-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

990 Resolution of Sickle Cell Disease Manifestations in Patients Treated with Lentiglobin Gene Therapy: Updated Results from the Phase 1/2 Hgb-206 Group C StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 114. Hemoglobinopathies, Excluding Thalassemia—Clinical: Poster I
Hematology Disease Topics & Pathways:
Diseases, HSCs, sickle cell disease, Biological, Therapies, Hemoglobinopathies, gene therapy
Saturday, December 7, 2019, 5:30 PM-7:30 PM
Hall B, Level 2 (Orange County Convention Center)

Julie Kanter, MD1, John F. Tisdale, MD2*, Markus Y. Mapara, MD, PhD3, Janet L. Kwiatkowski, MD, MSCE4,5, Lakshmanan Krishnamurti, MD6, Manfred Schmidt, PhD7*, Alexandra L. Miller8*, Francis J. Pierciey Jr.8*, Wenmei Huang, PhD, MS8*, Jean-Antoine Ribeil, MD, PhD8*, Alexis A. Thompson, MD9,10 and Mark C. Walters, MD11

1University of Alabama Birmingham, Birmingham, AL
2CMTB, NHLBI / NIDDK, NIH, Bethesda, MD
3Division of Hematology/Oncology, Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
4Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
5Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
6Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
7GeneWerk GmbH, Heidelberg, Germany
8bluebird bio, Inc., Cambridge, MA
9Northwestern University, Chicago, IL
10Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
11UCSF Benioff Children's Hospital, Oakland, CA

Background
β-globin gene transfer into hematopoietic stem cells (HSCs) could reduce or eliminate sickle cell disease (SCD)-related manifestations. LentiGlobin for SCD gene therapy contains autologous CD34+ cells transduced with the BB305 lentiviral vector (LVV), encoding a human β-globin gene with the anti-sickling T87Q mutation (βA-T87Q). The safety and efficacy of LentiGlobin for SCD is being evaluated in the ongoing Phase 1/2 HGB-206 Study (NCT02140554). The initial 7 patients (Group A) were treated with LentiGlobin made from bone marrow harvested HSCs. The protocol was modified to improve HbAT87Q production by including pre-harvest red blood cell (RBC) transfusions, increasing the total busulfan exposure, and using a refined LentiGlobin manufacturing process (Group B, n=2). An additional modification was made for Group C patients where HSC collection by plerixafor mobilization followed by apheresis was instituted. Data from these Group C patients are discussed here. Results from patients in Groups A and B are reported separately.

Methods

Patients (≥ 18 years) with severe SCD (including those with recurrent vaso-occlusive crisis [VOC] and acute chest syndrome [ACS]) were screened for eligibility. Patients received 240 µg/kg of plerixafor 4-6 hours prior to HSC collection via apheresis. CD34+ cells were transduced with BB305 LVV. Patients underwent myeloablative busulfan conditioning and subsequent LentiGlobin drug product (DP) infusion. Patients were monitored for adverse events (AEs), engraftment, vector copy number (VCN), total hemoglobin (Hb) and HbAT87Q expression, hemolysis markers, and SCD clinical manifestations. Data are presented as median (min-max).

Results:

As of 7 March 2019, 19 Group C patients, aged 26 (18–36) years, had initiated mobilization/apheresis and 13 patients were treated with LentiGlobin for SCD gene therapy. Median DP VCN, % transduced cells, and CD34+ cell dose in the 13 treated patients were: 3.8 (2.8–5.6) copies/diploid genome (c/dg), 80 (71–88) %, and 4.5 (3.0–8.0) x 106 CD34+ cells/kg, respectively. The median follow-up was 9.0 (1.0–15.2) months. Twelve patients achieved neutrophil and platelet engraftments at a median of 19 (15–24) days and 28 (19–136) days, respectively. As of the data cut-off, engraftment was not yet evaluable in 1 patient at 1-month post-infusion.

All patients stopped red blood cell (RBC) transfusions within about 3 months post-LentiGlobin gene therapy. Median total hemoglobin (Hb) and Hb fractions in patients at various time points are shown in Figure 1. Median HbS levels were at or below 50% in all patients with at least 6 months follow-up. The median total Hb at last visit in 8 patients with at least 6 months of follow-up, was 11.5 (10.2–15.0) g/dL, with a corresponding HbAT87Q median contribution of 5.3 (4.5–8.8) g/dL and a median HbS 5.7 (4.8–8.0) g/dL. Of these 8 patients, 6 had a history of VOCs or ACS. The median annualized VOC+ACS rate in these patients was 5.3 (3–14) pre-treatment and decreased to 0 (0–2)
post-treatment. One Grade 2 VOC was observed 3.5 months post-treatment. No ACS or serious VOCs were observed in Group C patients’ post- treatment. Lactate dehydrogenase, reticulocyte count, and total bilirubin at last visit post-LentiGlobin infusion were 225.0 (130.0–337.0) U/L, 150.0 (42.1–283.0) 109/L, 22.2 (3.42–39.3) µmol/L, respectively, trending towards normalization.

The most common non-hematologic Grade ≥ 3 AEs were febrile neutropenia (n=10) and stomatitis (n=7) post-DP infusion. Serious AEs were reported in 6 patients post-LentiGlobin treatment, most common being nausea and vomiting. To date, there have been no DP-related AEs or graft failure, vector-mediated replication competent lentivirus detected, or clonal dominance reported. Longer follow-up and additional patient data will be presented.

Summary

The safety profile of LentiGlobin gene therapy for SCD remains consistent with single-agent busulfan conditioning and underlying disease. Patients in HGB-206 Group C experienced high-level, sustained expression of gene-therapy derived hemoglobin, with median HbS levels reduced to ~50% and median total Hb levels of 11.5 g/dL at 6 months. The cessation of clinical complications (no ACS or serious VOCs) and decreased hemolysis suggest a strong therapeutic effect after LentiGlobin gene therapy in patients with SCD.

Disclosures: Kanter: Bluebird bio, Inc.; Editas Medicine; Global Blood Therapeutics Inc.; Imara, Inc.; Modus Therapeutics AB; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Other: VINDICO WILL FORWARD DISCLOSURES ONCE RECEIVED AND SIGNED NOT RECEIVED TO DATE; Bluebird bio, Inc.; Novartis Pharmaceuticals Corporation: Other: VINDICO WILL FORWARD DISCLOSURES ONCE RECEIVED AND SIGNED NOT RECEIVED TO DATE, Patents & Royalties: VINDICO WILL FORWARD DISCLOSURES ONCE RECEIVED AND SIGNED NOT RECEIVED TO DATE, Speakers Bureau. Kwiatkowski: Terumo: Research Funding; Novartis: Research Funding; Apopharma: Research Funding; Imara: Consultancy; Celgene: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy. Schmidt: German Cancer Research Center, Heidelberg, Germany: Employment; GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership. Miller: bluebird bio, Inc.: Employment, Equity Ownership. Pierciey: bluebird bio, Inc.: Employment, Equity Ownership. Huang: bluebird bio, Inc.: Employment, Equity Ownership. Ribeil: bluebird bio, Inc.: Employment, Equity Ownership. Thompson: Baxalta: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Walters: AllCells, Inc: Consultancy; TruCode: Consultancy; Editas Medicine: Consultancy.

*signifies non-member of ASH