Autor:innen:
H. Frangoul (Nashville, TN, US)
F. Locatelli (Rome, IT)
A. Sharma (Memphis, TN, US)
M. Bhatia (New York, NY, US)
M. Mapara (New York, NY, US)
L. Molinari (San Antonio, TX, US)
D. Wall (Toronto, CA)
R. Liem (Chicago, IL, US)
P. Telfer (London, GB)
A. Shah (Palo Alto, CA, US)
M. Cavazzana (Paris, FR)
S. Corbacioglu (Regensburg, DE)
D. Rondelli (Chicago, IL, US)
R. Meisel (Dusseldorf, DE)
L. Dedeken (Brussels, BE)
S. Lobitz (Koblenz, DE)
M. de Montalembert (Paris, FR)
M. Steinberg (MA, US)
M. Walters (Oakland, CA, US)
S. Imren (MA, US)
D. Shi (MA, US)
L. Bower (MA, US)
C. Simard (MA, US)
L. Zhang (MA, US)
P. Morrow (MA, US)
W. Hobbs (MA, US)
S. Grupp (Philadelphia, PA, US)
Exagamglogene autotemcel (exa-cel) is a cell therapy designed to reactivate fetal hemoglobin (HbF) via non-viral, ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). We report efficacy and safety data from the first 31 patients (pts) dosed with exa-cel in the CLIMB SCD-121 trial.
Patients aged 12-35 yrs with severe SCD and history of ≥ 2 VOCs/y in 2 yrs before screening were eligible. Following pharmacokinetic-adjusted, busulfan myeloablation and exa-cel infusion, pts are monitored for engraftment, Hb, HbF, BCL11A-edited alleles, VOCs, and adverse events (AEs). Primary endpoint is proportion of pts who have not experienced a severe VOC for at least 12 months (mos) after infusion, starting 60 days after last RBC transfusion. Data reported as mean (min–max) unless noted.
At most recent data cut (Feb 2022), 31 pts with SCD (age 22.5 [12–34] yrs) had been infused with exa-cel (follow-up 9.6 [2.0–32.3] mos); 6 (19.4%) were between age 12- < 18 yrs and 29 (93.5%) had βs/βs genotype. In 2-year period before screening, pts experienced 3.9 (2.0–9.5) severe VOCs/year. After exa-cel infusion, all pts engrafted neutrophils and platelets (median time 27 and 32 days, respectively). All pts were VOC-free at time of data cut (follow-up 2.0–32.3 mos after exa-cel infusion). Median time from exa-cel infusion to last RBC transfusion was 19 (11–52) days. Mean proportion of HbF was > 20% by Month 3, with mean total Hb > 11 g/dL on and after Month 3. All 11 pts with at least 12 mos follow-up after exa-cel infusion maintained HbF levels > 20% while experiencing no VOCs. At Month 6, mean proportion of edited BCL11A alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells was 86.6% and 76.0%, respectively. Proportions remained stable in all pts with ≥1 yr of follow-up. No pts had serious AEs considered related to exa-cel. There were no deaths, discontinuations, or malignancies.
Exa-cel infusion led to the elimination of VOCs in all pts with SCD, with associated clinically meaningful increases in HbF and total Hb that were maintained over time. Proportions of CRISPR/Cas9-edited BCL11A alleles remained stable after ≥ 1 yr, indicating long-term HSCs were successfully edited. Safety profile was generally consistent with busulfan myeloablation and autologous transplant. Exa-cel has the potential to be the first CRISPR/Cas9-based therapy to provide a one-time functional cure for SCD.