 and sustained this elevation to the LTP available. By M1, HbS% in non-transfused blood dropped to ≤36% in all 4 patients and was sustained through LTP. 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 patients having >19 pg HbF/F-cell at LTP available. 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 (lactate dehydrogenase, indirect bilirubin, haptoglobin, and reticulocyte counts) have normalized or improved for all patients. No VOCs have been reported by investigators following BEAM-101 treatment.

These initial data show a safety profile for BEAM-101 consistent with busulfan conditioning and autologous HSCT. Treatment with BEAM-101 resulted in rapid engraftment, improvement in hemolysis markers, and marked improvement of anemia in all 4 dosed patients. We observed rapid and robust HbF induction consistent with pre-clinical data by M1 (>60%) and corresponding HbS reduction (≤36%) in non-transfused blood in all post-treatment assessments. No VOCs were reported by investigators post-treatment. These initial data support base editing of the HBG1/2 promoters as an effective therapeutic modality for the treatment of SCD and will continue to be investigated in the ongoing BEACON study. Updated data to be presented.