Base Editing of HBG1 and HBG2 Promoters for Sickle Cell Disease

Clinical Snapshot

Key Findings

• P Value: Not reported for primary endpoint

• Effect Size: Mean HbF >60% of total hemoglobin, HbS <40% at 6 months

• Primary Outcome: No severe vaso-occlusive crises occurred >60 days after last red-cell transfusion

• Nnt Or Sensitivity: 67.4% mean on-target editing efficiency in peripheral blood at 6 months

• Confidence Interval: Not reported

Clinical Application

Limited feasibility in Australia - requires specialised gene therapy centres, complex manufacturing, and significant healthcare resources Not currently TGA-approved; would require compassionate access. Limited relevance given small Australian sickle cell population, but important for Indigenous communities and recent migrants from endemic regions Australian patients aged 12-35 years with severe sickle cell disease (≥4 annual crises) who have failed standard therapies

Abstract

BACKGROUND: Sickle cell disease is characterized by chronic hemolytic anemia and recurrent severe vaso-occlusive crises. Ristoglogene autogetemcel (risto-cel) includes autologous CD34+ hematopoietic stem and progenitor cells that have been base-edited to target the HBG1 and HBG2 promoters and inhibit BCL11A binding without altering BCL11A expression, yielding a switch in hemoglobin production from sickle hemoglobin (HbS) to antisickling fetal hemoglobin (HbF). METHODS: In this phase 1-2 study, we enrolled patients 12 to 35 years of age with sickle cell disease who had had at least four severe vaso-occlusive crises in the 2 years before enrollment. After myeloablative conditioning with pharmacokinetically guided administration of busulfan, patients received a single infusion of risto-cel (at a dose of ≥3.0×106 viable CD34+ cells per kilogram of body weight). The primary efficacy end point was freedom from severe vaso-occlusive crises for 12 consecutive months, starting later than 60 days after the last red-cell transfusion. This interim analysis was unplanned; here, we describe safety, editing, engraftment, and hemoglobin production and the number of severe vaso-occlusive crises starting later than 60 days after the last red-cell transfusion. RESULTS: A total of 31 patients received risto-cel and were followed for a mean of 6.6 months (range, 0.3 to 20.4). A median of one cycle (range, one to five) was required for stem-cell collection. Neutrophil engraftment occurred at a median of 17.5 days, and platelet engraftment at a median of 19 days. One patient died from idiopathic pneumonia syndrome. All 31 patients had at least one adverse event, 27 (87%) had an adverse event of grade 3 or higher, and 12 (39%) had a serious adverse event. At 6 months, the mean fraction of on-target edited alleles in peripheral blood was 67.4%, the mean HbF as a fraction of total hemoglobin was more than 60%, and the HbS as a fraction of total hemoglobin was less than 40% (among 13 patients); these levels were maintained throughout follow-up. No investigator-reported severe vaso-occlusive crises occurred later than 60 days after the last red-cell transfusion. CONCLUSIONS: Treatment with risto-cel was followed by rapid engraftment and durable expression of HbF and reduction in HbS. These data support further investigation of risto-cel to treat sickle cell disease. (Funded by Beam Therapeutics; BEACON ClinicalTrials.gov number, NCT05456880.).

References

1. 1.Gupta, A. O., Sharma, A., Frangoul, H., Kanter, J., Mapara, M. Y., Dalal, J., Alavi, A., Jaroscak, J. J., Ayala, E., DiPersio, J. F., Ziga, E. D., Eapen, M., Rifkin-Zenenberg, S., Minella, A. C., Chen, Y., Chesler, S., Ambati, S., Bowman, T. S., Habtemariam, B., Joseney-Antoine, M., Chockalingam, P. S., Lin, L., Goyal, S., Simon, A., Thompson, A. A., & Heeney, M. M. (2026). Base editing of HBG1 and HBG2 promoters for sickle cell disease. *New England Journal of Medicine*. https://doi.org/10.1056/NEJMoa2504835