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154 Favorable Outcomes in Pediatric Patients in the Phase 3 Hgb-207 (Northstar-2) and Hgb-212 (Northstar-3) Studies of Betibeglogene Autotemcel Gene Therapy for the Treatment of Transfusion-Dependent β-ThalassemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 112. Thalassemia and Globin Gene Regulation
Hematology Disease Topics & Pathways:
Biological, Diseases, thalassemia, Therapies, Pediatric, Hemoglobinopathies, gene therapy, Study Population
Saturday, December 5, 2020: 12:15 PM

Alexis A. Thompson, MD1,2, Janet L. Kwiatkowski, MD, MSCE3,4, John B. Porter, MA, M.D., FRCP, FRCPath5*, Suradej Hongeng, MD6, Evangelia Yannaki, MD7*, Andreas E. Kulozik, MD, PhD8,9*, Martin G. Sauer, MD10, Adrian J. Thrasher, MBBS, PhD, FMedSci11*, Isabelle Thuret, MD12*, Ashutosh Lal, MD13, Ruiting Guo, MS14*, Weijian Liu, PhD14*, Richard A. Colvin, MD, PhD14*, Mark C. Walters, MD13 and Franco Locatelli, MD, PhD15

1Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
2Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
3Division of Hematology, Children's Hospital of Philadephia, Philadelphia, PA
4Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA
5Haematology Department, University College London Hospitals, London, United Kingdom, United Kingdom
6Mahidol University, Ramathibodi Hospital, Bangkok, Thailand
7Hematology Department and HCT Unit, George Papanikolaou General Hospital, Thessaloniki, Greece
8Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany
9Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), University of Heidelberg, Heidelberg, Germany
10Pediatric Hematology and Oncology, Medizinische Hochschule Hannover, Hannover, Germany
11UCL Great Ormond Street Institute of Child Health, London, United Kingdom
12Pediatric Hematology, Hôpital de la Timone, Marseille, France
13UCSF Benioff Children's Hospital Oakland, Oakland, CA
14bluebird bio, Inc., Cambridge, MA
15Department of Pediatric Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy

Introduction

Betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia) gene therapy is being evaluated for the treatment of transfusion-dependent β-thalassemia (TDT). Initial positive results of beti-cel in the phase 3 studies, HGB-207 (NCT02906202; non-β00 genotypes) and HGB-212 (NCT03207009; β00, β0+ IVS-I-110 and β+ IVS-I-110+ IVS-I-110 genotypes), showed 10/12 adult patients achieved transfusion independence. The studies expanded enrollment to include adolescents and children. We present interim results from pediatric patients <18 yrs who received beti-cel in HGB-207 and HGB-212 as of 3 March 2020.

Methods

After mobilization and apheresis, autologous CD34+ cells were transduced ex vivo with BB305 lentiviral vector, containing a modified human β-globin gene to produce beti-cel drug product (DP). Patients underwent busulfan myeloablation and infusion with beti-cel and were then followed longitudinally. Transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without transfusions for ≥12 mo) was the primary endpoint in HGB-207 and a secondary endpoint in HGB-212. Transfusion reduction (≥60% reduction in transfusion volume between Month 12 to 24 versus baseline) is the primary endpoint in HGB-212. Hb levels, TI characteristics, and quality of life were secondary endpoints. Assessments of ineffective erythropoiesis were exploratory. Data presented as median (min–max).

Results

Twenty-four pediatric patients were treated including 13 patients <12 yrs old (207: n=8; 212: n=5) and 11 patients ≥12 to <18 yrs old (207: n=6; 212: n=5). Patient, DP, and engraftment characteristics are described in the Table. All patients achieved neutrophil engraftment. Twenty-one patients with >3 mo follow-up achieved platelet engraftment and had platelets ≥100 x109/L by Month 12; one 17-yr old patient did not have platelets ≥100 x109/L until Month 15.

