Acute Chest Syndrome

Studies point to preventive measures and therapies that can set children on a healthier course with lifelong benefits SAN DIEGO, Dec. 9, 2023 /PRNewswire/ -- Researchers report significant progress toward improving access to effective interventions to address blood disorders and promote healthy blood cell functioning in four studies presented during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition. The studies suggest new opportunities to act early in life to achieve lifelong benefits, including in children born with challenging disorders such as sickle cell disease (SCD) and hemophilia. "This research really highlights the importance of early action and prevention," said Sarah O'Brien, MD, of Nationwide Children's Hospital. "From prenatal supplements to optimizing therapies, these findings show ways we can help our young patients be as healthy as possible, which can also improve outcomes with more complex therapies." The first two studies examine life-changing therapies for people living with SCD, an inherited blood disorder that affects the blood's ability to carry oxygen, leading to organ damage and episodes of severe pain called vaso-occlusive crises. One provides new evidence that hydroxyurea, an oral medication widely available in the U.S. and other high-resource countries, is feasible, safe, and effective to administer at optimal doses in Africa, where many people with sickle cell currently lack access to treatment. The other study reports substantial and long-lasting benefits of a gene therapy for SCD, reflected not only in laboratory markers but in significant improvements in quality of life for people living with the disorder. The third study sheds light on how the amount of folic acid, or folate, a developing fetus is exposed to in the womb can affect the system that maintains blood and immune cells in adulthood, with important implications for lifelong health. The fourth study shows that a drug injected subcutaneously can help protect infants born with the bleeding disorder hemophilia from serious complications such as intracranial bleeds. Avoiding such events at an early age can reduce children's chances of permanent brain and tissue damage and potentially set them up to receive the greatest possible benefit from other therapies later in life. Lovo-cel gene therapy shows enduring results in preventing sickle cell pain crises 1051: Efficacy, Safety, and Health-Related Quality of Life (HRQOL) in Patients with Sickle Cell Disease (SCD) Who Have Received Lovotibeglogene Autotemcel (Lovo-cel) Gene Therapy: Up to 60 Months of Follow-up In the longest-running gene therapy trial for SCD to date, researchers report that a vast majority of patients have seen long-lasting, nearly complete resolution of vaso-occlusive events. With up to five years of follow-up and a median follow-up of three years, the new findings bolster evidence that lovo-cel is a safe and effective treatment for SCD. "It is a truly transformative therapy," said Julie Kanter, MD, director of the Adult Sickle Cell Disease Program and professor of Medicine and Pediatrics at University of Alabama, Birmingham, and the study's lead author. "Using gene therapy through lovo-cel, we've been able to essentially rid individuals with SCD of vaso-occlusive events. It results in normal hemoglobin levels and people just feeling amazing." SCD is caused by a gene that results in the production of abnormal hemoglobin, a protein in the red blood cells that carries oxygen. For lovo-cel therapy, stem cells are removed from a patient's bone marrow and a viral vector is used to add a gene to the stem cells that equips them to produce healthy hemoglobin. The modified stem cells are then returned to the bone marrow, where they manufacture blood cells with healthy hemoglobin. Several other gene therapies for SCD are being tested in separate clinical trials. Lovo-cel is the longest running gene therapy trial for SCD to date and the only current trial to use a gene addition therapy rather than gene editing techniques to alter the stem cell genome. The new findings include results from 34 pediatric and adult patients who completed lovo-cel therapy within the past 16 months to five years. Between six and 18 months following their lovo-cel infusion, 88.2% of the patients experienced no vaso-occlusive events at all and 94.1% experienced no severe vaso-occlusive events. By contrast, these patients suffered a median of three severe vaso-occlusive events per year for the two years before they enrolled in the trial. A vast majority of patients showed significant amounts of new, non-sickle hemoglobin (HbAt87Q) induced by the gene therapy, resulting in marked improvements in total hemoglobin, Dr. Kanter reported. "Even more exciting than the laboratory findings, many individuals have also reported significant improvements in terms of pain intensity, fatigue, and the degree to which pain interfered with daily life," said Dr. Kanter. The process of administering lovo-cel requires patients to undergo an autologous stem cell transplant (a transplant that uses a patient's own stem cells instead of those from a donor) and uses conditioning chemotherapy to remove the old bone marrow and prepare the space for the new, modified stem cells. Side effects were common and consistent with conditioning chemotherapy including mouth sores and low blood counts. One patient was diagnosed with a blood cancer known as myelodysplastic syndrome. Scientists determined that the viral vector used for lovo-cel therapy did not cause the disorder; the patient also has not required any blood transfusions or experienced any vaso-occlusive events and continues to