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According to new research presented at the 2024 Annual European Hematology Association (EHA) Congress, Vertex and Editas continue to provide positive results for patients with transfusion-dependent beta thalassemia (TDT) or severe sickle cell disease (SCD). Vertex announced encouraging long-term results for CASGEVY, the only FDA-approved CRISPR-based gene-editing treatment (exagamglogene autotemcel [exa-cel]), with the longest follow-up period currently exceeding five years. Reni-cel, a CRISPR gene-edited cell therapy for TDT and SCD, was shown to be safe and effective in clinical trials by Editas (previously known as EDIT-301).

CASGEVY: Steady as she goes

The ongoing post-approval global trial for CASGEVY, an ex vivo CRISPR/Cas9 gene-edited cell therapy that is non-viral and available to eligible patients with TDT or SCD, demonstrates that the treatment has transformative, long-term effects on these patients. These findings are based on data from over a hundred patients (46 SCD; 56 TDT) who received CASGEVY, which involves editing a patient’s own hematopoietic stem and progenitor cells at the erythroid-specific enhancer region of the BCL11A gene using a precise DNA double-strand break.

The safety profile of exa-cel was found to be mostly in line with autologous hematopoietic stem cell transplantation and myeloablative conditioning with busulfan. A successful editing of the long-term hematopoietic stem cells (HSCs) was indicated by the stable levels of edited BCL11A alleles in bone marrow and peripheral blood over time in both SCD and TDT patients. After exa-cel infusion, all patients who received CASGEVY showed engraftment of platelets and neutrophils, indicative of HSCs capable of generating a hematopoietic repertoire.

The effectiveness findings for CASGEVY align with the previously reported analyses of primary and important secondary endpoints from these exa-cel studies. The findings consistently demonstrate substantial clinical improvement, along with sustained and consistent levels of fetal hemoglobin (HbF). In CASGEVY-treated SCD patients, 92.3% (36 out of 39) and 97.4% (38 out of 39) of those who had at least 16 months of follow-up did not experience vaso-occlusive crises (VOCs) and hospitalizations related to VOCs for at least 12 consecutive months (VF12), respectively. These findings align with the previously reported data on the main objective. The average duration of VOC-free was 27.9 months, with a maximum of 54.8 months.

Out of the evaluable patients in TDT 49/52 (94.2%), those who were followed up for at least 16 months, were able to go without transfusions for a minimum of 12 consecutive months. Their average weighted hemoglobin (Hb) level was at least 9 g/dL (TI12), which aligns with the primary endpoint data reported earlier. The average length of time during which transfusion independence was maintained was 31.0 months, with a maximum duration of 59.4 months. All TDT patients who received treatment for a minimum of 16 months have not required any further blood transfusions. Two of the three TDT patients who did not achieve TI12 in the initial clinical trial, CLIMB-111, achieved TI12 in the long-term follow-up study, CLIMB-131, and have been transfusion independent for over one year. The third TDT patient has been transfusion-free for 3.4 months.

Editas’ reni-cel: small but mighty 

Editas Medicine also presented new safety and efficacy data for reni-cel in the Phase I/II/III RUBY trial for patients with sickle cell disease (SCD) and the Phase I/II EdiTHAL trial for patients with transfusion-dependent thalassemia (TDT) at the 2024 EHA Congress. Reni-cel differs from CASGEVY in that it employs a different RNA-guided editor, making it the first experimental Cas12a gene-edited cell therapy medicine. It also has a different genetic target (the HBG1/2 promoter) than CASGEVY, which uses Cas9 to target the BCL11A enhancer.

There have been no reported side effects in the RUBY trial, and reni-cel’s safety profile in SCD patients is similar to that of myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplantation. Patients who received reni-cel treatment remained VOE-free for up to 22.8 months and had total Hb levels that exceeded CASGEVY, with a mean within the normal range of >14 g/dL and rapid and sustained improvements in HbF levels of well over 40%.

All seven patients who received reni-cel in the EdiTHAL study reported few side effects, and the drug’s safety profile is comparable to that of myeloablative conditioning with busulfan and autologous hematopoietic stem cell transplant. Following reni-cel treatment, all EdiTHAL patients experienced an early and significant increase in total Hb and HbF, and they remained transfusion-free for 4.1 to 12.8 months at the final follow-up.

A third (genetic medicine) musketeer?

If Editas Medicine’s reni-cel continues to demonstrate advancement, there is a potential for the emergence of a third genetic medicine for SCD and TDT, which would join Vertex’s CASGEVY and Bluebird Bio’s LYFGENIA (lovotibeglogene autotemcel). LYFGENIA operates by genetically altering a patient’s blood stem cells to generate a hemoglobin known as HbAT87Q. This hemoglobin closely resembles the normal hemoglobin A (HbA) present in healthy adults, and red blood cells containing HbAT87Q have a lower risk of sickling and blocking blood flow. Bluebird Bio’s gene-edited cell therapy is slightly different from CASGEVY and reni-cel in that it uses a lentiviral vector (gene delivery vehicle) for genetic modification and does not employ CRISPR.

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