The gene therapy exagamglogene autotemcel (exa-cel; Casgevy) -- already approved for patients 12 years and older with transfusion-dependent beta-thalassemia (TDT) and sickle cell disease (SCD) -- led to durable clinical benefits in kids ages 5 to 11 years, two phase III trials showed.
Among the evaluable children with TDT in the CLIMB THAL-141 study, all six achieved transfusion independence for 12 or more consecutive months, with a mean transfusion-free duration of 19.8 months (range 14.0-22.5 months), reported Haydar Frangoul, MD, of the Sarah Cannon Research Institute and TriStar Centennial Children's Hospital in Nashville, Tennessee, during a press briefing in advance of the American Society of Hematology annual meeting.
Twelve of the 13 children included in the study stopped red blood cell (RBC) transfusions at a mean of 1.3 months after exa-cel treatment, with the duration of transfusion independence ranging from 2.3 to 22.5 months.
In the CLIMB SCD-151 study, all four evaluable children with SCD were able to go 12 or more consecutive months without experiencing severe vaso-occlusive crises (VOCs) or being hospitalized for severe VOCs.
None of the 11 participants in the SCD study had a VOC after exa-cel infusion, with VOC-free duration ranging from 3.2 to 24.1 months.
"Pediatric and adolescent participants have fewer VOC events after exa-cel than adult participants, consistent with treatment prior to the onset of chronic organ damage, including chronic pain," Frangoul said.
The efficacy of exa-cel was the same in patients ages 5 to 11 years compared with those ages 12 to 17 years, he noted, adding that exa-cel "has the potential to provide a one-time functional cure for children aged 5-11 years with TDT or sickle cell disease."
Exa-cel is the first FDA-approved therapy utilizing CRISPR/Cas9, a type of gene editing technology through which patients' hematopoietic stem cells are modified. It was approved for patients ages 12 and older with SCD in December 2023, and for the same age group with TDT in January 2024.
Frangoul noted that data from the CLIMB THAL-111 and CLIMB SCD-121 trials among patients ages 12 to 17 showed reactivation of the synthesis of hemoglobin F to levels that "are known to eliminate the need for transfusion in patients with TDT, and VOCs in sickle cell disease." He and his colleagues hypothesized that based on exa-cel's mechanism of action, efficacy was expected to be similar across all ages.
CLIMB THAL-141 included patients ages 2 to 11 years with TDT. Mean age at the time of screening was 7.4 years, 12 of the 13 children had an intact spleen, and the median annualized volume of historical packed RBC transfusions was 232.3 mL/kg.
CLIMB SCD-151 included SCD patients ages 2 to 11 with a history of two or more severe VOCs per year for the previous 2 years before enrollment, as well as hydroxyurea failure unless hydroxyurea intolerant. Mean age was 8.5 years, median number of severe VOCs per year was three, and median number of hospitalizations for severe VOCs per year was two.
In both studies, exa-cel was administered by intravenous infusion following myeloablative conditioning with busulfan.
Exa-cel's safety profile was "consistent with what we would expect with high-dose busulfan conditioning and autologous stem cell transplant," Frangoul said, adding that it was similar to what was observed in patients ages 12 to 35 in the CLIMB THAL-111 and CLIMB SCD-121 studies.
Frangoul reported that one patient in CLIMB THAL-141 died from pneumonia in the setting of multi-organ failure due to severe vaso-occlusive disease related to busulfan. Fatal veno-occlusive disease is a known risk of busulfan therapy that is known to occur at a higher frequency in children compared with adults, he said.
Disclosures
The CLIMB trials were sponsored by Vertex Pharmaceuticals.
Frangoul reported relationships with Jazz Pharmaceuticals, BioLine, Vertex Pharmaceuticals, Rocket Pharma, and Editas Medicine.
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