NEW YORK – Investigators at the American Society of Hematology's annual meeting in San Diego this week reported data on gene therapies for sickle cell disease and transfusion-dependent beta-thalassemia, two rare and inherited blood disorders. Below are brief reports on data readouts from the conference.
Editas Medicine's renizgamglogene autogedtemcel
Most patients who have received Editas Medicine's investigational gene-editing treatment for severe sickle cell disease, renizgamglogene autogedtemcel, or reni-cel for short, haven't experienced any painful vaso-occlusive events (VOEs) through their most recent follow-up visit, researchers presented Monday.
Editas in October announced it was seeking a global development and commercialization partner or an out-licensing deal for reni-cel, formerly EDIT-301, which the company has referred to as its lead candidate. Instead, the company said it intends to focus resources on developing a pipeline of in vivo gene-edited therapies, including a preclinical candidate in sickle cell.
Reni-cel is an ex vivo treatment, in which patients' autologous CD34-positive hematopoietic stem and progenitor cells are edited outside of the body at the gamma globin genes HBG1 and HBG2 promoters, in an effort to promote production of fetal hemoglobin. The adult version of hemoglobin is abnormal in sickle cell.
Reni-cel is the company's only clinical-stage candidate and is in late-stage clinical testing for sickle cell and in a Phase I/II trial for transfusion-dependent beta thalassemia.
During a poster session at the conference, researchers from the Cleveland Clinic and other institutions presented updated data from the ongoing open-label Phase I/II/III RUBY trial, in which patients with severe sickle cell receive a single infusion of reni-cell.
As of the data cutoff date of Oct. 29, 28 patients had received reni-cel with a median follow-up of 9.5 months post-infusion. These patients had severe disease burden and had experienced, on average, 4.6 severe VOEs per year before treatment. Eleven patients had at least one year of follow-up data; the earliest treated patients had more than two years of data.
Twenty-seven of the 28 patients, or 96.4 percent, were free of VOEs through their most recent follow-up.
In 18 patients with at least six months of posttreatment data, investigators have observed increases in total hemoglobin, with average total hemoglobin increasing from 9.8 grams per deciliter at baseline to 13.8. Patients had rapid increases in fetal hemoglobin levels, which reached more than 40 percent of total hemoglobin by six months posttreatment.
Patients also sustained high levels of allelic editing in peripheral blood nucleated cells and bone marrow-derived CD34-positive cells, according to researchers.
Two serious adverse events possibly related to reni-cel treatment occurred. One patient had grade 3 eosinophilic gastroenteritis, which began 47 days after receiving reni-cel and which remains ongoing as of the data cutoff date. Researchers continue to investigate the cause of the issue, which is unclear.
The other patient experienced grade 4 acute respiratory distress syndrome, with onset 11 days after infusion, but which resolved 10 days later. The patient had a history of recurrent acute chest syndrome, mild obstructive pattern observed in pulmonary function tests, recent history of smoking or vaping, and granulocyte colony stimulating factor administration, which may be contributing factors.
There were no treatment-related adverse events that led to discontinuation of the study or death. The safety profile for reni-cell has been consistent with busulfan conditioning and autologous hematopoietic stem cell transplant, researchers said.
Vertex Pharmaceuticals' Casgevy
The CRISPR gene-editing treatment Casgevy (exagamglogene autotemcel) has led to durable transfusion independence for up to five years in nearly all patients with transfusion-dependent beta-thalassemia (TDT) treated in a Phase III trial, researchers reported Sunday.
Vertex Pharmaceuticals and CRISPR Therapeutics developed Casgevy as a treatment for sickle cell disease and TDT. It became the first CRISPR gene-editing treatment to reach the US market in late 2023 when it was approved for sickle cell, and the US Food and Drug Administration approved it for TDT soon after.
Casgevy is a one-time infusion that's created from patients' autologous CD34-positive hematopoietic stem and progenitor cells, which are extracted and then modified ex vivo. CRISPR-Cas9 is used to edit the BCL11A gene and reactivate fetal hemoglobin, the adult version of which is abnormal in patients with TDT.
