Novel cell therapy ‘potentially life changing’ for people with sickle cell disease
Key takeaways:
- A base-edited cell therapy increased fetal hemoglobin and reduced sickle hemoglobin.
- No patients who received treatment experienced vaso-occlusive crises.
SAN DIEGO — An investigational cell therapy reduced sickle hemoglobin and increased fetal and total hemoglobin for certain patients with sickle cell disease, according to results presented at ASH Annual Meeting and Exposition.
The phase 1/phase 2 BEACON study evaluated treatment with BEAM-101 (Beam Therapeutics), which consists of autologous CD34-positive hematopoietic stem and progenitor cells base-edited to increase fetal hemoglobin production. Fetal hemoglobin has an anti-sickling effect.
“I’m pleased,” Matthew M. Heeney, MD, associate chief of hematology and director of the sickle cell program at Boston Children’s Hospital, as well as associate professor at Harvard Medical School, told Healio. “We had the first patient in the trial and have treated two more since. They’ve done amazingly well. This transformative approach is potentially life changing for patients who bear a particularly high burden in this disease.”
Background and methods
Previous trials showed knocking out BCL11A transcriptional repressor binding sites with CRISPR increased fetal hemoglobin to about 40%, Heeney said.
Researchers discovered in preclinical research that base-edited autologous CD34-positive hematopoietic stem and progenitor cells increased fetal hemoglobin more than 60% and decreased sickle hemoglobin to less than 40%.
“Base editing is a novel form of gene therapy. It’s quite exciting,” Heeney said. “It has some potential advantages over conventional endonuclease gene editing with CRISPR localizing, the main one being it’s gentler on the hematopoietic stem cells ex vivo. The other advantage of base editing is there’s no double-stranded DNA cuts. Even though there’s no reported issues of translocations or other issues, double-stranded DNA cuts from Cas9 cuts can increase DNA response or DNA repair pathways, and all that seems to potentially make things a little rougher on the hematopoietic stem cell.”
BEACON — a single-arm, open-label study — included adults aged 18 to 35 years with sickle cell disease who had at least four severe vaso-occlusive crises in the 2 years prior.
Participants received myeloablative conditioning with pharmacokinetically adjusted busulfan. They then received a single infusion of BEAM-101 ( 3 × 106 viable CD34-positive cells/kg).
As of Dec. 2, researchers had screened and enrolled more than 35 patients. Eleven had been dosed, and the analysis presented at ASH included data from seven of them.
Researchers collected patient stem cells in an average of 1.4 cycles (range, 1-2), which Heeney described as efficient.
Safety and efficacy served as primary endpoints.
Results and next steps
After mean follow-up of 5.6 months (range, 1.4-11), all seven patients in the analysis achieved neutrophil engraftment (median time to engraftment, 17.1 days; range, 15-21) and platelet engraftment (median time to platelet engraftment, 19.1 days; range, 11-34).
All seven patients experienced treatment-emergent adverse events (TEAEs), but only one experienced an event deemed related to BEAM-101.
All participants experienced grade 3 or worse TEAEs, but none were related to the therapy.
Common TEAEs included febrile neutropenia, stomatitis, skin hyperpigmentation, pharyngeal inflammation, anemia, peripheral edema, decreased appetite, headache, hypervolemia and hypokalemia.
Slightly more than half (57%) of participants experienced serious TEAEs, but researchers attributed none of those events to BEAM-101.
One patient died 4 months after infusion. Researchers attributed the death to busulfan conditioning.
All patients had their fetal hemoglobin increase to more than 60% and their sickle hemoglobin drop to less than 40% at 1 month, and they all maintained those numbers until the last time point available.
No patients who have received BEAM-101 have experienced vaso-occlusive crises.
Researchers plan to enroll about 50 participants into the study. They also want to evaluate the therapy in a younger cohort, Heeney said.
Future research will involve finding nonmyeloablative approaches to reduce toxicities.
The “Holy Grail,” Heeney said, would be an in vivo approach altering the sickle mutation as opposed to inducing fetal or other hemoglobin types.
“I think that’s ultimately where the path is going,” he said.
Study investigator Julie Kanter, MD, co-director of the Lifespan Comprehensive Sickle Cell Center and professor in the division of hematology and oncology at The University of Alabama at Birmingham, discussed some of the trials strengths during a press briefing.
She highlighted participants’ rapid engraftment, which she said “is probably indicative” of base-edited cells vs. those that have double-stranded DNA breaks, and how patients lost “considerably less cells” during the genetic modification process.
“Efficacy wise, you do see a significant increase in fetal hemoglobin,” Kanter said. “I don’t think we know yet how much fetal hemoglobin could be too much.
“There are questions that are going to need to be asked long term as we better understand the outcomes of this therapy and personalize the therapy,” Kanter added. “There may be individuals who need hemoglobin A — that’s the naturally occurring adult hemoglobin vs. fetal hemoglobin — but we are not going to know those answers for several years. Right now, I’m incredibly excited about this therapy.”
For more information:
Matthew M. Heeney, MD, can be reached at matthew.heeney@childrens.harvard.edu.
Perspective
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Despite recent FDA approvals of two gene therapies for severe sickle cell disease, potential safety concerns persist. Lentiviral gene addition carries a potential risk for leukemia due to insertional genotoxicity.
CRISPR/Cas gene editing induces double-stranded DNA breaks that can be toxic to hematopoietic stem cells.
Thus, there is intense interest in novel targeted approaches not predicted to share these risks. Base editing can modify individual DNA bases without inducing double-stranded DNA breaks.
This abstract reports very early results from a pioneering hematopoietic stem cell-based gene editing clinical trial of individuals with sickle cell disease. Two patients in this base-editing trial are now more than 46 months post-transplant, with high base editing levels in blood cells, increased fetal hemoglobin and a lack of pain crises.
However, another patient in the trial is reported to have died of complications attributed to toxicity of the drug busulfan, which was used as conditioning therapy to facilitate engraftment of edited cells.
With gene editing and gene therapy trials, the question is how long the effects will last, as well as how long until you get to a steady state?
In most prior trials — and we’d expect it to be about the same with base editing — it looks like it takes about 6 months for stabilization of long-term stabilization of long-term hematopoietic stem cells to contribute to hematopoiesis. After that time — even in some of the lentiviral gene transfer trials in which patients have been followed for more than 5 or 6 years — we don’t see fall-off. Although it’s hard to use the word “cure” without even longer follow-up, it really does look like if you see stabilization at 6 months, it does translate into a very long-term effect.
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Gupta AO, et al. Abstract 513. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2024; San Diego.