receive close monitoring. Overall, the study provides strong evidence that lovo-cel is effective at the genetic level to produce healthy (non-sickled) hemoglobin, reduce hemolysis (cell breakage), improve total hemoglobin, and prevent vaso-occlusive events over an extended period while also improving patient quality of life; however, Dr. Kanter and team cautioned that longer-term data will be needed to determine whether it also helps to prevent stroke, kidney disease, and other longer-term complications of SCD. To reduce health disparities commonly faced by people with SCD, Dr. Kanter added that it will also be important to work to address cost barriers and ensure equitable access to the therapy — as well as continuing care after patients receive it — if the therapy receives approval from the U.S. Food and Drug Administration. "We don't know the long-term effects yet, so we need to make sure that the patients who get this gene therapy also receive ongoing care," said Dr. Kanter. "We also want to make sure that the centers that are performing these therapies really understand SCD and are equipped to take care of people with SCD for the best possible outcomes." Dr. Kanter noted that the study has a relatively small sample size, was not randomized, and did not include people with severe renal disease, heart disease, or severe central nervous system vascular disease. The trial was funded by bluebird bio, developer of lovo-cel. This abstract will be presented by Julie Kanter of the University of Alabama, Birmingham in an oral presentation on Monday, December 11, 2023, at 4:30 p.m. Pacific time in Hall A (San Diego Convention Center). Extended use of hydroxyurea with optimal dosing found to be safe and effective in children with sickle cell anemia in Africa 6: Hydroxyurea Dose Optimization Is Safe and Improves Outcomes for Children with Sickle Cell Anemia Living in Sub-Saharan Africa: The Reach Experience Hydroxyurea is safe, well tolerated, and effective in Africa, according to the latest data from the Realizing Effectiveness Across Continents with Hydroxyurea (REACH) trial. REACH is the largest trial to test hydroxyurea in children anywhere in the world and among the first to test its feasibility in real-world settings in Africa, where children with sickle cell anemia face additional health risks such as malnutrition and malaria that are less prevalent elsewhere. The new data align with findings reported earlier in the study and, now with an average follow-up of over seven years, increase confidence that hydroxyurea treatment can be feasibly maintained in African settings with good safety and efficacy in the long term. In addition, the study underscores the importance of achieving the optimal dose of hydroxyurea, as higher doses lead to the best clinical responses. "It's really exciting to see that the optimal dose is safe and effective," said Banu Aygun, MD, Cohen Children's Medical Center of New York, and the study's lead author. "It suggests that we should advocate for giving the best dose to children living in Africa just like we are doing here in the United States." Newborns are routinely screened for SCD in the United States, where there are currently about 100,000 affected individuals, most of whom have access to treatments such as hydroxyurea, which reduces SCD complications by increasing the production of fetal hemoglobin. In Africa, where it is estimated that over 300,000 babies are born with sickle cell each year, newborn screening programs are just beginning to be established and the vast majority of children do not have access to hydroxyurea treatment. For the REACH trial, researchers worked with local partners in Angola, the Democratic Republic of Congo, Kenya, and Uganda to administer hydroxyurea to a total of 606 children with a genetic subtype of SCD known as sickle cell anemia, 86% of whom still remain on treatment an average of over seven years later. Participants received a low fixed dose of 15 to 20 mg/kg/day initially to ensure safety. Once safety was established, the dosing was raised and then further optimized to allow each patient to receive the highest dose they could tolerate safely. After this optimization process, the average dose reached about 27.5 mg/kg/day, which is similar to the optimal dosage of 25 to 30 mg/kg/day that is standard in the United States. These extended REACH results show both safety and strong efficacy, especially when comparing the optimized dose with the lower initial fixed dose. Laboratory responses including various measures of hemoglobin content in the blood improved with increasing dosage, while the rate of events including vaso-occlusive episodes, acute chest syndrome, enlargement of the spleen, stroke, transfusions, malaria, non-malarial infections, and deaths decreased. There were few safety concerns and a low overall rate of dose-related toxicities. Researchers say hydroxyurea is well suited for use in Africa because it is a daily pill that does not require refrigeration, is relatively inexpensive, and has a long track record of benefits. However, the feasibility of its implementation in Africa was uncertain until this study because of concerns about cost, how well the treatment would work in populations facing risks that have not been previously studied such as malnutrition and high rates of malaria, and whether issues such as lack of transportation, language barriers, and political instability would hinder families' ability to access clinics. Based on the results, researchers say there is now good evidence that hydroxyurea treatment at optimal dosing is feasible and beneficial for children living with sickle cell anemia in Africa. "Many