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EFFICACY AND SAFETY OF A SINGLE DOSE OF CTX001 FOR TRANSFUSION-DEPENDENT ΒETA-THALASSEMIA AND SEVERE SICKLE CELL DISEASE
Author(s): ,
Franco Locatelli
Affiliations:
Ospedale Pediatrico Bambino Gesù Rome, Sapienza, University of Rome,Rome,Italy
,
Haydar Frangoul
Affiliations:
Sarah Cannon Center for Blood Cancer at The Children’s Hospital at TriStar Centennial,Nashville,United States
,
Selim Corbacioglu
Affiliations:
University of Regensburg,Regensburg,Germany
,
Josu de la Fuente
Affiliations:
Imperial College Healthcare NHS Trust, St Mary’s Hospital,London,United Kingdom
,
Donna Wall
Affiliations:
The Hospital for Sick Children/University of Toronto,Toronto,Canada
,
Maria Domenica Capellini
Affiliations:
University of Milan,Milan,Italy
,
Mariane de Montalembert
Affiliations:
Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), University of Paris,Paris,France
,
Antonis Kattamis
Affiliations:
University of Athens,Athens,Greece
,
Stephan Lobitz
Affiliations:
Gemeinschaftsklinikum Mittelrhein,Koblenz,Germany
,
Damiano Rondelli
Affiliations:
University of Illinois at Chicago,Chicago,United States
,
Sujit Sheth
Affiliations:
Joan and Sanford I Weill Medical College of Cornell University,New York,United States
,
Martin Steinberg
Affiliations:
Boston University School of Medicine,Boston,United States
,
Mark C. Walters
Affiliations:
UCSF Benioff Children’s Hospital,Oakland,United States
,
Yael Bobruff
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
,
Chris Simard
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
,
Yang Song
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
,
Lanju Zhang
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
,
Anjali Sharma
Affiliations:
CRISPR Therapeutics,Cambridge,United States
,
Suzan Imren
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
,
Bill Hobbs
Affiliations:
Vertex Pharmaceuticals Incorporated,Boston,United States
Stephan Grupp
Affiliations:
Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania,Philadelphia,United States
(Abstract release date: 06/02/22) EHA Library. Locatelli F. 06/12/22; 366210; LB2367
Franco Locatelli
Franco Locatelli
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be made available as of Saturday, June 11, 2022 and will be accessible for on-demand viewing until August 15, 2022 on the Virtual Congress platform.

Abstract: LB2367

Type: Late breaking oral

Session title: Late breaking abstract session

Background
Elevated fetal hemoglobin (HbF) is associated with improved outcomes in patients (pts) with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD). CTX001™ 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). Early data from the pivotal trials CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) showed that a single dose of CTX001 increased HbF and total Hb sufficiently to eliminate red blood cell (RBC) transfusions (TDT) and vaso-occlusive crises (VOCs; SCD).

Aims
To report efficacy and safety data from the first 75 pts dosed with CTX001 in the ongoing CLIMB THAL-111 and CLIMB SCD-121 trials.

Methods
Following pharmacokinetic-adjusted busulfan myeloablation and CTX001 infusion, pts (12-35 years [y]) are monitored for engraftment, total Hb, HbF, BCL11A edited alleles, transfusions, VOCs (SCD only), and adverse events (AEs). All pts gave informed consent. Data presented as mean (min-max) unless noted.

Results

44 pts with TDT (aged 21.3 [12-35] y) and 31 pts with SCD (aged 22.5 [12-34] y) had been infused with CTX001 at data cut (follow-up 12.3 [1.2-37.2] months [mo] and 9.6 [2.0-32.3] mo, respectively). 26/44 pts with TDT (59.1%) had β00 or a β00‑like genotype (β0/IVS‑I‑110, IVS-I-110/IVS-I-110). In the 2-yr period before screening, pts with TDT received 36.0 (15.0-71.0) units RBCs/yr and pts with SCD had 3.9 (2.0-9.5) severe VOCs/yr. After CTX001 infusion, all pts engrafted neutrophils and platelets. Median time to neutrophil and platelet engraftment was 29 and 43 days in pts with TDT and 27 and 32 days in pts with SCD, respectively.

Overall, 42 of 44 pts with TDT stopped RBC transfusions (duration 0.8-36.2 mo; Figure); 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 levels (>9 g/dL) were achieved, with mean total Hb levels increasing to >11 g/dL thereafter and were maintained.

