Risto-cel Gene Therapy Shows High Fetal Hemoglobin and Elimination of Severe VOCs in Sickle Cell Disease: NEJM
USA: In an interim analysis of the phase I/II BEACON study, treatment with ristoglogene autogetemcel (risto-cel) demonstrated encouraging outcomes in patients with sickle cell disease.
Participants achieved mean fetal hemoglobin levels exceeding 60%, along with a sustained reduction in sickle hemoglobin to below 40%. Hematologic recovery was prompt, with median neutrophil and platelet engraftment occurring at 17.5 and 19 days, respectively. Notably, no investigator-reported severe vaso-occlusive crises were observed after engraftment.
The findings, published in the New England Journal of Medicine, come from a study led by Dr. Ashish O. Gupta from the University of Minnesota and colleagues. The trial evaluated a novel gene-editing therapy designed to address the underlying pathology of sickle cell disease, a condition marked by chronic hemolytic anemia and recurrent painful vaso-occlusive episodes.
Risto-cel is an autologous cell therapy that uses base editing to modify the promoters of the HBG1 and HBG2 genes. This approach disrupts the binding of the BCL11A protein, a key regulator that suppresses fetal hemoglobin production. By doing so, the therapy reactivates fetal hemoglobin (HbF), which has anti-sickling properties, thereby reducing the proportion of sickle hemoglobin (HbS) without directly altering BCL11A expression.
The phase 1–2 study enrolled patients aged 12 to 35 years who had experienced at least four severe vaso-occlusive crises in the two years before participation. Following myeloablative conditioning with busulfan, patients received a single infusion of risto-cel, consisting of gene-edited CD34+ hematopoietic stem and progenitor cells. The primary efficacy endpoint was the absence of severe vaso-occlusive crises for a continuous 12-month period, beginning at least 60 days after the last red blood cell transfusion.
A total of 31 patients were treated and followed for an average of 6.6 months. Stem-cell collection typically requires only one cycle. Engraftment occurred rapidly, with neutrophil recovery at a median of 17.5 days and platelet recovery at 19 days, indicating effective hematopoietic reconstitution.
Key Findings:
- At six months, the mean proportion of on-target edited alleles in peripheral blood exceeded 67%.
- Fetal hemoglobin levels increased substantially, accounting for more than 60% of total hemoglobin.
- Sickle hemoglobin levels declined to below 40% of total hemoglobin.
- These hematologic improvements were maintained throughout follow-up, indicating sustained therapeutic effect.
- No severe vaso-occlusive crises were reported after the early post-treatment phase.
- All patients experienced at least one adverse event during the study period.
- A majority of participants reported grade 3 or higher adverse events.
- Serious adverse events occurred in nearly 40% of patients.
- One death was reported, attributed to idiopathic pneumonia syndrome.
Overall, the interim results indicate that base editing of HBG1 and HBG2 promoters using risto-cel can achieve rapid engraftment and sustained hemoglobin switching, offering a promising therapeutic strategy for sickle cell disease. The authors emphasize that further studies with longer follow-up are needed to confirm long-term efficacy and safety.
Reference:
DOI: 10.1056/NEJMoa2504835
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