Novel gene therapy offers ‘clinically meaningful improvement’ in sickle cell disease
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Key takeaways:
- Three patients who received gene therapy experienced one vaso-occlusive event each during follow-up.
- Results establish the feasibility of using a final cryopreserved gene therapy apheresis product.
The first three patients who received an investigational gene therapy for sickle cell disease experienced dramatic reductions in complications related to sickle cell disease, according to results of a first-in-human study.
Findings showed marked increases in fetal hemoglobin levels among those who received the experimental therapy.
However, the encouraging results — published in The New England Journal of Medicine — come despite a recent announcement that the agent’s manufacturer no longer will support development of the product.
“Business objectives and scientific objectives are usually very different,” Akshay Sharma, MBBS, assistant member in the bone marrow transplant department at St. Jude Children’s Research Hospital, told Healio.
“Our trial allowed some of the sickest patients to enroll who would otherwise be ineligible for most trials,” he added. “If you look at the big picture, all of the patients we treated had clinically meaningful improvement in their scenarios.”
Background
OTQ923 (Intellia Therapeutics, Novartis) is an autologous gene therapy derived from ex vivo CRISPR-Cas9-edited hematopoietic progenitor stem cells.
Gene edits in the novel agent aim to target disruption of the gamma-globin gene promoters HBG1 and HBG2 to increase fetal hemoglobin expression in red blood cells.
"This is a novel site,” Sharma said. “Nobody has edited at the globin locus before in patients.”
The agent’s manufacturer announced in February that its partner and trial sponsor Novartis had chosen to discontinue the OTQ923 program.
Although no specific reason had been provided for halting the product’s development, Intellia officials said in the same quarterly earnings release that it would instead focus “on developing an in vivo editing approach for the treatment of sickle cell disease to avoid the need for bone marrow transplantation.”
Methodology
Sharma and colleagues conducted a phase 1/phase 2 multicenter study to determine the safety, tolerability and efficacy of OTQ923 for individuals with severe sickle cell disease.
The analysis included the first three patients — two men and one woman — who received the investigational therapy after myeloablative preconditioning.
Primary clinical outcomes included safety as determined by adverse events and blood transfusions, as well as time to engraftment and fetal hemoglobin expression.
Follow-up ranged from 6 months to 18 months, with a data cutoff date of March 27.
Key findings
All three study participants showed evidence of engraftment and stable induction of fetal hemoglobin after receiving QTQ923. Fetal hemoglobin as a percentage of total hemoglobin ranged from 19% to 26.8%.
Researchers also observed fetal hemoglobin as broadly distributed in red cells (F cells as a percentage of red cells: range, 69.7-87.8).
All study participants experienced “clinically meaningful improvement” in symptoms related to sickle cell disease after receiving OTQ923, Sharma said.
However, each of the three patients experienced one vaso-occlusive event during follow-up.
“Despite improved hematologic levels and a reduction in the incidence of symptoms of sickle cell disease, all the participants had ongoing mild hemolysis,” investigators wrote.
This finding suggested that increases in fetal hemoglobin induced by the gene therapy did not completely prevent the sickling effect on red blood cells, Sharma said.
"These patients had lower levels of sickling in their blood,” he told Healio. “Even though we could not see it, we knew there was some evidence of sickling.”
The results also validated the investigators’ decision to cryopreserve cells at the collection and manufacturing sites, Sharma said. Other gene therapy trials underway use shipping of freshly collected samples, he said.
"One of the disadvantages of this process is that manufacturing sites must be located in close proximity to the collection sites," Sharma said. “Otherwise, the longer fresh samples are in transit, the more stem cells die off.”
Clinical implications
Sharma confirmed that the trial is no longer accruing patients. However, those already treated and a handful more already enrolled will be treated and followed as part of a long-term follow-up study.
Despite the end of commercial support for the program, the therapy already provided to patients may end up being a functional cure and has at the very least armed the gene therapy field with evidence about the feasibility and safety of their gene editing approach, Sharma said.
“From a proof of concept, we have shown that editing at the globin locus raises fetal hemoglobin in individuals, and once you reinfuse those cells, they persist,” Sharma told Healio. “This finding will likely open up further avenues for scientific exploration into gene editing of the globin locus.”
Meanwhile, the therapy has continued to provide clinical benefits to those treated despite limited sickling within the blood after treatment, according to Sharma.
"These patients will probably lead normal lives, despite the presence of some sickled hemoglobin," he said. “The interesting question we will need to address through follow-up is, as we try to shoot for the moon, is it OK to be among the stars?"
References:
- Intellia Therapeutics. Intellia Therapeutics announces fourth quarter and full-year 2022 financial results and highlights recent company progress. Available at: https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-fourth-quarter-and-full-year-5. Published Feb. 23, 2023. Accessed Aug. 30, 2023.
- Sharma A, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2215643.
For more information:
Akshay Sharma, MBBS, can be reached at St. Jude Children’s Research Hospital, Department of Bone Marrow Transplantation and Cellular Therapy, 262 Danny Thomas Place, Mail Stop 1130, Memphis, TN 38105; email: akshay.sharma@stjude.org.
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