Background
Phase 1–2, multicenter, open-label, single-group study (EdiThal trial). 9 patients ages 18–35 with transfusion-dependent beta-thalassemia (TD-TDT): 4 with severe beta/beta-0 or similar, 5 with non-beta/beta-0 genotypes. Reni-cel uses CRISPR-Cas12a editing of BCL11A binding sites in HBG1/HBG2 promoters to reactivate fetal hemoglobin, eliminating transfusion dependence in beta-thalassemia. Myeloablative busulfan conditioning before reni-cel infusion. Study terminated early by sponsor (business reassessment).
Interventions and follow up
Arm A: Single infusion of reni-cel after myeloablative busulfan conditioning (all patients; no comparator)
Primary endpoint: Neutrophil engraftment by day 42; safety
mFollow up: Median 17.5 months (range 3.8–23.4)
Primary endpoint: Neutrophil engraftment by day 42; safety
mFollow up: Median 17.5 months (range 3.8–23.4)
Results
Neutrophil engraftment: 100% (all 9 patients) by day 42
Transfusion independence: 100% at last follow-up visit; all 6 evaluable at ≥12 months were transfusion-independent
Total hemoglobin (months 6–18): Mean >12 g/dL
Fetal hemoglobin (months 6–18): Mean >11 g/dL
Transfusion independence: 100% at last follow-up visit; all 6 evaluable at ≥12 months were transfusion-independent
Total hemoglobin (months 6–18): Mean >12 g/dL
Fetal hemoglobin (months 6–18): Mean >11 g/dL
Adverse events
Main adverse events: 69 grade 3–4 AEs (onset or worsening after reni-cel) in 9 patients. 6 serious AEs in 4 patients (infections, pyrexia, pneumonitis). 1 patient had decreased lymphocyte counts attributed to reni-cel. AE profile generally consistent with myeloablative conditioning.
Conclusions
All 9 patients with TD-TDT achieved transfusion independence with reni-cel, with sustained hemoglobin and HbF levels. Despite small numbers and early termination, CRISPR-Cas12a HbF induction produced durable transfusion independence in beta-thalassemia.
Key Limitations
Key Limitations: Very small sample size (9 patients). Study terminated early by sponsor for business reasons, not safety. Short to moderate follow-up. Unplanned analysis. No control group. Lymphocyte decrease potentially attributed to reni-cel — mechanism unclear. Direct comparison with exa-cel (Casgevy, approved for TD-TDT) not available.
Clinical Context
Exa-cel (Casgevy) and betibeglogene sparticulenvec (Zynteglo) are FDA-approved for TD-TDT. The reni-cel EdiThal data are published simultaneously with reni-cel SCD data (RUBY) and risto-cel SCD data (BEACON) in April 2026 NEJM, representing a landmark series of gene editing approaches for hemoglobinopathies. Despite the program termination, this NEJM publication validates the Cas12a approach for beta-thalassemia.
References