newborn screening programs are coming out [now], and we know for newborn screening programs, it's not enough to diagnose a condition if you can't tie it to a treatment," said Dr. Aygun. "If we are diagnosing children with sickle cell anemia, we have to be able to offer hydroxyurea to them." Banu Aygun of Cohen Children's Medical Center will present this study in the Plenary Scientific Session on Sunday, December 10, 2023, at 2:00 p.m. Pacific time in Hall A (San Diego Convention Center). Researchers trace lifelong impacts of folate deficiency during early development 5: Metabolic Programming of Hematopoietic Stem Cell Function By Prenatal Folate For decades, pregnant women have been advised to consume enough of the B-vitamin folic acid, or folate, to prevent neural tube defects in their babies, and many foods in the U.S. are fortified with folate for this reason. However, there has been little understanding of how folic acid might affect prenatal development in other ways. Now, a new study conducted in mice has uncovered some of the mechanisms by which exposure to too little — or too much — folate in the womb can affect a person's health and susceptibility to disease into adulthood. The study examines the relationship between prenatal folate availability and metabolic programming of hematopoietic, or blood, stem cells (HSCs), the stem cells that give rise to all blood and immune cells in the adult body. When functioning properly, HSCs ensure the body has the right types and amounts of blood and immune cells. "Our study shows how manipulation of nutrients during early development can shape the function of the adult blood system by programming blood stem cells during development," said Brian Krum, MSc, a PhD student at the University of Utah, and the study's lead author. "These changes persist into adulthood where they have permanent effects on the hematopoietic system and also potentially affect immune function and disease risk." Previous studies have shown that folate helps regulate red blood cell production; in adults, low-circulating folate can cause anemia. The new study is the first to examine how folate levels in a pregnant mother affect HSCs in her children. The results reveal that prenatal folate exposure can affect HSCs and their function into adulthood. The researchers assessed HSC function in the offspring of mice that were fed diets that were folate deficient, folate sufficient, or folate supplemented during pregnancy. The results showed that HSCs from adult mice that were exposed to folate deficiency during fetal development had poorer performance in producing all types of blood and immune cells, while those that were exposed to excess folate during development overproduced all the same blood and immune cells. Tracing the metabolic pathways involved, the researchers found evidence that mitochondrial dysfunction was instrumental in driving the effects of folate deficiency on HSCs. Dysregulation of mitochondrial metabolism was evident in HSCs during fetal development and persisted into adult HSCs, suggesting that sustained metabolic defects are a key driver of the underlying dysfunction. For pregnant women, researchers said the findings underscore the need to address folate deficiency, which is common in lower-resourced countries where people may not have access to enough folate-rich foods. While folate deficiency is rare in countries like the U.S. where food is fortified with folate and folic acid supplements are often taken during pregnancy, Krum noted that consuming excess folate may also have implications for blood and immune function. The study findings are also relevant to understanding the interactions between nutrition and anti-folate chemotherapy drugs. Researchers suggested future studies illustrating the metabolic aspects of HSC programming by folate might help identify novel pathways and targets to more selectively target folate metabolism in blood cancers, particularly pediatric leukemias, in order to achieve the best therapeutic benefit while minimizing toxicities. Brian Krum of the University of Utah will present this study during the Plenary Scientific Session on Sunday, December 10, 2023, at 2:00 p.m. Pacific time in Hall A (San Diego Convention Center). Emicizumab found safe and effective for preventing bleeding in infants with Hemophilia A 505: Emicizumab Prophylaxis in Infants with Severe Hemophilia A without Factor VIII Inhibitors: Results from the Primary Analysis of the HAVEN 7 Study In a new study, infants with severe hemophilia A who started receiving emicizumab in the first few months of life experienced few bleeding events, no other serious hemophilia complications, and no serious treatment-related adverse events. Researchers say the results offer reassurance that this hemophilia drug, which was previously tested mostly in older children and adults, is safe and effective for use in infants too. The drug could fill a significant gap for babies born with hemophilia A, who generally cannot receive factor VIII infusions to replace the clotting agent that their bodies do not make naturally, due to challenges with administering regular intravenous infusions in young infants (including challenges with venous access and the need for central venous access devices). Without factor VIII infusions or other therapies, these babies can be vulnerable to uncontrolled bleeding and damage to joints and organs, including bleeding in the brain. "Emicizumab proved to be highly efficacious in these infants in preventing all bleeds, traumatic bleeds, and spontaneous bleeding, and it was well tolerated," said Steven Pipe, MD, of the University of Michigan, the study's lead author. "I