Oral presentation of long-term results for betibeglogene autotemcel gene therapy (beti-cel) in adult, adolescent, and pediatric patients with beta-thalassemia who require regular red blood cell transfusions; data for up to seven years follow-up selected for ASH press program

New data and analyses from Groups A & C of the ongoing Phase 1/2 HGB-206 study of LentiGlobin for sickle cell disease gene therapy (bb1111) and sustained improvements in patient-reported quality of life in Group C will be delivered in two oral presentations

bluebird bio, Inc. (Nasdaq: BLUE) today announced that new data from its lentiviral vector (LVV) gene addition programs for patients with β-thalassemia (beta-thal) who require regular red blood cell (RBC) transfusions and sickle cell disease will be presented at the 63^rd American Society of Hematology (ASH) Annual Meeting and Exposition, taking place December 11-14, 2021, at the Georgia World Congress Center in Atlanta, Georgia, and virtually.

bluebird bio will present updated efficacy and safety results from its clinical programs, including long-term follow-up results of betibeglogene autotemcel (beti-cel) that demonstrate iron level stabilization in adult and pediatric patients living with beta-thal who require regular RBC transfusions followed for up to seven years; the oral presentation will also be featured in the ASH press program. Additional beti-cel data include improvement in health-related quality of life among adult and pediatric patients in the HGB-207 and HGB-212 Phase 3 studies.

Updated results from the Phase 1/2 HGB-206 study of LentiGlobin for sickle cell disease gene therapy (bb1111) will also be presented, including new analyses demonstrating improvements in clinical and biologic outcomes, as well as updated and longer-term data from HGB-206 Group C that show sustained improvements in quality of life.

β-Thalassemia Data

Oral Presentation [#573]: Restoring Iron Homeostasis in Patients who Achieved Transfusion Independence After Treatment with Betibeglogene Autotemcel Gene Therapy: Results from up to 7 Years of Follow-up

Presenting Author: Alexis A. Thompson, MD, MPH, Hematology Section Head, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL

Date/Time: Monday, December 13, 2021, 11:00 am ET

Poster [#3085]: Improvement in Health-Related Quality of Life Following Treatment with Betibeglogene Autotemcel in Patients with Transfusion-Dependent β-Thalassemia Enrolled in Phase 3 Studies

Presenting Author: Janet L. Kwiatkowski, MD, MSCE, Director, Thalassemia Center at Children's Hospital of Philadelphia, Philadelphia, PA

Date/Time: Monday, December 13, 2021, 6:00 – 8:00 pm ET

Sickle Cell Disease Data

Oral Presentation [#7]: Sustained Improvements in Patient Reported Quality of Life up to 24 Months Post-treatment with LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Presenting Author: Mark C. Walters, MD, Medical Director, Jordan Family Center for BMT & Cellular Therapies Research, UCSF Benioff Children’s Hospital Oakland, Oakland, CA

Date/Time: Saturday, December 11, 2021, 9:30 am ET

Oral Presentation [#561]: Polyclonality Strongly Correlates with Biological Outcomes and is Significantly Increased Following Improvements to the Phase 1/2 HGB-206 Protocol and Manufacturing of LentiGlobin for Sickle Cell Disease (SCD; bb1111) Gene Therapy

Presenting Author: John F. Tisdale, MD, Chief, Cellular and Molecular Therapeutics Branch, NHLBI, Bethesda, MD

Date/Time: Sunday, December 12, 2021, 5:00 pm ET

Poster [#3093]: Severe Acute Complications of Sickle Cell Disease in two Expert Referral Centers (UK and Italy): Natural History Studies Highlight Ongoing Unmet Need for Effective Disease Modifying or Curative Therapies

Presenting Author: Raffaella Colombatti, MD, PhD, Pediatric Hematologist, University of Padova, Padua, Italy

Date/Time: Monday, December 13, 2021, 6:00 – 8:00 pm ET

Abstracts outlining bluebird bio’s accepted data at ASH are available on the ASH conference website.

About betibeglogene autotemcel (beti-cel)

betibeglogene autotemcel (beti-cel) (pronounced beh TEE cell) is a one-time gene therapy custom-designed to treat the underlying cause of beta-thalassemia in patients who require regular transfusions. In order to correct the deficiency of adult hemoglobin that is the hallmark of beta-thalassemia, beti-cel adds functional copies of a modified form of the β-globin gene (β^A-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells (HSCs). Once a patient has the β^A-T87Q-globin gene, they have the potential to produce HbA^T87Q, which is beti-cel-derived adult hemoglobin (Hb) at levels that may eliminate or significantly reduce the need for transfusions. In beti-cel studies, transfusion independence (TI) is defined as no longer needing RBC transfusions for at least 12 months while maintaining a weighted average Hb of at least 9 g/dL. Across Phase 3 studies, 89% (32/36) of evaluable patients across ages and genotypes, including pediatric patients as young as four years of age and those with the most severe β⁰/β⁰ genotypes, achieved TI.

beti-cel is manufactured using the BB305 lentiviral vector (LVV), a third-generation, self-inactivating LVV that has been studied for more than a decade.

