Gene therapy for sickle cell disease shows curative potential
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Three patients with sickle cell disease who received the investigational gene therapy ARU-1801 achieved and maintained normal hemoglobin levels, according to early results of a phase 1/phase 2 trial.
The findings, presented during the virtual American Society of Gene & Cell Therapy Annual Meeting, showed successful engraftment of the autologous gene therapy after reduced-intensity conditioning with melphalan.
ARU-1801 (Aruvant Sciences), given as a one-time IV infusion, aims to increase functioning of red blood cells by inserting a modified fetal hemoglobin gene into the patient’s CD34-positive hematopoietic stem cells through a lentiviral vector.
The therapy delivers gene-encoding fetal hemoglobin that has been modified to optimize oxygen-carrying capacity and anti-sickling properties, according to the manufacturer.
Curative options exist for patients with sickle cell disease, including allogeneic stem cell transplant, according to Will Chou, MD, CEO of Aruvant Sciences. However, finding a suitable donor for transplant and patient reluctance to undergo the procedure remain challenges.
“Many patients with sickle cell disease are scared to get an allogeneic stem cell transplant,” Chou said, because of the high dose of chemotherapy required to achieve engraftment and risk for graft-versus-host disease.
“Our gene therapy, like all gene therapies, helps solve these problems because there is no donor needed and no possibility of graft-versus-host disease because it is an autologous product,” he said.
Further, “the potency of our vector allows it to engraft with less [preconditioning] chemotherapy than other gene therapies that are currently being researched,” Chou added.
ARU-1801 with reduced-intensity conditioning offers “potentially curative levels of efficacy,” Chou said.
During the meeting, Punam Malik, MD, director of the Cincinnati Comprehensive Sickle Cell Center and program leader of the hematology and gene therapy program at Cincinnati Children's Hospital Medical Center, presented clinical data on the safety and efficacy of ARU-1801 among the first three patients with severe sickle cell disease treated as part of the MOMENTUM trial.
Patients underwent collection of peripheral blood stem cells to isolate CD34-positive stem cells followed by ex vivo transduction of the cells.
Each patient received reduced-intensity conditioning with 140 mg/m2 melphalan to promote engraftment before receiving an infusion of ARU-1801.
The first patient — a woman aged 34 years — and the second patient, a man aged 24 years, received treatment in an academic setting.
The 3-day gene therapy manufacturing process was amended for the third patient — a woman aged 19 years — and included refinements to the peripheral blood collection method, the vector and the transduction process.
“We made a more pure vector that transduces more efficiently,” Chou told Healio.
The first two patients had at least 36 months of follow-up after infusion, whereas the third patient has been followed for at least 12 months.
Results showed a favorable safety profile “as expected,” Chou said. This included cytopenia of at least a week’s duration among all three patients.
“The adverse events we are seeing were associated with the melphalan reduced-intensity conditioning chemotherapy,” Chou told Healio. “It’s a toxicity profile that is quite familiar to transplant physicians who use this dose of melphalan.”
No adverse events related to the ARU-1801 infusion occurred as of the data cutoff date. Additionally, researchers observed no evidence of clonal dominance, Chou said. This issue has gained attention lately as a possible cause of secondary malignancies after gene therapy, he added.
“We monitor for anything that could become a cancer clone, and we have seen none so far,” Chou said.
All three patients achieved neutrophil engraftment within 7 to 9 days and platelet engraftment within 6 to 12 days after infusion, and all maintained engraftment as of last follow-up.
The first patient achieved stable expression of ARU-1801-derived HbFG16D (20%) and total anti-sickling globin (31%), which includes endogenous HbF, HbA2 and HbFG16D. Thus, the patient achieved the 30% threshold of total anti-sickling globin required for complete sickle cell disease symptom resolution at 12 months after infusion, which the patient maintained at 36 months.
The second patient experienced rapid clearance of melphalan during conditioning therapy that resulted in decreased engraftment. As a result, the patient had lower Hb levels and 22% anti-sickling globin expression. The patient remained below the 30% threshold for symptom resolution at 36 months.
The third patient — treated with the refined manufacturing process — had the best response to therapy, with 41% anti-sickling globin expression and 27% HbFG16D at month 10 after infusion.
Treatment with ARU-1801 led to large declines in vaso-occlusive events (VOEs). The first patient had a 93% reduction in total VOEs, decreasing from 41 in the 2 years before infusion to three in the 2 years after. The patient also had an 81% reduction in days hospitalized due to VOEs.
The second patient had an 85% decrease in VOEs, from 20 to three. The third patient, who had 12 VOEs in the 2 years before receiving ARU-1801, had yet to experience a VOE in the 12 months after treatment. Neither patient had required hospitalization due to a VOE as of last follow-up.
These early results demonstrated that gene therapy with reduced-intensity conditioning can achieve long-term engraftment and expression of fetal hemoglobin levels high enough to resolve symptoms, Chou told Healio.
Reports questioning the safety of gene therapies present valid concerns for patients considering participation in gene therapy trials, he said.
“Because of these concerns,” Chou added, “I believe there is a market for products like ours that can provide long-term engraftment and durable efficacy with a more favorable toxicity profile.”
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