think this is going to be adopted broadly [as a prophylactic agent in infants]." Factor VIII infusions are a mainstay of hemophilia A treatment, particularly for stemming severe bleeding or controlling bleeding during surgery. However, these infusions can become less effective if patients develop antibodies that inhibit factor VIII, something that grows more likely with increased exposure to factor VIII. Emicizumab is an effective prophylactic therapy even in the presence of factor VIII inhibitors, Dr. Pipe explained. Since its approval as a first-line hemophilia therapy in 2017, emicizumab has been increasingly adopted as a prophylactic drug to prevent bleeding and reduce the number of factor VIII infusions patients require. Until now, there has been little data on the use of emicizumab in young babies. For the study, researchers administered the drug to 55 infants with hemophilia A starting at a median age of four months and continuing for a median of just under two years and a minimum of one year. After an initial loading period of four weekly injections, parents administered the drug at home via subcutaneous injection every two weeks. Throughout the study, over half of the study participants (54.5%) had no bleeds requiring treatment. All treated bleeding events were related to trauma such as scrapes and falls; no participants had bleeding in the brain or spontaneous bleeds requiring treatment. Laboratory tests showed that most participants were able to maintain therapeutic concentrations of the study drug in their bodies and none developed antidrug antibodies. Adverse events such as fevers and infections were common, which was expected given that infants frequently experience minor illnesses. The only adverse events that were considered treatment-related were low-grade reactions (localized redness of the skin) at the injection site, which occurred in 16.4% of participants and were temporary, said Dr. Pipe. Researchers noted that more research will be needed to gauge any long-term effects of emicizumab use in babies, including whether it helps reduce the use of factor VIII and consequently the development of factor VIII inhibitors. In the meantime, Dr. Pipe suggested that emicizumab represents a good prophylactic option for babies, especially during the first year when administering factor VIII as a prophylactic therapy is often not feasible. "Many people would call this a game-changer as far as clinical practice is concerned," said Dr. Pipe. "If you're a parent of an infant with hemophilia, to have a therapeutic option that you can get your baby started on as soon as possible just provides such reassurance for the family." Steven Pipe, University of Michigan, will present this study in an oral presentation on Sunday, Dec. 10, 2023, at 12:00 noon in room 29 (San Diego Convention Center). ### The American Society of Hematology (ASH) (hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. ASH's flagship journal, Blood (bloodjournal.org) is the most cited peer-reviewed publication in the field, and Blood Advances (bloodadvances.org) is an open-access, online journal that publishes more peer-reviewed hematology research than any other academic journal worldwide. Two new journals will be joining the Blood Journals portfolio in 2024, Blood Neoplasia (bloodneoplasia.org) and Blood Vessels, Thrombosis & Hemostasis (bloodvth.org). Contact: Melissa McGue, ASH, [email protected] Kira Sampson, ASH, [email protected] Brianne Cannon, FleishmanHillard, [email protected] SOURCE American Society of Hematology

SOMERVILLE, Mass.--( BUSINESS WIRE )--bluebird bio, Inc. (NASDAQ: BLUE) (“bluebird bio” or “bluebird”) today announced new and updated efficacy, safety and health-related quality of life (HRQoL) data from the Phase 1/2 HGB-206 Group C and Phase 3 HGB-210 studies of lovotibeglogene autotemcel (lovo-cel) gene therapy for sickle cell disease through five years of follow-up (median 35.5 months, range 0.3-61 months). Data were highlighted in a press briefing at the 65 th American Society of Hematology (ASH) Annual Meeting & Exposition and will be presented in an oral presentation on Monday, December 11, 2023 at 4:30 p.m. Pacific Time. “Years of long-term follow-up continue to suggest that lovo-cel has the potential to address the underlying cause of sickle cell disease and provide robust clinical benefits for patients,” said Richard Colvin, M.D., Ph.D., chief medical officer, bluebird bio. “The data presented at ASH give us confidence that these results can be sustained over time and may translate to meaningful and lasting impact on quality of life for people living with sickle cell disease who need and deserve new treatment options.” The analysis presented at ASH focused on 47 people living with sickle cell disease who received lovo-cel in the HGB-206 Group C and HGB-210 studies following enhancements to the treatment process and manufacturing protocols. Over 85% of patients required ≤2 mobilization cycles prior to infusion. As of the February 13, 2023 cutoff date, all patients had stable production of anti-sickling adult hemoglobin after infusion through last follow-up (median >40% HbA T87Q ), and vaso-occlusive events (VOEs) and severe vaso-occlusive events (sVOEs) were eliminated or significantly reduced in all patients, further suggesting that lovo-cel has shown a durable impact on the underlying cause of sickle cell disease. The majority of adverse events in treated patients were attributed to underlying sickle cell disease or conditioning with busulfan. Lovo-cel is the most deeply studied gene therapy in development for sickle cell disease, with the most patients treated and longest follow-up in the