In 53 of 54 patients, or 98.1 percent, treated in the open-label Phase I/II/III CLIMB THAL-111 trial and the long-term follow-up CLIMB-131 trial, patients achieved transfusion independence, meaning that they did not need red blood cell transfusions for at least one year. These patients initially stopped needing transfusions on average 1.1 months after receiving Casgevy.
The 54 patients included in this readout were followed for at least 16 months, and the median follow-up in the trial was 38.1 months, or more than three years.
The average duration of transfusion independence so far is 34.5 months, or nearly three years, with the earliest patient remaining transfusion independent at 64.1 months, or more than five years.
The one patient who has not achieved at least a year of transfusion independence initially stopped transfusions after 21.6 months, but experienced transient gastroenteritis leading to anemia and required a transfusion at 32.2 months. Since then, the patient has been transfusion independent for 8.2 months.
The clinical benefits were consistent for adults and adolescents across genotypes, including those with more severe genotypes, said Franco Locatelli, a professor of pediatrics at the Catholic University of the Sacred Heart in Rome and director of the pediatric hematology and oncology department at Bambino Gesù Hospital, during a presentation.
Investigators also observed stable increases in hemoglobin and fetal hemoglobin levels, as well as in the proportion of edited BCL11A alleles in peripheral blood nucleated cells. "These data provide support to the durability of the therapeutic benefit for the patients … supporting the hypothesis that transfusion independence for these patients is very likely to be sustained over time," indicating Casgevy may be a one-time, functional cure, Locatelli said.
Separately, in a poster presented Monday, researchers reported that sickle cell patients treated in the open-label Phase I/II/III CLIMB SCD-121 trial and in the CLIMB-131 trial experienced sustained reduction in painful vaso-occlusive crises (VOCs). The median follow-up was 33.2 months, or nearly three years, with the longest follow-up at more than five years.
Thirty-nine of 42 patients, or 92.9 percent, with at least 16 months of follow-up were free of VOCs for at least a year, and the average duration patients have remained VOC-free is 2.5 years, ranging from 12.9 months to 59.6 months. For the three patients who did not achieve this outcome, their rate of hospitalizations for VOCs reduced by 91 percent, 71 percent, and 100 percent.
Outside the US, Casgevy is approved for sickle cell disease and TDT in the EU, Great Britain, Canada, Switzerland, Bahrain, and Saudi Arabia, according to Vertex. The company on Sunday said it is planning regulatory submissions in the United Arab Emirates and Kuwait and working with authorities in various countries to secure reimbursement and access for patients.
Beam Therapeutics' BEAM-101
Beam Therapeutics' investigational gene-editing candidate for sickle cell disease has shown initial promising safety and efficacy data, with seven patients who have received the therapy so far achieving robust increases in hemoglobin after treatment, researchers reported Sunday.
BEAM-101 uses base-editing, a type of gene editing that doesn't require double-stranded breaks, to modify the promoter regions of the HBG1/2 genes. It aims to block the binding of BCL11A, which typically represses fetal hemoglobin, thus allowing production of fetal hemoglobin. The adult version of hemoglobin is the protein that's abnormal in sickle cell disease.
The treatment involves extracting CD34-positive hematopoietic stem and progenitor cells from the patient that are edited ex vivo and then infused back into the patient.
Researchers on Sunday reported initial results from the open-label Phase I/II BEACON trial, in which they are investigating a single dose of BEAM-101 in patients with sickle cell disease and a history of severe vaso-occlusive crises (VOCs). More than 35 patients have been enrolled into the trial, 11 of whom have received the gene therapy, according to Beam.
As of the data cutoff in October, seven patients had been treated and monitored for at least one month post-infusion. The earliest treated patient had 11 months of follow-up data.
So far, no patients have experienced VOCs post-engraftment, said Matthew Heeney, director of the sickle cell program at Dana-Farber/Boston Children's Cancer and Blood Disorders Center in Boston, during a presentation.
Patients have experienced "rapid and robust" induction of fetal hemoglobin, with corresponding reductions in sickled hemoglobin, he added. By one month posttreatment, all patients achieved endogenous fetal hemoglobin levels of at least 60 percent and at least a 40 percent reduction in sickled hemoglobin.
Investigators also observed high rates of on-target gene editing in peripheral blood after treatment.
The safety profile of BEAM-101 has been consistent with busulfan, a conditioning chemotherapy that patients receive in the study, and autologous hematopoietic stem cell transplantation.
