Findings from clinical studies (N=63) through eight years of long-term follow-up (n=3) continue to support ZYNTEGLO as a potentially curative one-time gene therapy for patients with beta-thalassemia who require regular red blood cell (RBC) transfusions through the achievement of durable transfusion independence and normal or near normal total hemoglobin levels

Detailed investigations affirm that two cases of anemia in patients with sickle cell disease following treatment with lovo-cel in HGB-206 Group C are consistent with alpha-thalassemia trait

Today new and updated data from bluebird bio inc.’s (NASDAQ: BLUE) gene therapy programs in beta-thalassemia and sickle cell disease were presented at the 64^th American Society of Hematology (ASH) Annual Meeting and Exposition. The updated data demonstrate sustained treatment effect in patients treated with betibeglogene autotemcel (beti-cel) and lovotibeglogene autotemcel (lovo-cel) gene therapies through additional follow-up. Case studies of two patients diagnosed with persistent anemia following lovo-cel treatment were also presented. The ASH Annual Meeting is taking place December 10-13, 2022, in New Orleans and virtually.

“In 2014, bluebird bio presented the first data demonstrating the potential of lentiviral vector gene therapy at ASH. Today, with the first FDA approved gene therapy for beta-thalassemia in patients requiring regular red blood cell transfusions, and as we prepare to submit a BLA for lovo-cel for sickle cell disease, we are extremely pleased to be sharing updated data demonstrating the potentially life-changing impact of our programs,” said Richard Colvin, M.D., Ph.D., chief medical officer, bluebird bio. “Long-term results presented at ASH show durable transfusion independence in beta-thalassemia patients treated with beti-cel through eight years of follow-up, as well as sustained treatment effect in patients with sickle cell disease treated with lovo-cel. Additionally, case studies from our lovo-cel clinical program have enhanced the field’s understanding of the mechanism of action of LVV gene therapy and its impact on clinical safety and efficacy.”

Updated data continue to demonstrate sustained treatment effect and quality of life improvements in patients with beta-thalassemia who require regular red blood cell transfusions following treatment with beti-cel

Long-term follow-up data presented at ASH include follow-up for patients living with beta-thalassemia who require regular red blood cell (RBC) transfusions up to 8 years post-treatment (n=3), across ages and genotypes.

As of July 2022, 63 patients received beti-cel across four clinical studies and were followed for a median of 52.0 (20.1–101.7) months. These include two Phase 3 studies (n=41) which led to the U.S. Food and Drug Administration (FDA) approval of ZYNTEGLO as the first and only gene therapy for patients with beta-thalassemia who require regular RBC transfusions in August 2022. In those studies, 90.2% (37/41) of patients achieved transfusion independence (TI). Patients who achieved TI produced normal or near normal levels of total hemoglobin and demonstrated improvements in markers of iron overload and markers of ineffective erythropoiesis.

Patients who achieved TI also showed continued improvement in quality-of-life measures through 3 years following treatment in long-term follow up study, LTF-303. Based on patient testimonials collected at Month 36, the ability to seek employment or be employed increased to 93% of patients (13/14) from 67% (10/15) at baseline. There was also a reduction in school absences compared with baseline (from 95% [18/19] of impacted patients to 50% [5/10]). In addition, 81% (17/21) reported improvement in physical activity at three years, and 100% (20/20) reported an overall benefit from undergoing treatment with beti-cel.

No hematologic malignancies, insertional oncogenesis, vector-derived replication competent lentivirus, or clonal predominance was observed and overall, the safety of the beti-cel treatment regimen largely reflected the known side effects the busulfan conditioning regimen. Nineteen percent (12/63) of patients experienced ≥1 adverse event (AE) considered related or possibly related to beti-cel; the most common beti-cel related AEs were abdominal pain (5/63 [8%]) and thrombocytopenia (3/63 [5%]). Veno-occlusive liver disease, observed in 11% (7/63) of patients, resolved after treatment. One patient who achieved TI required packed red blood cell (pRBC) transfusions for acute events (for surgery, Phase 3, n=1).