field. As of February 13, 2023, 59 patients were treated across the entire clinical development program with follow-up beyond 8 years in the earliest treated patients. The therapy was approved on December 8, 2023 by the U.S. Food and Drug Administration and is currently marketed as LYFGENIA in the U.S. Updated efficacy data continue to support transformational impact on VOE burden In the studies, VOEs are defined as episodes of acute pain with no medically determined cause other than a vaso-occlusion, lasting more than two hours and severe enough to require care at a medical facility. This includes acute chest syndrome requiring oxygen treatment and/or blood transfusion, acute hepatic sequestration, acute priapism lasting 2 hours and requiring care at a medical facility and acute splenic sequestration. sVOEs require a 24-hour hospital stay or emergency room visit, or at least two visits to a hospital or emergency room over a 72-hour period, with both visits requiring intravenous treatment; all VOEs of priapism are also considered sVOEs. As of February 13, 2023, 34 of the 47 patients treated in HGB-206 Group C and HGB-210 were evaluable for the primary and secondary endpoints of complete resolution of VOEs and sVOEs with a median follow-up 36.3 months (12.1, 61). 32/34 patients (94%) experienced complete resolution of sVOEs, maintained for a median (min, max) of 35.8 months (20.2, 61). 30/34 patients (88.2%) experienced complete resolution of all VOEs, maintained for a median (min, max) of 35.8 months (20.2, 61). Patients who experienced VOEs at any time post-treatment through long-term follow-up (n=8) experienced significant reduction in VOE frequency and severity compared to before treatment. All 8 patients experienced a reduction in VOEs of at least 50%. Hospital days and admissions were reduced by as much as 100% (annualized median hospital days reduced from 15.75 (3.5, 136) pre-treatment to 2.20 (0.0, 25.4); (annualized median reduction in hospital days was 85.5% (31.7%, 100%). Results of a sub-analysis of data from adolescent patients, presented for the first time, showed complete resolution of VOEs and sVOEs in 10/10 (100%) of patients during the 6-18 month enrollment period. “These new data provide further evidence that lovo-cel can provide significant improvements in quality of life for people living with sickle cell disease and that the effects are durable for at least five years,” said Julie Kanter, M.D., a lovo-cel investigator and director of the University of Alabama Birmingham Adult Sickle Cell Clinic and associate professor in the Division of Hematology and Oncology. “We see meaningful changes in hemoglobin, excellent production of anti-sickling hemoglobin, and improvement in all markers of hemolysis which further reinforces the clinical effects of lovo-cel. This one-time, transformative therapy has the potential to target the underlying cause of the disease and reduce both pain and fatigue—outcomes that matter to people living with sickle cell disease and their families. These findings support the positive impact of lovo-cel on the biology of sickle cell disease and on patients’ clinical outcomes and quality of life.” Clinical outcomes were further supported by improvements in total hemoglobin and markers of hemolysis Red blood cells normally break down in the body through a naturally occurring process called hemolysis. In sickle cell disease, hemolysis happens too quickly due to the fragility of sickled red blood cells, resulting in hemolytic anemia. With the exception of patients with alpha-thalassemia trait, all patients had improvement in total hemoglobin and markers of hemolysis; improvements were sustained through last follow-up. As of the February 13, 2023 cut-off date: Following engraftment, non‑transfused total Hb and %Hb fractions stabilized by approximately 6 months after lovo-cel infusion. Median percent of gene-therapy derived anti-sickling adult hemoglobin (HbA T87Q ) was maintained generally at >40% of non-transfused total Hb throughout follow-up. From six months post-infusion through the last visit, several indicators of the health of red blood cells suggest that treatment with lovo-cel improved biological markers for sickle cell disease to normal or near-normal levels. Lactate dehydrogenase and indirect bilirubin levels normalized and reticulocyte counts approached normal levels. The majority of patients experienced sustained improvements in key domains of health-related quality of life measures The burden of sickle cell disease impacts every aspect of patients' lives. Health-related quality of life (HRQoL) findings in patients treated in HGB-206 Group C were generated using the Patient Reported Outcomes Measurement Information System 57 (PROMIS-57), a validated instrument in sickle cell disease. Improvements in key domains including pain interference, pain intensity, and fatigue were demonstrated, showing statistically significant improvements as early as month six which were sustained up to 36 months for pain intensity and 48 months for pain interference and fatigue. These findings provide a broader understanding of the potential impact to daily life over time following treatment with lovo-cel. Safety results summary The majority of adverse events in patients treated in HGB-206 Group C and HGB-210 were attributed to underlying sickle cell disease or conditioning with busulfan. Nonserious adverse events related to lovo-cel included infusion reactions (abdominal discomfort, decreased diastolic blood pressure, and nasal congestion) each in one patient (2.1% each). Serious adverse events related to lovo-cel were reported in two patients with comorbid alpha-thalassemia