There have been no serious adverse events related to BEAM-101. The most common serious adverse events, unrelated to BEAM-101, include febrile neutropenia, anemia, and headache.
Heeney reported additional details on a patient death that Beam disclosed last month, in which a 21-year-old woman enrolled in the study died due to respiratory failure four months after infusion. Her death was determined likely related to busulfan conditioning, which has known pulmonary toxicity, and unrelated to BEAM-101.
This patient had an "uneventful" treatment process through conditioning, dosing, and engraftment, Heeney said. However, two months after infusion, she was admitted with a febrile gastrointestinal illness with vomiting. She subsequently developed respiratory symptoms and progressive respiratory distress.
The patient had a history of sickle cell disease with acute chest syndrome, obstructive sleep apnea, and e-cigarette use. E-cigarette use may have been a contributing factor to her death, researchers said.
In response to an audience question about whether investigators would screen for e-cigarette use moving forward, Heeney said that while there's not an exclusion criterion related to this within the clinical trial, his sense is that physicians are watching this area and asking patients about e-cigarette use before transplantation.
Bluebird Bio's Zynteglo
Patients treated with Bluebird Bio's Zynteglo (betibeglogene autotemcel), a gene therapy for transfusion-dependent beta-thalassemia (TDT), within Phase I/II and Phase III trials have sustained long-term benefits, according to updated long-term follow-up data of up to 10 years that researchers reported Saturday.
The US Food and Drug Administration approved Zynteglo as a treatment for adults and children with TDT in 2022 based on patients no longer needing red blood cell transfusions following the gene therapy. Zynteglo, a lentiviral vector-based gene therapy that's created ex vivo using patients' own CD34-positive hematopoietic stem and progenitor cells, is designed to deliver a functional copy of a modified beta-globin gene to enable production of HbAT87Q.
HbAT87Q is a type of anti-sickling hemoglobin that functions similarly to normal adult hemoglobin, the protein that's abnormal in patients with TDT, according to Bluebird.
Researchers from the University of Pennsylvania's Perelman School of Medicine presented results at a poster session demonstrating durable transfusion independence and nearly normal or normal hemoglobin levels among patients treated in clinical trials.
The analysis comprises adult and pediatric patients with TDT from four clinical trials, two Phase I/II trials and two Phase III trials, who enrolled into a long-term follow-up study, known as LTF-303. As of February 2024, there were 63 patients who had received Zynteglo within a clinical trial and who had been followed for a median 71.2 months, or nearly six years.
Two participants had at least a decade of follow-up data and 51 patients, or about 80 percent, had at least five years of data. One patient withdrew consent 39 months after receiving the gene therapy due to personal reasons, researchers said.
Patients' HbAT87Q levels were stable by six months post-infusion and were durable through follow-up across the clinical studies. However, HbAT87Q levels tended to be higher among patients treated in Phase III trials, compared to Phase I/II trials, which researchers attributed to new drug product manufacturing processes that are similar to the commercial process.
Fifteen of 22 patients, or 68.2 percent, achieved transfusion independence in the Phase I/II trials, defined as at least a year without red blood cell transfusions and a weighted average hemoglobin of at least 9 grams per deciliter. In Phase III trials, 37 of 41 patients, or 90.2 percent, achieved that outcome.
Of these 52 patients who achieved transfusion independence, all but one patient sustained that independence through their last follow-up visit. That one patient, who is no longer transfusion independent as of six years post-infusion, was treated within a Phase I/II trial and later diagnosed with HIV complicated by gastrointestinal infection and bleeding.
In the Phase III trials, 28 of the 37 patients who achieved transfusion independence, or 75.7 percent, were able to discontinue iron-chelation therapy, a type of therapy that aims to prevent iron overload related to red blood cell transfusions. How to manage the use of iron removal therapy after gene therapy was at the treating physician's discretion.
These data provide "additional confidence in that the transformational outcomes observed in parent studies are sustained over time," Alexis Thompson, chief of the hematology division at Children's Hospital of Philadelphia and co-first author on the poster, said in a news release Bluebird issued during the conference. "These long-term data demonstrate beti-cel's continued positive impact on iron management outcomes over time, which can help inform treatment decisions," she added.