Adverse reactions considered related to beti-cel were uncommon and consisted primarily of infusion-related reactions (abdominal pain, hot flush, dyspnea, tachycardia and non-cardiac chest pain) and cytopenias (thrombocytopenia, leukopenia and neutropenia). Pain in extremity shortly after treatment was also documented. One of these adverse events (AE) was a serious adverse event (SAE) of thrombocytopenia considered possibly related to beti-cel.

The majority of AEs and SAEs unrelated to beti-cel were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan (including several SAEs of veno-occlusive disease). The Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies evaluating beti-cel are ongoing; enrollment is complete, and all patients have been treated. bluebird bio is also conducting a long-term follow-up study, LTF-303, to monitor safety and efficacy for people who have participated in bluebird bio-sponsored beti-cel clinical studies through 15 years, post treatment with beti-cel.

A biologics license application (BLA) for beti-cel has been submitted to the FDA.

About LentiGlobin^® for sickle cell disease (bb1111)

LentiGlobin gene therapy for sickle cell disease (bb1111) is an investigational one-time treatment being studied for sickle cell disease, that is designed to add functional copies of a modified form of the β-globin gene (β^A-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells (HSCs). Once patients have the β^A-T87Q-globin gene, their red blood cells can produce anti-sickling hemoglobin (HbA^T87Q) that decreases the proportion of HbS, with the goal of reducing sickled red blood cells, hemolysis and other complications. bluebird bio’s clinical development program for LentiGlobin for sickle cell disease includes the completed Phase 1/2 HGB-205 and ongoing Phase 1/2 HGB-206 and Phase 3 HGB-210 studies. bluebird bio is also conducting a long-term safety and efficacy follow-up study (LTF-307) for people who have participated in bluebird bio sponsored clinical studies of LentiGlobin for sickle cell disease.

As of February 17, 2021, a total of 49 patients have been treated with LentiGlobin for SCD, with up to 6 years of patient follow-up, in the HGB-205 (n=3), HGB-206 (n=44) and HGB-210 (n=2) clinical studies. The HGB-206 total includes: Group A (n=7), B (n=2) and C (n=35), representing progressive adaptations to the treatment and manufacturing processes. In the Group C cohort of the Phase 1/2 HGB-206 study of LentiGlobin for sickle cell disease, no severe vaso-occlusive events (VOEs) were reported with up to 24 months of follow-up in patients with a history of at least four severe VOEs and at least six months of follow-up.

The safety data profile remains generally consistent with the risks of autologous stem cell transplantation and myeloablative single-agent busulfan conditioning, as well as underlying SCD.

In the Group C cohort of the HGB-206 study, one patient with underlying cardiopulmonary disease and SCD-related complications died 20 months post-treatment; the treating physician and an independent monitoring committee agreed his death was unlikely related to LentiGlobin for SCD.

In the initial cohort (Group A) of the HGB-206 study, two patients treated with LentiGlobin for SCD developed acute myeloid leukemia (AML). After thorough investigations into the cases, bluebird bio determined that these were unlikely related to the insertion of bluebird’s lentiviral vector (LVV) gene therapy for SCD.

For more information on LentiGlobin for SCD studies, visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov.

The FDA has granted orphan drug designation, fast track designation, regenerative medicine advanced therapy (RMAT) designation and rare pediatric disease designation for LentiGlobin for sickle cell disease.

LentiGlobin for sickle cell disease is investigational and has not been approved in any geography.

About bluebird bio, Inc.

bluebird bio is pursuing curative gene therapies to give patients and their families more bluebird days.

With a dedicated focus on severe genetic diseases, bluebird has industry-leading clinical and research programs for sickle cell disease, β-thalassemia and cerebral adrenoleukodystrophy. We custom design each of our therapies to address the underlying cause of disease and have developed in-depth and effective analytical methods to understand the safety of our lentiviral vector technologies and drive the field of gene therapy forward.

Founded in 2010, bluebird has the longest and deepest ex-vivo gene therapy data set in the world—setting the standard for industry. Today, bluebird continues to forge new paths, combining our real-world experience with a deep commitment to patient communities and a people-centric culture that attracts and grows a diverse flock of dedicated birds. ​

For more information, visit bluebirdbio.com or follow us on social media at @bluebirdbio, LinkedIn, Instagram and YouTube.

LentiGlobin and bluebird bio are trademarks of bluebird bio, Inc.

bluebird bio Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect bluebird bio’s business, particularly those identified in the risk factors discussion in bluebird bio’s Annual Report on Form 10-K, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, bluebird bio undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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