The data were presented in Poster #2348: Long Term Outcomes of 63 Patients with Transfusion-Dependent Beta-Thalassemia (TDT) Followed Up to 8 Years Post-Treatment with betibeglogene autotemcel (beti-cel) Gene Therapy and Exploratory Analysis of Predictors of Successful Treatment Outcomes in Phase 3 Trials, and Poster #3665: Long-Term Patient-Reported Outcomes Following Treatment with Betibeglogene Autotemcel in Patients with Transfusion-Dependent Beta-Thalassemia.

New analyses deepen understanding of safety profile for lovo-cel gene therapy in sickle cell disease

Case studies presented at ASH provided detail on investigations into two cases of persistent anemia observed in an adult and pediatric patient in Group C, the pivotal cohort of the HGB-206 study of lovo-cel; data were as of August 2022.

Both patients had two α-globin gene deletions (−α3.7/−α3.7), also known as alpha-thalassemia trait, and notably are the only patients in the study with this specific genotype. Integration site analysis and next-generation sequencing showed no evidence of clonal processes (vector-related or otherwise) and findings are not consistent with an emerging hematologic malignancy. Clinical investigations presented suggest that the alpha-thalassemia trait likely contributed to anemia after lovo-cel infusion. Following these cases, this genotype was added to exclusion criteria for ongoing studies.

“An in-depth analysis of two cases of ineffective erythropoiesis with persistent anemia following lovo-cel treatment reassure that these cases do not have clonal evolution or an emerging malignancy. The working hypothesis is that the anemia is attributable to alpha-thalassemia trait with robust HbA^T87Q production,” said Mark C. Walters, M.D., Jordan Family Director, BMT Program, UCSF Benioff Children’s Hospital Oakland, Oakland, CA.

Updated data from the HGB-206 parent study presented at ASH showed 96% (31/32) of patients treated in Group C experienced complete resolution of severe vaso-occlusive events (sVOE) through 24 months of follow-up; a single sVOE was observed in the adult patient experiencing persistent anemia. As of last follow-up of 24 months, the adult patient is transfusion dependent and experiencing intermittent exacerbations of chronic pain, while the pediatric patient has not required transfusions and remains clinically well.

In Group C of HGB-206, the safety profile of the lovo-cel treatment regimen from Day 1 to Month 24 generally reflects the known side effects of busulfan conditioning regimen, and AEs commonly seen in the population being evaluated. The most frequently reported serious AEs after lovo-cel infusion in two or more HGB-206 Group C patients were pain (11.1%), abdominal pain, anemia, drug withdrawal syndrome (opiate), nausea, suicidal ideation, and vomiting (5.6% each). There have been no cases of veno-occlusive liver disease, graft failure, insertional oncogenesis or replication-competent lentivirus.

The data were presented in Oral #11: lovo-cel (bb1111) Gene Therapy for Sickle Cell Disease: Updated Clinical Results and Investigations into Two Cases of Anemia from Group C of the Phase 1/2 HGB-206 Study​.

Studies evaluating lovo-cel in sickle cell disease represent the most mature sickle cell disease gene therapy dataset in the industry, with the longest available follow-up data. As of August 2022, 50 patients have been treated with lovo-cel across the HGB-205 (n=3), HGB-206 (n=45) and HGB-210 (n=2) clinical studies, with up to 7 years of patient follow-up (median: 37.7 months) representing 176.5 total patient-years of data.

bluebird bio remains on track to submit a biologics license application (BLA) for lovo-cel in Q1 2023.