In HGB-207, 6/7 (86%) patients <12 yrs and 6/6 (100%) patients ≥12 to <18 yrs with >3 mo follow-up have stopped transfusions for ≥6 mo. TI was achieved in 3/4 (75%) evaluable patients <12 yrs with weighted average Hb during TI of 10.0 (9.4–10.3) g/dL. At last visit, gene therapy–derived HbAT87Q in these patients was 5.1–7.1 g/dL. In patients ≥12 to <18 yrs, all 6 patients achieved TI with weighted average Hb during TI of 11.6 (11.3–12.3) g/dL. These patients had 8.4–10.5 g/dL HbAT87Q at last visit. Myeloid:erythroid (M:E) ratio in patients <12 yrs with TI improved from 1:3.7–1:1.1 at baseline to 1:2–1.5:1 at Month 12; in patients ≥12 to <18 yrs with TI, M:E ratio improved from 1:7.3–1.6:1 at baseline to 1:2.7–1.9:1 at Month 12. Patients <18 yrs who achieved TI in HGB-207 had an improved health state today score as assessed using EQ-5D-Y from 67 (50–96) at baseline (n=7) to 92.5 (85–95) at Month 12 (n=6).

In HGB-212, 3/5 (60%) patients <12 yrs and 4/4 (100%) patients ≥12 to <18 yrs with >3mo follow-up have stopped transfusions for ≥6 mo. TI was achieved in 1/2 evaluable patients <12 yrs. Weighted average Hb during TI was 10.3 g/dL and HbAT87Q was 9.2 g/dL at last visit in this patient. All 3 evaluable patients ≥12 to <18 yrs achieved TI with weighted average Hb of 9.6 (9.5–12.8) g/dL. HbAT87Q in these patients was 8.0–10.9 g/dL at last visit. The M:E ratio in the patient <12 yrs with TI improved from 1:4.7 at baseline to 1.2:1 at Month 12. In the 2 patients ≥12 to <18 yrs with baseline and Month 12 assessments, M:E ratios improved from 1:5.1 to 1:1.4 and 1:3.3 to 1:1.8.

Post-infusion non-hematologic grade ≥3 adverse events (AEs) in ≥3 patients aged <12 yrs in either study were febrile neutropenia (n=9), stomatitis (n=6), decreased appetite (n=4), increased alanine aminotransferase (n=3), and epistaxis (n=3); in patients ≥12 to <18 yrs, these were stomatitis (n=8), febrile neutropenia (n=3) and hypoxia (n=3). Grade 4 veno-occlusive disease occurred in 2 patients ≥12 to <18 yrs and one grade 2 event occurred in a patient <12 yrs; all cases were successfully treated with defibrotide. Neither replication-competent lentivirus, insertional oncogenesis, nor clonal dominance were observed.

Summary

Interim results in HGB-207 and HGB-212 show that after treatment with beti-cel, pediatric patients <18 yrs achieved transfusion independence with comparable rates as in adults, suggesting that beti-cel gene therapy represents an effective treatment option across ages. The safety profile of gene therapy with beti-cel was consistent with busulfan myeloablation.

Disclosures: Thompson: Beam: Consultancy; Agios: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Baxalta: Research Funding; BMS: Consultancy, Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Kwiatkowski: Novartis: Research Funding; Agios: Consultancy; Sangamo: Research Funding; bluebird bio,Inc.: Consultancy, Research Funding; Apopharma: Research Funding; Imara: Consultancy; BMS: Consultancy; Terumo Co: Research Funding; Celgene: Consultancy. Porter: Vifor Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; La Jolla Pharmaceuticals: Honoraria; Silence Therapeutics: Honoraria; Protagonist Therapeutics: Honoraria; BMS: Consultancy, Honoraria. Kulozik: Novartis: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria. Thrasher: Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; Orchard Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Equity ownership; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees. Thuret: Novartis pharma: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials; Apopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Investigator in clinical trials. Lal: Insight Magnetics: Research Funding; Agios Pharmaceuticals: Consultancy; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; La Jolla Pharmaceutical Company: Research Funding; Celgene, BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio, Inc.: Research Funding; Chiesi USA: Consultancy; Terumo Corporation: Research Funding. Guo: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Liu: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Colvin: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Walters: Veevo Biomedicine: Consultancy; AllCells, Inc: Consultancy; Editas: Consultancy. Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

*signifies non-member of ASH