trait and they included two SAEs each of Anemia (4.3%) and 1 SAE of Myelodysplastic syndrome (2.1%), the diagnosis of which remains under evaluation. One patient died due to sudden cardiac death which was deemed unrelated to lovo-cel. As previously reported, cases of acute myeloid leukemia were observed in two patients from the HGB-206 Group A cohort who were treated with an earlier version of the therapy prior to enhancements to the treatment and manufacturing processes. Both patients died due to aforementioned leukemia. No graft failure, replication-competent lentivirus or vector-mediated insertional oncogenesis was observed across the entire clinical development program. About sickle cell disease Sickle cell disease is a complex and progressive genetic disease associated with debilitating and unpredictable pain crises, anemia, irreversible damage to vital organs, and early death. In SCD, high concentrations of sickle hemoglobin (HbS) in red blood cells (RBCs) cause RBCs to become sickled, sticky, and rigid with a shorter life span, which manifests acutely as hemolytic anemia, vasculopathy, and vaso-occlusion. Pain onset can be sudden and unpredictable, often requiring hospitalization. Fifty to sixty percent of adults with SCD have end organ damage, with 24 percent experiencing damage in multiple organs, and one in four patients have a stroke by the age of 45. The impact of SCD is pervasive and affects every aspect of life for patients and their families and caregivers – from missed work and school, decreased quality of life and mental health, and ability to complete daily tasks. In the U.S., there are approximately 100,000 people living with SCD, and the median age of death is 45 years of age. About LYFGENIA™ (lovotibeglogene autotemcel) or lovo-cel LYFGENIA is a one-time ex-vivo lentiviral vector gene therapy approved for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events (VOEs). LYFGENIA works by adding a functional β-globin gene to patients’ own hematopoietic (blood) stem cells (HSCs). Durable production of adult hemoglobin with anti-sickling properties (HbA T87Q ) is possible following successful engraftment. HbA T87Q has a similar oxygen-binding affinity to wild-type HbA, limits sickling of red blood cells and has the potential to reduce and VOEs. The Phase 1/2 HGB-206 study of LYFGENIA is ongoing with enrollment and treatment complete; and the Phase 3 HGB-210 study evaluating LYFGENIA is ongoing. bluebird bio is also conducting a long-term safety and efficacy follow-up study (LTF-307) for patients with sickle cell disease who have been treated with LYFGENIA in bluebird bio-sponsored clinical studies. Indication LYFGENIA is indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events (VOEs). Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. LYFGENIA has not been studied in patients with more than two α-globin gene deletions. Important Safety Information Boxed WARNING: HEMATOLOGIC MALIGNANCY Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted. Hematologic Malignancy Hematologic malignancy has occurred in patients treated with LYFGENIA (Study 1, Group A). At the time of initial product approval, two patients treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A) developed acute myeloid leukemia (AML). One patient with α-thalassemia trait (Study 1, Group C) has been diagnosed with myelodysplastic syndrome (MDS). The additional hematopoietic stress associated with mobilization, conditioning, and infusion of LYFGENIA, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. Patients treated with LYFGENIA may develop hematologic malignancies and should have lifelong monitoring. Monitor for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment with LYFGENIA, 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. Post-Marketing Long Term Follow-Up Study : Patients who intend to receive treatment with LYFGENIA are encouraged to enroll in the study, as available, to assess the long-term safety of LYFGENIA and the risk of malignancies occurring after treatment with LYFGENIA by calling bluebird bio at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion. Delayed Platelet Engraftment Delayed platelet engraftment has been observed with LYFGENIA. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients (4%) required more than 100 days post treatment with LYFGENIA to achieve platelet engraftment. 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. Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with LYFGENIA. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 10 9 cells/L obtained on different days by Day 43 after infusion of LYFGENIA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with LYFGENIA, provide rescue treatment with the back-up collection of CD34+ cells. Insertional Oncogenesis There is a potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with LYFGENIA. Hypersensitivity Reactions Allergic reactions may occur with the infusion of LYFGENIA. The dimethyl sulfoxide (DMSO) or dextran 40 in LYFGENIA may cause hypersensitivity reactions, including anaphylaxis. Anti-retroviral Use Patients should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. Hydroxyurea Use Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning. Iron Chelation Drug-drug interactions between iron chelators and the mobilization process and myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of mobilization or conditioning. Do not administer myelosuppressive iron chelators (e.g., deferiprone) for 6 months post-treatment with LYFGENIA. Non-myelosuppressive iron chelation should be restarted no sooner than 3 months after LYFGENIA infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate. Interference