Northstar-3: Interim Results from a Phase 3 Study Evaluating Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Either a β0 or IVS-I-110 Mutation at Both Alleles of the HBB Gene
Authors: Lal Ashutosh , Locatelli Franco , Kwiatkowski Janet L. , Kulozik Andreas E. , Yannaki Evangelia , Porter John B. , Thuret Isabelle , Sauer Martin G. , Elliot Heidi , Chen Ying , Colvin Richard A. , Thompson Alexis A. 
Published: February 2020

Background
Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease caused by impaired β-globin production leading to severe anemia and lifelong transfusion dependence. Autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is currently being evaluated in patients with TDT. In the phase 1/2 Northstar study, 3/8 patients with β0/β0 genotypes became transfusion independent. The drug product (DP) manufacturing process (CD34+ cell transduction) was then refined to improve clinical outcomes. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-3 study (HGB-212; NCT03207009) evaluating LentiGlobin gene therapy in patients ≤50 years of age with TDT and either β0 or β+ IVS-I-110 mutations on both HBB alleles.
Methods
Patients with TDT undergo hematopoietic stem cell mobilization with G-CSF and plerixafor. CD34+ cells collected via apheresis are transduced with BB305 lentiviral vector. Patients undergo myeloablative, single-agent, pharmacokinetic-adjusted busulfan conditioning over 4 days and are infused with transduced cells. The primary efficacy endpoint is transfusion reduction (≥60% reduction in transfused red blood cell (RBC) volume post-DP infusion compared with pre-DP infusion). A key secondary endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics presented as median (min - max).
Results
As of 12 April 2019, 11 patients (7 β0/β0, 2 β0/IVS-I-110, 2 homozygous IVS-I-110genotypes) were treated with LentiGlobin and have a median follow-up of 4.6 (1.5 - 15.7) months. Median age at enrollment was 17 (7 - 33) years; 3 patients were &lt;12 years of age. DP vector copy number (VCN) and proportion of transduced cells were higher in Northstar-3 (N=11) compared to Northstar (N=18). In Northstar-3, median DP VCN was 2.5 (1.2 - 4.3) copies/diploid genome (c/dg) compared to 0.7 (0.3 - 1.5) c/dg in Northstar; 74% (34% - 83.5%) and 32% (17% - 58%) of cells were transduced in Northstar-3 versus Northstar, respectively.
Median time to neutrophil and platelet engraftment was 26 (14 - 38) days and 36 (25 - 64) days, respectively; 3 patients with 1 - 3 months follow-up had not yet achieved platelet engraftment. There was one grade 3 bleeding adverse event (AE) of epistaxis from DP infusion to platelet engraftment, but no grade ≥ 3 bleeding AEs after platelet engraftment. Non-hematologic grade ≥3 AEs in ≥2 patients after DP infusion were febrile neutropenia, stomatitis, and pharyngeal inflammation. AEs considered possibly related to LentiGlobin were abdominal pain (n=2) and leukopenia and thrombocytopenia in one patient. Serious AEs after DP infusion were pyrexia (n=2), and one event each of febrile neutropenia, headache, neutropenia, stomatitis, thrombocytopenia, and congestive heart failure. Congestive heart failure occurred in a patient (screening cardiac T2* 16.6 msec) who had a fall in left ventricular ejection fraction associated with worsening of cardiac iron pre-engraftment.
Three of 4 patients followed for ≥ 6 months have stopped transfusions for ≥ 6 months with total Hb of 10.5 - 13.6 g/dL at last visit. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion and was 9.5 - 12.6 g/dL at last assessment. The fourth patient with ≥ 6 months follow-up had a Hb of 8.6 g/dL at last visit after being off transfusions for 2.8 months; however, has since received additional transfusions due to symptomatic anemia. The only patient with ≥12 months follow-up (β0/β0 genotype) achieved transfusion independence. Of the 5 patients with ≥3 to &lt;6 months follow-up, 4 have been off transfusions for ≥2 months and one patient continues to receive transfusions. Longer follow-up and outcomes from additional patients treated will be presented.
Summary
Interim results from Northstar-3 indicate that refinements in the manufacturing of LentiGlobin gene therapy led to higher DP VCN and proportion of transduced cells. In patients with TDT and either a β0 or IVS-I-110 mutation at both alleles of the HBB gene, 3/4 with ≥ 6 months have stopped transfusions and one patient has achieved the protocol definition of transfusion independence. The safety profile of LentiGlobin gene therapy was generally consistent with myeloablative busulfan conditioning.

Disclosures
Lal: Terumo Corporation: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Insight Magnetics: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding; Novartis: Research Funding; La Jolla Pharmaceutical Company: Research Funding. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kwiatkowski:Terumo: Research Funding; Novartis: Research Funding; Imara: Consultancy; Apopharma: Research Funding. Kulozik:Bluebird Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Porter:Celgene: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria; Bluebird bio: Consultancy, Honoraria. Thuret:Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy; BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Chen:bluebird bio, Inc.: Consultancy. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding.