- In patients with sickle cell disease treated with ristoglozin autogetamcel, the average level of anti-sickle fetal hemoglobin was above 60%, while the average durable reduction in corresponding sickle hemoglobin was less than 40%.
- The average time for neutrophil and platelet engraftment was relatively short – 17.5 days and 19 days, respectively.
- No patients were reported to have serious vaso-occlusive crisis after engraftment by the investigators.
Treatment with the investigational base-editing gene therapy ristologin autogetamcel (Risto-CL) showed promise in patients with sickle cell disease, according to an interim analysis of the phase I/II BEACON study.
Neutrophil and platelet engraftment occurred over a median of 17.5 and 19 days, respectively, and all 31 patients had at least one adverse event, with 27 experiencing a grade 3 or higher adverse event and 12 having a serious adverse event (none considered related to Risto-Cell), Matthew M. Haney, MD, of Boston Children’s Cancer and Blood Disorders Center, and colleagues reported.
The average fraction of on-target edited alleles in peripheral blood was 67.4%, the average anti-sickle fetal hemoglobin (HbF) as a fraction of total hemoglobin was more than 60%, and sickle hemoglobin (HbS) as a fraction of total hemoglobin was less than 40% at 6 months, and these levels were maintained during follow-up, they wrote. New England Journal of Medicine.
The final primary efficacy endpoint of the study is freedom from severe vaso-occlusive crisis for at least 12 consecutive months, starting 60 days after the last red-cell transfusion, as decided by the Endpoint Adjudication Committee. In this interim analysis, no patients had serious vaso-occlusive crisis after transplantation as reported by the investigators.
“To some extent, more non-sickling Hb is better, or actually the opposite, less sickling Hb is better,” Heaney explained. Medpage Today.
“Sickle syndrome – which is usually asymptomatic under normal physiological conditions – consists of approximately 55-60% HbA (hemoglobin A, the primary type of adult hemoglobin) and 40-45% HbS,” he explained. “We expect about 60% HbF and 40% HbS to be the same. Some people may have concerns about too high HbF, but naturally occurring HPFH (hereditary persistence of fetal hemoglobin) with very high HbF levels does not appear to be harmful.”
Regarding the rapid uptake reported in the study, researchers said it has the potential to “reduce the length of hospitalization, limit transfusions, and accelerate recovery from conditioning-related complications such as infection or mucositis, thereby increasing safety and reducing the treatment burden on patients, families, and health care facilities.”
As described by Heaney and colleagues, unlike other gene therapy strategies, Risto-Cell offers precise editing. HBG1 And HBG2 Promoter regions prevent BCL11A binding and promote expression of anti-sickle fetal hemoglobin.
“This targeted approach preserves overall BCL11A expression, avoiding disruption of its broad biological functions,” they explain.
Gene-editing strategies are designed to directly address the underlying genetic mutation responsible for the disease or to induce the production of fetal hemoglobin.
This approach was supported by the FDA with the approval of axagammagglutinin autotemcel (Axa-Cell; CasJV) – a CRISPR/Cas9 gene-edited therapy – for use in patients 12 years of age and older with sickle cell disease. transfusion-dependent beta thalassemia.
Overall, the results of BEACON and the studies evaluating Renizhemoglobin autogenomecell (Rennie-Cell) confirmed the role of gene editing “as a potentially curative treatment of hemoglobinopathies,” wrote Franco Locatelli, MD, PhD, of the IRCCS Bambino Gesù Children’s Hospital in Rome. with editorial.
are evaluated in the study Renée-cell in sickle cell diseaseTreatment normalized total hemoglobin levels and increased the percentage of fetal hemoglobin, with no vaso-occlusive events in 27 of 28 patients after infusion.
Locatelli said Beacon’s results — while preliminary — “may point toward a therapeutic option for patients in the future.” However, in the case of Renée-Cell, its sponsor has reevaluated the company’s clinical development priorities and decided stop gene therapy.
“Thus, although the reported data (in the Renée-cell study) are remarkable with respect to safety and efficacy, the decision to end research on Renée-cell eliminates a potential option for patients: these two studies therefore represent a kind of Pyrrhic victory,” he said.
Locatelli explained that ex vivo gene therapy is resource-intensive and unsuitable for treating large numbers of patients in countries with limited resources, where the majority of patients with sickle cell disease and transfusion-dependent beta thalassemia live.
They wrote, “Scientists and physicians working in the field of hemoglobinopathies have an ethical duty to invest energy in identifying or validating strategies capable of offering curative gene-therapy options in a broader perspective.” “Although in vivo gene-editing approaches are currently far from the patient’s bedside, their systemic delivery may one day be deployed to address this need.”
Phase I/II Beacon Study Enrolled patients aged 12 to 35 years with sickle cell disease who had experienced at least four severe vaso-occlusive crises in the 2 years prior to enrollment. The mean age was 22.8, 52% were male, and 81% were black.
After myeloablative conditioning with administration of busulfan, patients received a single infusion of Risto-Cell. Patients were followed for an average of 6.6 months.
One patient died from idiopathic pneumonia syndrome—”a known noninfectious inflammatory lung injury that can occur after (hematopoietic stem and progenitor cell) transplantation in the context of a high-dose conditioning regimen such as busulfan,” Heaney and colleagues noted. No patients had engraftment failure or cancer.
They acknowledged that the current analysis was limited due to the short period of follow-up.