with PCR-based Testing Patients who have received LYFGENIA are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, patients who have received LYFGENIA should not be screened for HIV infection using a PCR-based assay. Adverse Reactions The most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. Three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A). Pregnancy/Lactation Advise patients of the risks associated with myeloablative conditioning agents, including on pregnancy and fertility. LYFGENIA should not be administered to women who are pregnant, and pregnancy after LYFGENIA infusion should be discussed with the treating physician. LYFGENIA is not recommended for women who are breastfeeding, and breastfeeding after LYFGENIA 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 LYFGENIA 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 LYFGENIA. Advise patients of the options for fertility preservation. Please see full Prescribing Information for LYFGENIA including Boxed WARNING and Medication Guide . About bluebird bio, Inc. bluebird bio is pursuing curative gene therapies to give patients and their families more bluebird days. Founded in 2010, bluebird has been setting the standard for gene therapy for more than a decade—first as a scientific pioneer and now as a commercial leader. bluebird has an unrivaled track record in bringing the promise of gene therapy out of clinical studies and into the real-world setting, having secured FDA approvals for three therapies in under two years. Today, we are proving and scaling the commercial model for gene therapy and delivering innovative solutions for access to patients, providers, and payers. With a dedicated focus on severe genetic diseases, bluebird has the largest and deepest ex-vivo gene therapy data set in the field, with industry-leading 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. bluebird continues to forge new paths as a standalone commercial gene therapy company, 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 . LYFGENIA and bluebird bio are trademarks of bluebird bio, Inc. 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 as statements regarding the therapeutic potential of lovo-cel, including with respect to its durable, one-time transformative, and potentially curative benefits and its impact on quality of life for patients. Such forward-looking statements are based on historical performance and current expectations and projections about bluebird’s future 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 bluebird’s control and could cause bluebird’s future 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 for the year ended December 31, 2022, as updated by its subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. These risks and uncertainties include, but are not limited to: delays and challenges in bluebird’s commercialization and manufacturing of its products; the internal and external costs required for bluebird’s ongoing and planned activities, and the resulting impact on expense and use of cash, has been, and may in the future be, higher than expected which has caused bluebird, and may in the future cause bluebird to use cash more quickly than it expects or change or curtail some of its plans or both; substantial doubt exists regarding bluebird’s ability to continue as a going concern; bluebird’s 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 its assumptions; the risk that the efficacy and safety results from bluebird’s prior and ongoing clinical trials will not continue or be seen in the commercial context; the risk of insertional oncogenic or other safety events associated with lentiviral vector, drug product, or myeloablation; and the risk that lovo-cel will not be successfully 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.

Outcomes-based contract offerings available to both commercial payers and Medicaid LYFGENIA will be available through bluebird’s established national network of Qualified Treatment Centers beginning in Q1 2024 “my bluebird support” patient services program will provide personalized support for patients and their families throughout their treatment journey Price of LYFGENIA reflects its value as a potentially curative gene therapy for sickle cell disease through durable production of anti-sickling adult hemoglobin (HbAT87Q) and resolution of vaso-occlusive events SOMERVILLE, Mass.--(BUSINESS WIRE)-- bluebird bio, Inc. (NASDAQ: BLUE) (“bluebird bio” or the “bluebird”) today announced the details of its U.S. commercial infrastructure to support timely, equitable access to LYFGENIA™ (lovotibeglogene autotemcel, also known as lovo-cel), an FDA-approved gene therapy for the treatment of patients 12 years of age and older with sickle cell disease and a history of vaso-occlusive events (VOEs). The LYFGENIA launch builds on bluebird’s demonstrated success delivering ex vivo gene therapies to patients in the United States and includes outcomes-based contract offerings for payers, as well as a personalized patient support program. “Our approach is built on the principle that timely, equitable access to gene therapy is imperative for people living with sickle cell disease,” said Tom Klima, chief commercial & operating officer, bluebird bio. “As an established commercial gene therapy leader, we believe bluebird is well positioned to partner with providers and payers to deliver LYFGENIA to a community that is long overdue for meaningful treatment advances. The location of our Qualified Treatment Centers and our patient services offering are designed to minimize burdens for patients and their families and caregivers, while our outcomes-based contract