KEY TAKEAWAYS
- Researchers examined exa-cel’s efficacy and safety in TDT and severe SCD patients.
- The study demonstrated the exa-cel treatment has lasting benefits for patients with TDT and severe SCD while maintaining a manageable safety profile.
Exagamglogene autotemcel (exa-cel) is a cellular therapy aimed at reactivating fetal hemoglobin (HbF) through non-viral, ex vivo CRISPR/Cas9 gene editing in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). Initial data from two crucial trials demonstrated that a single administration of exa-cel resulted in significant increases in HbF and total hemoglobin (Hb) levels, leading to the cessation of red blood cell (RBC) transfusions in patients (pts) with transfusion-dependent β-thalassemia (TDT) and relief from vaso-occlusive crises (VOCs) in pts with sickle cell disease (SCD). Researchers reported the efficacy and safety findings from the first 75 pts treated with exa-cel.
Post-pharmacokinetic-adjusted busulfan myeloablation and exa-cel infusion, pts aged 12-35 years were monitored for engraftment, total Hb, HbF, BCL11A edited alleles, transfusion requirements, VOCs (in SCD pts), and adverse events (AEs). Data are presented as mean values with ranges unless otherwise specified.
At the data cutoff, 44 pts with TDT (average age 21.3 years, range 12-35) and 31 pts with SCD (average age 22.5 years, range 12-34) had received exa-cel infusions, with follow-up durations of 12.3 months (range 1.2-37.2) and 9.6 months (range 2.0-32.3), respectively. Among TDT pts, 26 out of 44 (59.1%) had a β0/β0 genotype or a β0/β0-like genotype (e.g., β0/IVS-I-110 or IVS-I-110/IVS-I-110). In the two years before screening, TDT pts received an average of 36.0 units of RBC transfusions per year, while SCD pts experienced an average of 3.9 severe VOCs per year.
Following exa-cel infusion, all pts achieved engraftment of neutrophils and platelets. The median time to neutrophil and platelet engraftment was 29 and 43 days for TDT patients and 27 and 32 days for SCD patients, respectively.
In the TDT group, 42 out of 44 pts discontinued RBC transfusions, with durations of transfusion independence ranging from 0.8 to 36.2 months. The remaining two pts significantly reduced the transfusion volume by 75% and 89%. By the third month, there were notable increases in HbF and mean total Hb levels (exceeding 9 g/dL), which continued to rise, reaching over 11 g/dL and maintaining thereafter.
In the SCD cohort (n=31), all pts were free from severe VOCs after exa-cel infusion, with durations of relief ranging from 2.0 to 32.3 months. The mean proportion of HbF exceeded 20% by the third month, rose to approximately 40% by the fourth month, and remained stable thereafter. Mean total Hb levels exceeded 11 g/dL after the third month.
Patients with TDT and SCD with a follow-up of at least one year showed stability of edited BCL11A alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells. Additionally, two TDT pts experienced serious AEs (SAEs) related to exa-cel, with one previously reported case and a second patient showing delayed neutrophil engraftment and thrombocytopenia, both considered related to exa-cel and busulfan. All SAEs were resolved, and no SAEs were related to exa-cel in SCD pts. No deaths, discontinuations, or malignancies were reported.
Exa-cel infusion could eliminate transfusions in nearly all TDT pts and VOCs in all SCD pts. This was accompanied by clinically significant increases in HbF and total Hb levels, which were sustained over time. The stability of CRISPR/Cas9-edited BCL11A alleles in long-term HSCs suggested successful editing. The safety profile was usually consistent with busulfan myeloablation and autologous transplantation. These results suggest that exa-cel may become the first CRISPR/Cas9-based therapy offering a one-time functional cure for TDT and severe SCD.
Source: https://ebmt2023.abstractserver.com/program/#/details/presentations/1814
Clinical Trials: https://classic.clinicaltrials.gov/ct2/show/NCT03655678
https://classic.clinicaltrials.gov/ct2/show/NCT03745287
Locatelli, F., Frangoul, H., Corbacioglu, S., de la Fuente, J., Wall, D., Cappellini, M.D., de Montalembert, M., Kattamis, A., Lobitz, S., Rondelli, D., Sheth, S., Steinberg, M., Walters, M.C., Bobruff, Y., Simard, C., Song, Y., Zhang, L., Sharma, A., Imren, S., Hobbs, B., Grupp, S. GS02-09 EFFICACY AND SAFETY OF A SINGLE DOSE OF EXAGAMGLOGENE AUTOTEMCEL FOR TRANSFUSION-DEPENDENT Β-THALASSEMIA AND SEVERE SICKLE CELL DISEASE.