All pts with SCD (n=31) no longer had severe VOCs after CTX001 infusion (duration 2.0-32.3 mo; Figure). The mean proportion of HbF was >20% by Month 3, increasing to ~40% at Month 4, and was stable thereafter, with mean total Hb levels >11 g/dL after Month 3.

Pts with TDT and SCD with ≥1 yr of 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 CTX001. The first pt was previously reported. The second pt had delayed neutrophil engraftment and thrombocytopenia, which were considered related to both CTX001 and busulfan. All SAEs resolved. No pts with SCD had SAEs considered related to CTX001. There were no deaths, discontinuations, or malignancies.

Conclusion

CTX001 infusion led to the elimination of transfusions in almost all patients with TDT and elimination of VOCs in all patients 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 that long-term HSCs were successfully edited, providing the basis for the significant, durable efficacy observed. The safety profile was generally consistent with busulfan myeloablation and autologous transplant. These results indicate that CTX001 has the potential to be the first CRISPR/Cas9-based therapy to provide a one-time functional cure for TDT and severe SCD.

Keyword(s):

Presentation during EHA2022: All Oral presentations will be made available as of Saturday, June 11, 2022 and will be accessible for on-demand viewing until August 15, 2022 on the Virtual Congress platform.

Abstract: LB2367

Type: Late breaking oral

Session title: Late breaking abstract session

Background
Elevated fetal hemoglobin (HbF) is associated with improved outcomes in patients (pts) with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD). CTX001™ 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). Early data from the pivotal trials CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) showed that a single dose of CTX001 increased HbF and total Hb sufficiently to eliminate red blood cell (RBC) transfusions (TDT) and vaso-occlusive crises (VOCs; SCD).

Aims
To report efficacy and safety data from the first 75 pts dosed with CTX001 in the ongoing CLIMB THAL-111 and CLIMB SCD-121 trials.

Methods
Following pharmacokinetic-adjusted busulfan myeloablation and CTX001 infusion, pts (12-35 years [y]) are monitored for engraftment, total Hb, HbF, BCL11A edited alleles, transfusions, VOCs (SCD only), and adverse events (AEs). All pts gave informed consent. Data presented as mean (min-max) unless noted.

Results

44 pts with TDT (aged 21.3 [12-35] y) and 31 pts with SCD (aged 22.5 [12-34] y) had been infused with CTX001 at data cut (follow-up 12.3 [1.2-37.2] months [mo] and 9.6 [2.0-32.3] mo, respectively). 26/44 pts with TDT (59.1%) had β00 or a β00‑like genotype (β0/IVS‑I‑110, IVS-I-110/IVS-I-110). In the 2-yr period before screening, pts with TDT received 36.0 (15.0-71.0) units RBCs/yr and pts with SCD had 3.9 (2.0-9.5) severe VOCs/yr. After CTX001 infusion, all pts engrafted neutrophils and platelets. Median time to neutrophil and platelet engraftment was 29 and 43 days in pts with TDT and 27 and 32 days in pts with SCD, respectively.

Overall, 42 of 44 pts with TDT stopped RBC transfusions (duration 0.8-36.2 mo; Figure); 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 levels (>9 g/dL) were achieved, with mean total Hb levels increasing to >11 g/dL thereafter and were maintained.

All pts with SCD (n=31) no longer had severe VOCs after CTX001 infusion (duration 2.0-32.3 mo; Figure). The mean proportion of HbF was >20% by Month 3, increasing to ~40% at Month 4, and was stable thereafter, with mean total Hb levels >11 g/dL after Month 3.

Pts with TDT and SCD with ≥1 yr of 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 CTX001. The first pt was previously reported. The second pt had delayed neutrophil engraftment and thrombocytopenia, which were considered related to both CTX001 and busulfan. All SAEs resolved. No pts with SCD had SAEs considered related to CTX001. There were no deaths, discontinuations, or malignancies.

Conclusion

CTX001 infusion led to the elimination of transfusions in almost all patients with TDT and elimination of VOCs in all patients 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 that long-term HSCs were successfully edited, providing the basis for the significant, durable efficacy observed. The safety profile was generally consistent with busulfan myeloablation and autologous transplant. These results indicate that CTX001 has the potential to be the first CRISPR/Cas9-based therapy to provide a one-time functional cure for TDT and severe SCD.

Keyword(s):

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