About ZYNTEGLO® (betibeglogene autotemcel) or beti-cel

ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene therapy approved for the treatment of beta-thalassemia in adult and pediatric patients who require regular red blood cell transfusions. ZYNTEGLO works by adding functional copies of a modified form of the beta-globin gene (β^A-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells to enable the production of a modified functional adult hemoglobin (HbA^T87Q). Once a patient has the β^A-T87Q-globin gene, they have the potential to increase ZYNTEGLO-derived adult hemoglobin (HbA^T87Q) and total hemoglobin to normal or near normal levels that can eliminate the need for regular red blood cell (RBC) transfusions.

Indication

ZYNTEGLO is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions.

Important Safety Information

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with ZYNTEGLO treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100.

Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

Risk of Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with ZYNTEGLO. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells.

Risk of Insertional Oncogenesis

There is a potential risk of LVV mediated insertional oncogenesis after treatment with ZYNTEGLO.

Patients treated with ZYNTEGLO may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted.

In the event that a malignancy occurs, contact bluebird bio at 1 833-999-6378 for reporting and to obtain instructions on collection of samples for testing.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO may cause hypersensitivity reactions, including anaphylaxis.

Anti-retroviral and Hydroxyurea Use

Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed. If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.

Interference with Serology Testing

Patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a false-positive test for HIV. Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR‑based assay.

Adverse Reactions

The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Drug Interactions

Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates.

Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation, when appropriate.

Pregnancy/Lactation

Advise patients of the risks associated with conditioning agents, including on pregnancy and fertility.

ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician.

ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO infusion should be discussed with the treating physician.

Females and Males of Reproductive Potential

A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before ZYNTEGLO administration.

Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of ZYNTEGLO.

Advise patients of the option to cryopreserve semen or ova before treatment if appropriate.

Please see full Prescribing Information for ZYNTEGLO.

About lovotibeglogene autotemcel (lovo-cel; formerly bb1111)

lovotibeglogene autotemcel (lovo-cel) gene therapy is an investigational one-time treatment being studied for sickle cell disease (SCD), 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 (RBCs) can produce anti-sickling hemoglobin (HbA^T87Q) that decreases the proportion of HbS, with the goal of reducing sickled RBCs, hemolysis, and other complications. bluebird bio’s clinical development program for lovo-cel 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 lovo-cel.

The lovo-cel clinical program is currently on a partial clinical hold related to an adolescent patient with persistent, non-transfusion-dependent anemia. The Company remains in active communication with the FDA to resolve the partial clinical hold and resume enrollment and treatment of patients under the age of 18.

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 programs for sickle cell disease, β-thalassemia and cerebral adrenoleukodystrophy and is advancing research to apply new technologies to these and other diseases. 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 largest and deepest ex-vivo gene therapy data set in the world—setting the standard for the 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.

ZYNTEGLO 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, including our statements regarding the timing for a potential BLA submission for lovo-cel and the potential impact of our clinical trial data and findings. 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. These risks include, but are not limited to: the risk that we may not realize expected cost savings from the restructuring, including the anticipated decrease in operational expenses, at the levels we expect; we may encounter additional delays in the development of our programs, including the imposition of new clinical holds or delays in resolving existing clinical holds, that may impact our ability to meet our expected timelines and increase our costs; the internal and external costs required for our ongoing and planned activities, and the resulting impact on expense and use of cash, may be higher than expected which may cause us to use cash more quickly than we expect or change or curtail some of our plans or both; our expectations as to expenses, cash usage and cash needs may prove not to be correct for other reasons such as changes in plans or actual events being different than our assumptions; the risk that the efficacy and safety results from our prior and ongoing clinical trials will not continue or be seen in additional patients treated with our product candidates; the risk that additional insertional oncogenic or other reportable events associated with lentiviral vector, drug product, or myeloablation will be discovered or reported over time; the risk that our eli-cel, beti-cel and lovo-cel programs may be subject to further delays in their development, including but not limited to the imposition of new clinical holds; the risk that lovo-cel may not be approved within the priority review timeframe or at all; and the risk that any one or more of our products and product candidates, including eli-cel, beti-cel or lovo-cel, will not be successfully developed, approved or commercialized. 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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