RUBY: Promising data for first AsCas12a gene-editing therapy in sickle cell disease

Renizgamglogene autogedtemcel (reni-cel) established a swift and durable normalisation in haemoglobin (Hb) and improved haemolysis markers in participants with severe sickle cell disease, supporting further evaluation of this first AsCas12a gene-edited cell therapy.

Reni-cel is a gene-edited stem cell therapy of CD34+ cells, edited at the γ-globin gene (HBG1 and HBG2) promoters. The reasoning for this therapy is that these edits will induce the production of foetal Hb (HbF), which is an important factor in reducing sickle cell disease. The phase 1/2 RUBY trial (NCT04853576) exposed 18 participants with severe sickle cell disease to a single infusion of reni-cel. Dr Rabi Hanna (Cleveland Clinic, OH, USA) shared findings from an interim analysis of this study [1].

After a mean post-infusion follow-up of 6.2 months, none of the participants had experienced a vaso-occlusive event (VOE), compared with a mean of 5.2 severe VOEs per year in the 2 years before the reni-cel infusion. The mean Hb levels increased rapidly and were sustained at 14.4 g/dL from month 5. Dr Hanna added that the mean percentage of foetal Hb was 48.0% at month 4. Likewise, F-cells and mean HbF concentration/F-cell increased quickly and these changes were maintained over time. Key markers of haemolysis indicated improvement and/or normalisation in all participants treated with reni-cel.

The safety profile of reni-cel was comparable with myeloablative conditioning with busulfan and there were no adverse events directly related to reni-cel.

Reni-cel induced a swift and sustained normalisation of Hb, an early increase in foetal Hb, and improvements in key markers of haemolysis. Combining the VOE-free status of the participants after infusion and the favourable safety profile, the results suggest that this promising gene-editing therapy should be further investigated in larger cohorts of patients with sickle cell disease.

1. Hanna R, et al. Reni-cel, the first AsCas12a gene-edited cell therapy, led to hemoglobin normalization and increased fetal hemoglobin in severe sickle cell disease patients in an interim analysis of the RUBY trial. S285, EHA congress 2024, 13–16 June, Madrid, Spain.

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Posted on 12 August 2024