Background
Phase 1–2, multicenter, open-label, single-group study (BEACON trial). 31 patients (ages 12–35) with sickle cell disease and ≥4 severe VOEs in 2 years before enrollment. Risto-cel (ristoglogene autogetemcel) uses adenine base editing (not CRISPR nuclease cleavage) of the HBG1/HBG2 promoters to inhibit BCL11A binding without altering BCL11A expression itself, switching hemoglobin production from HbS to antisickling HbF. Myeloablative pharmacokinetically-guided busulfan conditioning before single risto-cel infusion (≥3.0×10⁶ viable CD34+ cells/kg).
Interventions and follow up
Arm A: Single infusion of risto-cel after myeloablative busulfan (all patients; no comparator)
Primary endpoint: Freedom from severe VOEs for 12 consecutive months (starting >60 days after last transfusion)
mFollow up: Mean 6.6 months (range 0.3–20.4)
Primary endpoint: Freedom from severe VOEs for 12 consecutive months (starting >60 days after last transfusion)
mFollow up: Mean 6.6 months (range 0.3–20.4)
Results
Neutrophil engraftment: Median 17.5 days
Platelet engraftment: Median 19 days
On-target edited alleles at 6 months: 67.4% (peripheral blood)
HbF fraction at 6 months (n=13): >60% of total hemoglobin
HbS fraction at 6 months: <40% of total hemoglobin
Severe VOE-free (>60 days post-last transfusion): 0 investigator-reported severe VOEs
Platelet engraftment: Median 19 days
On-target edited alleles at 6 months: 67.4% (peripheral blood)
HbF fraction at 6 months (n=13): >60% of total hemoglobin
HbS fraction at 6 months: <40% of total hemoglobin
Severe VOE-free (>60 days post-last transfusion): 0 investigator-reported severe VOEs
Adverse events
Main adverse events: All 31 patients had ≥1 AE; grade ≥3 in 87%; serious AEs in 39%. 1 patient died (idiopathic pneumonia syndrome — attributed to conditioning). AE profile consistent with myeloablative conditioning and autologous HSCT.
Conclusions
Risto-cel produced rapid engraftment, durable HbF expression, and near-complete elimination of HbS, with no investigator-reported severe VOEs after engraftment. Base editing offers a novel precision genome editing approach for SCD with a distinct mechanism from CRISPR nuclease-based therapies.
Key Limitations
Key Limitations: Single-arm study, no control group. Interim unplanned analysis. Short mean follow-up (6.6 months). Primary endpoint (12-consecutive-month VOE freedom) not yet evaluable in most patients. One treatment-related death. Grade ≥3 AEs in 87% reflect intensive conditioning. Small sample size (31 patients).
Clinical Context
Base editing (Beam Therapeutics) does not introduce double-strand DNA breaks, potentially offering a safer editing approach than nuclease-based CRISPR. Risto-cel joins exa-cel (Casgevy), reni-cel, and betibeglogene sparticulenvec in the emerging gene therapy landscape for hemoglobinopathies. These three NEJM publications in April 2026 represent simultaneous reporting of three distinct next-generation gene therapy approaches for SCD.
References