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1: Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia and Severe Sickle Cell Disease
Type: General Session
Presentation Details
Session Title: Presidential Symposium and Presentation of Top Abstracts
Location: West Hall B
Start Time: 5/17/2023 14:30
End Time: 5/17/2023 14:45
Elevated fetal hemoglobin (HbF) is associated with improved outcomes in patients (pts) with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD). Exagamglogene autotemcel (exa-cel) is a cell therapy designed to reactivate 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 75 pts dosed with exa-cel in the ongoing CLIMB THAL-111 and CLIMB SCD-121 pivotal trials. Following pharmacokinetic-adjusted busulfan myeloablation and exa-cel infusion, pts (12-35y) are monitored for engraftment, total Hb, HbF, BCL11A edited alleles, transfusions, VOCs (SCD only), and adverse events (AEs). Data presented as mean (min-max) unless noted. 44 pts with TDT (age 21.3 [12-35] y) and 31 pts with SCD (22.5 [12-34 ] y) had been infused with exa-cel at data cut (follow-up 12.3 [1.2-37.2] mo and 9.6 [2.0-32.3] mo, respectively). 26/44 pts with TDT (59.1%) had β0/β0 or a β0/β0‑like genotype (β0/IVS‑I‑110, IVS-I-110/IVS-I-110). In 2y period before screening, pts with TDT received 36.0 (15.0-71.0) units RBC/y and pts with SCD had 3.9 (2.0-9.5) severe VOCs/y. After exa-cel infusion, all pts engrafted neutrophils and platelets (median 29 and 43 days in pts with TDT and 27 and 32 days in pts with SCD, respectively). 42/44 pts with TDT stopped RBC transfusions (duration 0.8-36.2 mo); 2 pts had not yet stopped transfusions but had 75% and 89% reductions in transfusion volume. By Month 3, increases in HbF and mean total Hb (>9 g/dL) were achieved, with mean total Hb increasing to >11 g/dL thereafter and maintained. All pts with SCD (n=31) no longer had severe VOCs (duration 2.0-32.3 mo). Mean proportion of HbF was >20% by Month 3, increasing to ~40% at Month 4 and stable thereafter, with mean total Hb >11 g/dL after Month 3. Pts with TDT and SCD with ≥1 y follow-up had stable proportions of edited BCL11A alleles in bone marrow CD34+ HSPCs and peripheral blood mononuclear cells. 2 pts with TDT had serious AEs (SAEs) considered related to exa-cel. First pt was previously reported. Second pt had delayed neutrophil engraftment and thrombocytopenia, which were considered related to both exa-cel and busulfan. All SAEs resolved. No pts with SCD had SAEs considered related to exa-cel. There were no deaths, discontinuations, or malignancies. In summary, exa-cel infusion led to elimination of transfusions in almost all pts with TDT and elimination of VOCs in all pts with SCD, with associated clinically meaningful increases in HbF and total Hb that were maintained. Proportions of CRISPR/Cas9-edited BCL11A alleles remained stable after >1 y, indicating long-term HSCs were successfully edited. Safety profile was generally consistent with busulfan myeloablation and autologous transplant. These results indicate exa-cel has the potential to be the first CRISPR/Cas9-based therapy to provide a one-time functional cure for TDT and severe SCD.
Haydar Frangoul1, Franco Locatelli2, Selim Corbacioglu3, Josu De La Fuente4, Donna Wall5, Maria Domenica Cappellini6, Mariane de Montalembert7, Antonis Kattamis8, Stephan Lobitz9, Damiano Rondelli10, Sujit Sheth11, Martin Steinberg12, Mark Walters13, Yael Bobruff14, Chris Simard14, Yang Song14, Lanju Zhang14, Anjali Sharma15, Suzan Imren14, Bill Hobbs14, Stephan A. Grupp16
1Children's Hosp TriStar Centennial, Nashville, TN,2Uni of Rome, Rome, Italy,3Uni of Regensburg, Regensburg, Germany,4Imperial Coll London, ST. ALBANS, United Kingdom,5The Hosp for Sick Children, Toronto, ON, Canada,6Uni of Milan, Milan, Italy,7Uni of Paris, Paris, France,8Uni of Athens, Athens, Greece,9Gemeinschaftsklinikum Mittelrhein, Koblenz, Germany,10Uni of Ill at Chicago, Chicago, IL,11Weill Cornell Med, New York, NY,12BU Sch of Med, Boston, MA,13UCSF Benioff Children’s Hosp, Oakland, CA,14Vertex Pharmaceuticals, Boston, MA,15CRISPR Therapeutics, Cambridge, MA,16Uni of Penn Perelman Sch of Med, Philadelphia, PA
H. Frangoul: 1; Commercial Interest i.e. Company X; Vertex Pharmaceuticals, Editas Medicine, Rocket Pharmaceuticals. 1; What was received? i.e. Honorarium; Consulting Fees. 1; For what role? i.e. Speaker; Consultant. 2; Commercial Interest i.e. Company X; Jazz Pharmaceuticals. 2; What was received? i.e. Honorarium; Honoraria. 2; For what role? i.e. Speaker; Speaker Bureau.
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