Reni-Cel, an Investigational AsCas12a Gene-Edited Cell Medicine, Led to Sustained Hemoglobin Normalization and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease Treated in the RUBY Trial

Abstract

Introduction

Sickle cell disease (SCD) complications, including vaso-occlusive events (VOEs), are reduced when fetal hemoglobin (HbF, α2γ2) is durably increased. Renizgamglogene autogedtemcel (reni-cel), an investigational gene-edited autologous hematopoietic stem cell therapy, is comprised of CD34⁺ cells edited at the γ-globin gene (HBG1/2) promoters with a highly efficient and specific, proprietary gene-editing nuclease, AsCas12a. These edits mimic naturally occurring variants of hereditary persistence of HbF. In preclinical studies, editing CD34⁺ cells from patients with SCD at this genomic region led to robust HbF production and significantly reduced sickling in erythroid lineage cells. The ongoing RUBY trial (NCT04853576) is a Phase I/II/III, multicenter, open label, single arm study evaluating safety, tolerability, and efficacy of reni-cel in patients with severe SCD.

Methods

Participants (pts) 12–50 years (yrs) of age who have severe SCD, defined as ≥2 severe VOEs/yr in the 2 yrs before consent, are eligible. Autologous CD34⁺ hematopoietic stem and progenitor cells are mobilized using plerixafor, collected, and edited at the HBG1/2 promoters. After myeloablative conditioning with busulfan, pts receive a single infusion of reni-cel (≥3 × 10⁶ CD34⁺ cells/kg) and are monitored for 24 months (mos).

Results

As of June 28, 2024, 21 pts received reni-cel and were a median (range) of 8.0 (0.6–24.1) mos post-reni-cel infusion; 7 pts had >1 yr follow-up. Median (range) days to neutrophil and platelet engraftment was 23.0 (15–29) and 24.5 (18–51) days, respectively (n=20). At Mo 6, mean (standard deviation [SD]) total hemoglobin (Hb) was 14.2 (2.0) g/dL (n=10) and HbF was 48.2% (3.4%; n=12). These levels were the same or higher through last follow-up. The % F-cell and mean HbF concentration/F-cell (MCH-F/F-cell) increased early. The MCH-F/F-cell ratio was >10 pg/F-cell through last follow-up. Hemolysis markers improved or normalized by Mo 6 and were generally maintained over time. No pts experienced VOEs post-infusion compared with a mean (SD) of 4.9 (2.8) severe VOEs/yr in the 2 yrs before enrollment (n=21). There were high levels of allelic editing at Mo 12 (mean [SD]: in peripheral blood nucleated cells [n=4], 80.9% [5.9%]; in bone marrow-derived CD34⁺ cells [n=3], 86.9% [4.1%]). The safety profile reflected myeloablative conditioning with busulfan.

Conclusions

Results with reni-cel treatment were promising, including reliable and prompt engraftment, early Hb normalization, and durable increases in HbF. The data also demonstrate improvement in hemolysis markers, sustained high levels of editing, resolution of VOEs, and a safety profile consistent with myeloablative conditioning with busulfan. These findings build on clinical evidence supporting continued investigation of reni-cel in the RUBY trial.

© American Society of Hematology (2024). Reused with permission.