A PHASE 3 STUDY TO EVALUATE SAFETY AND EFFICACY OF LENTIGLOBIN GENE THERAPY FOR TRANSFUSION-DEPENDENT Β-THALASSEMIA IN PATIENTS WITH NON-Β0/Β0 GENOTYPES: THE NORTHSTAR-2 (HGB-207) TRIAL
Author(s): ,
Mark Walters
Affiliations:
UCSF Benioff Children's Hospital and Research Center,Oakland,United States
,
Alexis Thompson
Affiliations:
Lurie Children's Hospital,Chicago,United States
,
Suradej Hongeng
Affiliations:
Ramathibodi Hospital,Bangkok,Thailand
,
Janet Kwiatkowski
Affiliations:
Children's Hospital of Philadelphia,Philadelphia,United States
,
Franco Locatelli
Affiliations:
IRCCS Ospedale Pediatrico Bambino Gesù,Rome,Italy
,
John Porter
Affiliations:
University College London Hospital,London,United Kingdom
,
Martin Sauer
Affiliations:
Medizinische Hochschule Hannover,Hannover,Germany
,
Adrian Thrasher
Affiliations:
Great Ormond Street Hospital,London,United Kingdom
,
Isabelle Thuret
Affiliations:
Hôpital d'enfants de La Timone,Marseille,France
,
Evangelia Yannaki
Affiliations:
General Hospital of Thessaloniki,Thessaloniki,Greece
,
Alexandria Petrusich
Affiliations:
bluebird bio,Cambridge,United States
Mohammed Asmal
Affiliations:
bluebird bio,Cambridge,United States
(Abstract release date: May 18, 2017) EHA Learning Center. Walters M. Jun 25, 2017; 182101
Mark Walters
Mark Walters
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Abstract
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Abstract: S814

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:00 - 08:15

Location: Room N111

Background
Standard treatment for transfusion-dependent β-thalassemia (TDT) includes regular red blood cell (RBC) transfusions and management of iron overload. Successful allogeneic hematopoietic cell transplantation (HCT) can eliminate RBC transfusions and, eventually, chelation. However, due to transplant-related risks such as graft-versus-host disease (GVHD), as well as donor constraints, HCT is rarely an option for TDT patients. By transferring a functioning copy of the β-globin (HBB) gene into hematopoietic stem cells (CD34+ cells) and re-infusing the modified cells, gene therapy may be an alternative one-time treatment available to all patients with TDT, without risks of GVHD.

LentiGlobin gene therapy is an investigational treatment consisting of autologous CD34+ cells transduced with the BB305 lentiviral vector. The Northstar (HGB-204) phase 1/2 clinical study of LentiGlobin gene therapy for TDT included 18 patients who received LentiGlobin drug product (DP).  As of September 2016, all patients in Northstar with non-β00 genotypes and at least 12 months of follow-up stopped transfusions (median total hemoglobin [Hb] 11.2 [range 9.4−12.2] g/dL) and there was >60% reduction in transfusions in patients with a β00 genotype.  The safety profile was consistent with autologous HCT. In this initial study, the average number of therapeutic gene copies per CD34+ cell in the DP (i.e. DP vector copy number per diploid genome or DP VCN; median 0.7, range 0.3 to 1.5) correlated with peripheral HbAT87Q (genetically engineered hemoglobin) expression at 6 months (ASH, 2016). In an effort to optimize the proportion of patients able to discontinue blood transfusions to achieve “transfusion independence” in all patients and increase unsupported Hb levels after treatment, the manufacturing process for LentiGlobin DP was modified to increase the DP VCN and the proportion of genetically modified cells. Northstar-2 (HGB-207) is a recently initiated phase 3 study using this new manufacturing process in patients with TDT and a non-β00 genotype.

Aims
To evaluate safety and efficacy of autologous HCT with LentiGlobin DP in patients with TDT and a non-β00 genotype.

Methods
After providing informed consent, patients 12 to 50 years of age (N=15) will have CD34+ cells collected via mobilization and apheresis. After individualized DP manufacture and satisfaction of release criteria, the patient will receive myeloablative conditioning with single-agent busulfan (starting dose 3.2 mg/kg/day for 4 days, with target AUC 4500 [range 4000−5000] µM*min) followed by infusion of LentiGlobin DP. Patients will be followed for engraftment, safety and efficacy endpoints for 2 years after infusion; patients will then have the option to enroll in a 13-year follow-up study. The primary endpoint is the proportion of patients who achieve transfusion independence after DP infusion, defined as total Hb ≥9g/dL without RBC transfusions for a continuous period of ≥12 months. Secondary endpoints include time to neutrophil engraftment, adverse events, and biological parameters including VCN in peripheral blood and levels of HbAT87Q over time.

Results
As of March 1, 2017, two 20-year-old females with β0E genotypes have been treated with LentiGlobin DP in the Northstar-2 trial. The DP VCN was 2.9 and 2.4 copies per diploid genome, respectively. Outcomes in all evaluable patients will be presented.

Conclusion
Results from the Northstar-2 study will provide data on safety and demonstrate the extent to which an increase in LentiGlobin DP VCN yields normalization of total Hb and consistently achieves transfusion independence in patients with TDT of non-β00 genotypes. Optimizing DP VCN has the potential to improve outcomes across all TDT genotypes treated by investigational LentiGlobin gene therapy.

Session topic: 24. Gene therapy, cellular immunotherapy and vaccination

Keyword(s): Thalassemia, Lentiviral vector, Gene therapy

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