CRISPR Therapeutics : ASH 2022 (Exa-cel) 1.1 MB

Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Transfusion-Dependentβ-Thalassemia and Severe Sickle Cell Disease

Haydar Frangoul,1 Franco Locatelli,2 Monica Bhatia,3 Selim Corbacioglu,4 Josu de la Fuente,5 Donna Wall,6 Amanda Li,7 Peter Lang,8 Robert Liem,9 Maria Domenica Cappellini,10 Markus Mapara,11 Roland Meisel,12 Lyndsay Molinari,13 Mariane de Montalembert,14 Antonis Kattamis,15 Stephan Lobitz,16 Damiano Rondelli,17 Ami Shah,18 Akshay Sharma,19 Sujit Sheth,20 Martin Steinberg,21 Mark C. Walters,22 Yael Bobruff,23 Laura Bower,23 Chris Simard,23 Yang Song,23 Lanju Zhang,23 Anjali Sharma,24 Suzan Imren,23 Bill Hobbs,23 Stephan Grupp25 on behalf of the CLIMB THAL-111 and CLIMB SCD-121 teams

1Sarah Cannon Center for Blood Cancer at The Children's Hospital at TriStar Centennial, Nashville, TN, USA; 2Ospedale Pediatrico Bambino Gesù Rome, Sapienza, University of Rome, Italy; 3Department of Pediatrics, Columbia University, NewYork-Presbyterian Morgan Stanley Children's Hospital, New York, NY, USA; 4University of Regensburg, Regensburg, Germany; 5Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK; 6The Hospital for Sick Children/University of Toronto, Toronto, Canada; 7BC Children's Hospital, University of British Columbia, Vancouver, Canada; 8University of Tübingen, Tübingen, Germany; 9Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA; 10University of Milan, Milan, Italy; 11Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; 12Division of Pediatric Stem Cell Therapy, Heinrich-Heine-University, Duesseldorf, Germany; 13Sarah Cannon Pediatric Transplant and Cellular Therapy Program at Methodist Children's Hospital, San Antonio, TX, USA; 14Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), University of Paris, Paris, France; 15University of Athens, Athens, Greece; 16Gemeinschaftsklinikum Mittelrhein, Koblenz, Germany; 17University of Illinois at Chicago, Chicago, IL, USA; 18Stanford University, Palo Alto, CA, USA; 19Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA; 20Joan and Sanford I Weill Medical College of Cornell University, New York, NY, USA; 21Boston University School of Medicine, Boston, MA, USA; 22UCSF Benioff Children's Hospital, Oakland, CA, USA; 23Vertex Pharmaceuticals Incorporated, Boston, MA, USA; 24CRISPR Therapeutics, Cambridge, MA, USA; 25Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

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Exa-cel is a Cell Therapy that Uses Non-Viral,Ex Vivo Editing of BCL11A to Increase HbF Levels1

CRISPR/Cas9-Mediated

Cas9

• Naturally occurring genetic polymorphisms in BCL11A are associated with elevated HbF and decreased severity of TDT and SCD2-4
• BCL11A suppresses expression of γ-globin and thus HbF

BCL11A gene

(chromosome 2)

DNA Guide RNA

Erythroid enhancer

• Editing of BCL11A reactivates γ-globin expression and formation of HbF (α2γ2) in mouse models4
• Exa-cel is produced using non-viral,ex vivo editing of the erythroid-specific enhancer region of BCL11A in CD34+ HSPCs and reduces erythroid-specificexpression of BCL11A

			Reduced expression in
BCL11A	erythroid lineage

• Infusion of exa-celleads to an increase in HbF levels in erythroid cells in vivo

β-globin locus

Gγ

Aγ

δ

β

(chromosome 11)

Figure modified from Canver, et al.1

BCL11A, B-cell lymphoma/leukemia 11A; CRISPR, clustered regularly interspaced short palindromic repeats; DNA, deoxyribonucleic acid; HbF, fetal hemoglobin; HSPC, hematopoietic stem and progenitor cell; RNA, ribonucleic acid; SCD, sickle cell disease; TDT, transfusion dependent β-thalassemia.

1. Canver MC, et al. Blood. 2016;127:2536-2545; 2. Murray N, et al. Br J Haematol. 1988;69:89-92; 3. Bank A. Blood. 2006;107:435-443; 4. Bauer DE, et al. Science. 2013;342:253-257.

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CLIMB THAL-111 and CLIMB SCD-121 Pivotal Trials of Exa-cel in Patients With TDT and Severe SCD Are Ongoing

Design

Key Inclusion Criteria

Primary Endpoint

Clinical Assessments

International, multicenter, open-label,

single-arm pivotal study of exa-cel

(NCT03655678)

Twelve to 35 years of age with TDT, including β0/β0 genotypes, defined as a history of ≥100 mL/kg/year or ≥10 units/year of pRBC transfusions in the previous 2 years

Primary efficacy endpoint: Proportion of patients

achieving a maintained weighted average

Hb ≥9 g/dL without RBC transfusions for at least 12 consecutive months after exa-cel infusion

Engraftment, total Hb, HbF, BCL11A edited

alleles, transfusions, and AEs

International, multicenter, open-label,

single-arm pivotal study of exa-cel

(NCT03745287)

Twelve to 35 years of age with severe SCD and a history of ≥2 VOCs per year in the previous 2 years

Primary efficacy endpoint: Proportion of patients who have not experienced any severe VOC for at least 12 consecutive months after exa-celinfusion

Engraftment, total Hb, HbF, BCL11A edited

alleles, transfusions, VOCs, and AEs

Data presented on all patients infused with exa-cel who have

TDT (n = 44) or severe SCD (n = 31) as of February 2022 (N = 75)

AE, adverse event; BCL11A, B-cell lymphoma/leukemia 11A; Hb, hemoglobin; HbF, fetal hemoglobin; pRBC, packed red blood cell; RBC, red blood cell; SCD, sickle cell disease; TDT, transfusion dependent β-thalassemia;VOC, vaso-occlusive crisis.

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Baseline Demographics and Clinical Characteristics of the 44 Patients With TDT Infused With Exa-cel

	Exa-cel (TDT)
	n = 44
Sex, n (%)
Male	21	(47.7)
Female	23	(52.3)
Genotype, n (%)
β0/β0	14	(31.8)
β0/β0-like(β0/IVS-I-110;IVS-I-110/IVS-I-110)	12	(27.3)
Non-β0/β0-like	18	(40.9)
Age at baseline, years, mean (min, max)	21.3	(12, 35)
Historical RBC transfusions per year,a units, mean (min, max)	36.0	(15, 71)

Data cut-off February 2022

RBC, red blood cell; TDT, transfusion dependent β-thalassemia.

1. Annualized over 2 years before signing of the informed consent form or the latest rescreening.

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Baseline Demographics and Clinical Characteristics of the 31 Patients With SCD Infused With Exa-cel

	Exa-cel (SCD)
	n = 31
Sex, n (%)
Male	16	(51.6)
Female	15	(48.4)
Genotype, n (%)
βS/βS	29	(93.5)
βS/β0	2	(6.5)
Age at baseline, years, mean (min, max)	22.5	(12, 34)
Historical VOC episodes per year,a mean (min, max)	3.9 (2.0, 9.5)

Data cut-off February 2022

SCD, sickle cell disease; VOC, vaso-occlusive crisis.

1. Annualized rate during the 2 years before signing of the informed consent form or the latest rescreening.

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