Paper Details

ABSTRACT

Sickle cell disease (SCD), characterized by recurrent severe vaso-occlusive crises (sVOCs) and multi-organ disease, reduces lifespan and quality of life. Ristoglogene autogetemcel (risto-cel, BEAM-101) is an investigational autologous cell therapy comprising CD34+ hematopoietic stem and progenitor cells base edited ex vivo at the HBG1/2 promoters to disrupt BCL11A binding, switching sickle hemoglobin (HbS) production to anti-sickling fetal hemoglobin (HbF). We report longer-term efficacy and safety data, including adolescents and adults (age data detailed in presentation), and initial patient-reported outcomes (PROs) from the pivotal BEACON study (NCT05456880).

BEACON is a Phase 1/2, open-label, single-arm, multicenter study in adolescents aged 12–17 and adults 18–35 years, with SCD and ≥4 sVOCs within 2 years before enrollment. After plerixafor mobilization, leukapheresis, and busulfan (Bu) conditioning, patients received a single dose of risto-cel (≥3.0×106 CD34+ viable cells/kg) and were monitored over 24 months (M) for neutrophil and platelet engraftment, sVOCs, total Hb, Hb fractions, %F-cells, HbF/F-cell, hemolysis markers, adverse events, and PROs (key PRO endpoints: 36-Item Short Form Survey [SF-36], Physical Component Summary [PCS] and Adult Sickle Cell Quality of Life Measurement Information System [ASCQ-Me]). Primary endpoint was ≥12M sVOCs-free 60-days (D) after last red blood cell transfusion.

As of May 20, 2026, 47 patients received risto-cel (8 adolescents, 39 adults); mean follow-up 6.9 (range [r]: 5.2–10.1) and 13.2 (1.7–25.2) M, respectively. Baseline demographics were consistent between adolescents and adults: 92% βS/βS; median investigator-reported sVOCs 24 M prior to informed consent, 5.0 (4–8) and 6.0 (4–42), respectively. 

Adolescents and adults had similar median mobilization cycles (1.0, r: 1–5), mean risto-cel dose (8.73 [3.1–13.8] and 8.36 [3.1–23.4] ×106 CD34+ cells/kg), and median time to neutrophil (16.5 [14–28] and 17.0 [12–30] D) and platelet engraftment (23 [11–40] and 19 [11–53] D), respectively. For all patients, mean endogenous HbF (HbF/[HbF+HbS]) was 63.5% (52.2–80.3) at M6, sustained through follow-up. Mean %F-cells reached 99.2% (97.0–99.9) by M6, with calculated mean HbF/F-cell values above the anti-sickling protective threshold (10pg) and sustained through follow-up. Mean hemolysis markers normalized or improved. In the evaluable efficacy population, no patient experienced investigator-reported sVOCs post risto-cel. 

Risto-cel treatment regimen’s safety profile was consistent with Bu conditioning and prior data. 

PROs were completed by n=44 (as of February 27, 2026). SF-36 PCS improved from severely impaired at baseline (mean 36.6; ~1.3 standard deviation below US population norm of 50) toward the general population norm. Mean change from baseline (MCFB) was +12.6 (M6, n=16) and +14.0 (M12, n=6), greater than the established minimal clinically important difference (MCID) +2 to +3. ASCQ-Me Emotional Impact and Social Functioning improved concordantly with MCFB ~twice the MCID (+5) at every post-baseline timepoint through M12 (+10.7, +9.95, respectively); mean total scores were above the SCD reference population norm through M12. On Patient Global Impression of Change, all patients reported improvement at every post-baseline visit; ‘very much better’ ratings: 51.7% at M3, 83.3% at M12. On Brief Pain Inventory-SF, all severity and interference items improved by M3 (n=27), with all severity and 6 of 7 interference items sustained through M12 (n=3). On Patient Global Impression of Severity, baseline moderate-to-very severe symptoms of 65.2% fell to 13.8% by M3 and all patients previously reporting severe/very severe ratings shifted to less severe categories. FACIT-Fatigue MCFB exceeded the MCID (+4) at M6 and 12 (+6.8, +7.2, respectively), indicating reduced fatigue.

In adolescents and adults with severe SCD, risto-cel continues to show rapid neutrophil and platelet engraftment, durable pancellular HbF induction (>60%), resolution of investigator-reported sVOCs, and improved or normalized hemolysis, with a safety profile consistent with Bu conditioning and underlying SCD. Consistent, early, and sustained improvements across PROs spanning physical function, pain, fatigue, emotional/social wellbeing, and symptom severity support risto-cel as an effective SCD treatment delivering consistent benefits across multiple clinical outcomes and PROs.