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Sickle cell disease is characterized by the painful recurrence of vaso-occlusive events. Gene therapy with the use of LentiGlobin for sickle cell disease (bb1111; lovotibeglogene autotemcel) consists of autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which produces an antisickling hemoglobin, HbAIn this ongoing phase 1-2 study, we optimized the treatment process in the initial 7 patients in Group A and 2 patients in Group B with sickle cell disease. Group C was established for the pivotal evaluation of LentiGlobin for sickle cell disease, and we adopted a more stringent inclusion criterion that required a minimum of four severe vaso-occlusive events in the 24 months before enrollment. In this unprespecified interim analysis, we evaluated the safety and efficacy of LentiGlobin in 35 patients enrolled in Group C. Included in this analysis was the number of severe vaso-occlusive events after LentiGlobin infusion among patients with at least four vaso-occlusive events in the 24 months before enrollment and with at least 6 months of follow-up.As of February 2021, cell collection had been initiated in 43 patients in Group C; 35 received a LentiGlobin infusion, with a median follow-up of 17.3 months (range, 3.7 to 37.6). Engraftment occurred in all 35 patients. The median total hemoglobin level increased from 8.5 g per deciliter at baseline to 11 g or more per deciliter from 6 months through 36 months after infusion. HbAOne-time treatment with LentiGlobin resulted in sustained production of HbA

Gene therapy with LentiGlobin for sickle cell disease (bb1111, lovotibeglogene autotemcel) consists of autologous transplantation of a patient's hematopoietic stem cells transduced with the BB305 lentiviral vector that encodes the β

Increasing cases of SARS-CoV-2 breakthrough infections from immunization with current spike protein-based COVID-19 vaccines highlight the need to develop alternative vaccines using different platforms and/or antigens. In this study, we expressed SARS-CoV-2 spike and nucleocapsid proteins based on a novel vaccinia virus (VACV) ACAM2000 platform (rACAM2000). In this platform, the vaccinia virus host range and immunoregulatory gene E3L was deleted to make the virus attenuated and to enhance innate immune responses, and another host range gene, K3L, was replaced with a poxvirus ortholog gene, taterapox virus 037 (TATV037), to make virus replication competent in both hamster and human cells. Following a single intramuscular immunization, the rACAM2000 coexpressing the spike and nucleocapsid proteins induced significantly improved protection against SARS-CoV-2 challenge in comparison to rACAM2000 expressing the individual proteins in a hamster model, as shown by reduced weight loss and shorter recovery time. The protection was associated with reduced viral loads, increased neutralizing antibody titer, and reduced neutrophil-to-lymphocyte ratio. Thus, our study demonstrates that rACAM2000 expressing a combination of the spike and nucleocapsid antigens is a promising COVID-19 vaccine candidate, and further studies will investigate if the rACAM2000 vaccine candidate can induce a long-lasting immunity against infection by SARS-CoV-2 variants of concern.

SUMMARYIncreasing cases of SARS-CoV-2 breakthrough infections from immunization with predominantly spike protein based COVID-19 vaccines highlight the need for alternative vaccines using different platforms and/or antigens. In this study, we expressed SARS-CoV-2 spike and nucleocapsid proteins in a novel vaccinia virus ACAM2000 platform (rACAM2000). Following a single intramuscular immunization, the rACAM2000 co-expressing the spike and nucleocapsid proteins induced significantly improved protection against SARS-CoV-2 challenge in comparison to rACAM2000 expressing the individual proteins in a hamster model, as shown by reduced weight loss and quicker recovery time. The protection was associated with reduced viral loads, increased neutralizing antibody titre and reduced neutrophil-to-lymphocyte ratio. Thus, our study demonstrates that the rACAM2000 expressing a combination of the spike and nucleocapsid antigens is a promising COVID-19 vaccine candidate and further studies will investigate if the rACAM2000 vaccine candidate can induce a long lasting immunity against infection of SARS-CoV-2 variants of concern.

