BASE EDITING FOR SICKLE CELL DISEASE: ONGOING RESULTS FROM THE BEACON STUDY EVALUATING THE SAFETY AND EFFICACY OF BEAM-101, THE FIRST BASE-EDITED AUTOLOGOUS CD34+ HSPC ONE-TIME CELL THERAPY

Document Type

Conference Proceeding

Publication Date

6-12-2025

Publication Title

HemaSphere

Keywords

adenine, busulfan, hemoglobin, hemoglobin F, lactate dehydrogenase, plerixafor, rapcabtagene autoleucel, adult, anemia, binding site, cell therapy, clinical article, clinical trial, conference abstract, controlled study, cytokine release syndrome, cytopenia, diffuse large B cell lymphoma, drug concentration, drug therapy, engraftment, ex vivo study, female, follow up, gene expression, hemolysis, high risk population, human, International Prognostic Index, leukapheresis, low drug dose, lymphocytopenia, male, mobilization, mortality, myeloablative conditioning, neurotoxicity, neutropenia, neutrophil, open study, phase 2 clinical trial, probability, promoter region, real time polymerase chain reaction, relapse, repressor gene, respiratory failure, sickle cell anemia, sickle cell crisis, side effect, single drug dose, thrombocytopenia, upregulation

Abstract

Background Individuals with sickle cell disease (SCD) with elevated levels of anti-sickling fetal hemoglobin (HbF) have attenuated disease manifestations. BEAM-101 is an investigational cell therapy consisting of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that are base edited ex vivo to mimic naturally occurring A-to-G substitutions in the promoters of the HBG1/2 genes, disrupting BCL11A transcriptional repressor binding sites, leading to upregulation of HbF. Aims We present updated 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 (pts) with SCD and frequent and severe vaso-occlusive crises (VOCs). Methods Pts aged 18-35 years with SCD and ≥ 4 severe VOCs in the 2-year period prior to provision of informed consent were eligible. After mobilization with plerixafor, autologous CD34+ HSPCs were collected by leukapheresis and genetically modified with an adenine base editor. After myeloablative conditioning with pharmacokinetically adjusted busulfan, pts 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, and VOCs along with additional endpoints per protocol for 24 months (M). Results As of Feb 28, 2025, 47 pts are enrolled, and 17 pts have been dosed; 1 pt discontinued during the mobilization/collection period prior to BEAM-101 treatment for non-medical reasons. The 7 pts included in the initial analysis from Oct 28, 2024 had 11, 9, 5, 4 (n=3), and 1 M of follow up each. Baseline characteristics and dosing are displayed in Table A. All 7 pts required a maximum of 2 mobilization cycles, with 4 pts requiring just 1 cycle, and achieved neutrophil and platelet engraftment at a mean (range) of 17 (15-21) and 19 (11-34) days, respectively (Figure A). The mean duration of neutropenia was 6.3 (4-9) days. Pt3 died due to respiratory failure, likely related to busulfan conditioning and unrelated to BEAM-101, 4 M after infusion. Otherwise, there have been no ≥ Grade 3 AEs or serious AEs related to BEAM-101. Mean total Hb increased to >12 g/dL by M1 and >14 g/dL by M2. All pts achieved HbF >60% and HbS <40% in untransfused blood (HbF+HbS) by M1 after BEAM-101 treatment and, except pt3, sustained through follow up (Figure B). Pancellular HbF expression was observed and pts with available F-cell data had a mean HbF per F-cell >16 pg, above the protective threshold against sickling, at last timepoint available. Markers of hemolysis have normalized or improved for all pts. No VOCs have been reported by investigators post engraftment. Summary/Conclusion Ongoing data from the BEACON study support the safety of BEAM-101 as consistent with busulfan conditioning and autologous hematopoietic stem cell transplant. Pts required 1-2 mobilization cycles and achieved rapid engraftment. Rapid and robust HbF induction and corresponding decrease in HbS was observed in all pts following treatment with BEAM-101, with resolution of anemia. No VOCs have been reported by investigators post engraftment. These data support base editing of the HBG1/2 promoters as a potentially effective therapeutic modality for the treatment of SCD. Study enrollment, treatment initiation, and pt follow up continue. We plan to include updated data from 17 pts with follow up to 15 M at the time of presentation. Results As of February 1, 2024, 63 patients had received rapcabtagene autoleucel with a median follow-up of 16.4 months (range: 0.1-44.1; Table 1). Among the 60 infused patients with r/r DLBCL who had ≥ 1 month follow-up, ORR was 88% and CRR was 65%. CRR at 3, 6, and 12 months were 55% (30/55), 57% (25/44), and 47% (18/38), respectively. Median DOR was 15.2 months (5.1-not estimable [NE]); in patients with a BOR of CR, the median DOR was not reached (10.4-NE) and the 12-month DOR was 69%. Median PFS was 11.9 months; among patients in CR at 3 months, the median PFS was not rea hed. PFS rates at 12 months were 48% for all patients and 79% for patients in CR at 3 months. High CR rates at 3 months were observed across most patient subgroups including high-risk populations; 64% for patients age ≥ 65 years, 53% for patients with ≥ 3 prior therapies, 46% for patients with an International Prognostic Index ≥ 3; a lower CR rate of 29%was reported for patients with elevated lactate dehydrogenase before infusion. Among the 63 infused patients, adverse events (AEs) were reported in 98% (grade ≥ 3, 84%) including infections (all grade, 49%; grade ≥ 3, 27%), cytokine release syndrome (CRS; all grade, 43%; grade ≥ 3, 6%), and immune effector cell-associated neurotoxicity syndrome (ICANS; all grade, 6%; grade ≥ 3, 3%). Grade ≥ 3 infections were reported in 27% (17/63), 15% (8/55), and 19% (6/32) of patients any time, between 12 weeks and 1 year, and >1 year post infusion, respectively. Median time to onset of CRS and ICANS were 8 days (range: 1-20) and 13 days (range: 10-28), respectively. Grade ≥ 3 cytopenias included neutropenia (62%), anemia (33%), thrombocytopenia (25%), and lymphopenia (16%). Probability of resolution by 3 months for neutropenia and anemia was 100%; for thrombocytopenia and lymphopenia 3 and 6 months resolution was 92%/100% and 65%/74%, respectively. As of data cutoff, 12 deaths had occurred, all unrelated to rapcabtagene autoleucel; 6 each due to disease progression and AEs. Four deaths reported were non-relapse mortalities; 2 deaths due to AEs were reported post progression. Cellular kinetics showed robust in vivo expansion by quantitative polymerase chain reaction with a median maximum observed drug concentration (Cmax) of 41,800 copies/μg DNA. Summary/Conclusion At the 12.5×106 CAR positive cell dose, rapcabtagene autoleucel showed promising efficacy and a favorable safety profile. Although patient numbers were limited, risk-benefit analysis supports use of the lower-dose lymphodepletion regimen before infusion; continued assessment of long-term efficacy and safety outcomes is needed. American Society of Hematology (2024). Reused with permission.

Volume

9

Issue

S1

First Page

1739

Last Page

1741

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