Background: The ongoing Phase 1/2 HGB-206 study (NCT02140554) of LentiGlobin for SCD (bb1111) GT uses a modified human β-globin gene that expresses an anti-sickling hemoglobin (HbA T87Q). The relationships between biological outcomes, clinical outcomes, and clonality in the initial cohort (Group A) and the cohort treated after substantial changes were made to the study protocol and manufacturing process to improve clinical benefit (Group C) are presented here. Methods: Patients (pts; ≥18 in Group A and ≥12-≤50 yrs in Group C) with SCD and recurrent severe vaso-occlusive events (VOEs), overt stroke, or tricuspid regurgitant jet velocity of >2.5 m/s, were enrolled. The initial protocol (cell collection and target busulfan dose) and manufacturing process in Group A was modified to improve cell dose, transduction efficiency, HbA T87Q expression, and clinical benefit. CD34+ cells (collected by bone marrow [BM] harvesting in Group A and plerixafor mobilization/apheresis in Group C) were transduced with BB305 lentiviral vector (LVV). LentiGlobin was infused after myeloablative busulfan conditioning. Transduction, SCD-related outcomes, clonality, and safety were assessed; data are median (min-max) unless otherwise stated. Results: As of 17 February 2021, there were 61.5 (55.5-66.1) months of follow-up post-LentiGlobin infusion in Group A (n=7) and 17.3 (3.7-37.6) months in Group C (n=35). After protocol and manufacturing modifications, median drug product vector copy number (DP VCN) and transduction efficiency were increased in Group C (3.7 c/dg with 80.3% transduced cells) compared with Group A (0.6 c/dg with 27.7% transduced cells). Peripheral blood (PB) VCN stabilized by Month 6 post-infusion and was sustained throughout follow up in both groups; however, the median PB VCN was correspondingly higher in Group C than in Group A (1.45 c/dg vs 0.09 c/dg). A higher DP VCN, %LVV+, and PB VCN in Group C generated increased HbA T87Q of 5.2 (2.6-8.8) g/dL (n=30) compared with HbA T87Q of 0.5 (0.1-1.8) g/dL (n=7) in Group A at Month 6. This was associated with near pancellular expression of HbA T87Q at ≥6 months post-infusion in Group C with a mean of 87% of red blood cells containing β A-T87Q by 18 months (n=14). Group C featured significantly higher median unique insertion sites (UIS) than Group A (p = 1.43 x 10 -12;Fig 1), consistent with increased polyclonality. Critically, median UIS also correlated strongly with PB VCN (Spearman rho = 0.97; Fig 1) and HbA T87Q at Month 6 post-infusion and was associated with improved clinical efficacy in Group C, with complete resolution of severe VOEs and near normal levels of key hemolysis markers. In Group C, the only treatment (tx) emergent serious adverse events (TESAEs) reported in >1 pt were abdominal pain, nausea, opioid withdrawal syndrome, and vomiting (n=2, 5.7% each). No events of malignancy were reported in Group C. One event of sudden death, considered unlikely related to LentiGlobin, occurred >18 months post-tx in a patient with significant baseline SCD-related cardiopulmonary disease. In Group A, the most common TESAE was sickle cell anemia with crisis (n=4, 57%). Two events of acute myeloid leukemia (AML) were reported in Group A pts at 3 and 5 years post-tx, both of which were considered unlikely related to the LVV. Both pts had classic AML driver mutations identified post-diagnosis. One pt died of AML and the second pt is receiving therapy for AML. The modifications made in Group C are anticipated to reduce risk of AML. To monitor safety, BM and PB will be screened for the presence of AML driver mutations prior to treatment, and patients already treated will have regular cytogenetic screening in addition to BB305 LVV integration site analysis. Summary: Alterations to the protocol and manufacturing process in HGB-206 resulted in improved cell dose, transduction efficiency, HbA T87Q expression, and clinical outcomes in Group C compared with Group A. Polyclonality was strongly correlated to PB VCN and HbA T87Q production, indicating that superior engraftment of LVV-transduced cells leads to favorable clinical outcomes. The safety profile post-LentiGlobin for all treated patients with SCD remains generally consistent with the risks of autologous stem cell transplant, myeloablative busulfan conditioning, and underlying SCD. Figure 1 Figure 1. Disclosures Thompson: Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Global Blood Therapeutics: Current equity holder in publicly-traded company. Kwiatkowski: Bluebird Bio: Other: Consultancy Fees; Imara: Other: Consultancy Fees; Celgene: Honoraria; Silence Therapeutics: Honoraria; Agios: Honoraria; ApoPharma: Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Sangamo: Research Funding; Terumo BCT: Research Funding. Aygun: National Heart, Lung, Blood Institute: Research Funding; Global Blood Therapeutics: Consultancy; National Institute of Nursing Research: Research Funding; Patient Centered Outcomes Research Institute: Research Funding; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmidt: GeneWerk GmbH, Heidelberg, Germany: Current equity holder in publicly-traded company; German Cancer Research Center, Heidelberg, Germany: Current Employment. Pierciey: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Whitney: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Rogers: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Nnamani: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Foos: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Miller: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Lynch: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Walters: Vertex pharmaceuticals: Consultancy; Ensoma, Inc.: Consultancy; BioLabs, Inc: Consultancy; AllCells, Inc: Consultancy. Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Bonner: bluebird bio, Inc.: Current Employment, Current equity holder in publicly-traded company.

This analysis aims to describe the outcomes of two nonambulatory patients with Duchenne muscular dystrophy (DMD) who participated in two clinical studies. The two consecutive trials of eteplirsen (studies 201 and 202) were conducted in patients with DMD (N = 12) and confirmed genetic mutations amenable to exon 51 skipping. In study 201, 12 patients were randomized to receive once-weekly, double-blind intravenous infusions of eteplirsen 30 or 50 mg/kg or placebo for 24 weeks; patients then received open-label eteplirsen during weeks 25 through 28. All 12 patients continued onto open-label extension study 202 and received long-term treatment with eteplirsen. We compared cardiac, pulmonary, and upper limb function and dystrophin production in the nonambulatory twin patients versus the 10 ambulatory patients through 240 combined treatment weeks. Ten study patients remained ambulatory through both studies, while the identical twin patients both experienced early, rapid loss of ambulation. The twin patients had greater disease severity at baseline (6-minute walk test [6MWT], 330 and 256 m) versus the other patients (n = 10; 6MWT range, 341–418 m). They maintained cardiac and upper limb function through combined week 240, with outcomes similar to those of the patients who remained ambulatory. Dystrophin production was confirmed following eteplirsen treatment. Despite the loss of ambulation, other markers of disease progression remained relatively stable in the eteplirsen-treated twin patients and were similar to those of the ambulatory patients.