offerings have been created specifically to address challenges payers face as they adapt to provide access to one-time, transformative therapies.” Data from clinical studies support LYFGENIA as a potentially curative gene therapy for sickle cell disease through durable production of anti-sickling adult hemoglobin (HbAT87Q) and resolution of vaso-occlusive events. bluebird has set the wholesale acquisition cost of LYFGENIA in the U.S. at $3.1M in recognition of the value the therapy may deliver through robust and sustained clinical benefits and the estimated lifetime impact that reducing or eliminating VOEs may have on patients’ healthcare utilization, future earnings, and life opportunities. The burden of sickle cell disease is immense and can impact every aspect of life for patients and their loved ones. Beyond the debilitating and unpredictable vaso-occlusive events that are most associated with the disease, patients are at risk for irreversible damage to vital organs, diminished quality of life, and early death. Fifty to 60% of adults living with sickle cell disease have end organ damage, and one in four people living with sickle cell disease have a stroke by age 45. Despite a median age of death of 45 years, it is estimated that U.S. patients with frequent VOEs average $4.0 -$6.0 million in direct lifetime medical costs, not including patient-incurred out-of-pocket costs or the impact on caregivers. Patients also forgo approximately $1.3 million in lifetime earnings compared to their peers based on how their disease can limit academic and professional opportunities. Payers Are Anticipated to Enable Timely Access and Reimbursement To support timely and equitable access, bluebird has designed outcomes-based contract options unique to LYFGENIA that offer payers meaningful risk sharing tied to VOE-related hospitalizations—a claims-based metric that is directly correlated with clinical benefit and aligned with study endpoints in the LYFGENIA clinical development program—with patients followed for three years. A second contracting option is available specifically for state Medicaid agencies, based on direct input from these payers that predictability and operational ease are essential for states that are grappling with resource constraints. Both options tie the cost of LYFGENIA to its performance and manage payer risk as clinical experience is translated into the commercial setting. “The FDA approval of a sickle cell disease gene therapy may be a game changer,” said Dr. Shantel Herbert-Magee, Chief Medical Director, Louisiana Medicaid. “Knowing that serious consequences of sickle cell disease can now potentially be averted, there is an expectation for Medicaid programs to provide access to cutting-edge therapies that seemingly have been impenetrable for the disadvantaged and underinsured. Given the vulnerabilities of the Medicaid population, we must not only consider the near-term drug cost but the potential for lower long-term health expenditures. Hence, policymakers are exploring collective approaches to making access less challenging from a fiscal and operational stance, including working with manufacturers on innovative contracts and examining the geographic and provider barriers to the administration of gene therapy. Indisputably, Medicaid is critical to the strategy.” bluebird is in advanced discussions with the nation’s largest commercial payers and more than 15 Medicaid agencies representing 80% of individuals with sickle cell disease in the U.S. Qualified Treatment Centers Are Ready for Patients LYFGENIA will be available through bluebird’s established national network of Qualified Treatment Centers (QTCs), leading healthcare institutions with experience in delivering gene and cell therapies in the commercial setting, beginning in early 2024. One hundred percent of those centers have initiated the activation process for LYFGENIA. Centers will be onboarded to deliver LYFGENIA on a rolling basis. Today, 27 QTCs are ready to receive patient referrals and we anticipate the full network will be fully activated by the end of Q1 2024. Details are available at mybluebirdsupport.com/qualified-treatment-center-locator. my bluebird support Available to Assist Patients and Families Throughout the LYFGENIA Treatment Journey bluebird’s patient support program, my bluebird support, will offer personalized support for each patient/family who enrolls in the program related to all stages of the gene therapy journey—from education and decision-making resources to benefits verification and logistical and financial support for eligible patients. bluebird’s Patient Navigators are experienced professionals with success supporting patients with both commercial and public insurance and are in place now to assist in accessing bluebird’s FDA-approved therapies. Patients can call 833-888-NEST (833-888-6378) or visit mybluebirdsupport.com for more information. LYFGENIA Clinical Data The FDA approval of LYFGENIA builds on decades of research into lentiviral vector gene addition therapy and the largest clinical development program of any gene therapy for sickle cell disease. The label is based on data from patients from the Phase 1/2 HGB-206 study. Safety data supporting the application includes data from 54 patients who initiated stem cell collection. Efficacy for LYFGENIA was supported by data from 36 patients in the Phase 1/2 HGB-206 Group C study following enhancements to the treatment and manufacturing processes made through the course of the clinical development program. 32 patients were evaluable for the endpoints of complete resolution of VOEs and severe VOEs in the 6-18 months post-infusion including 8 adolescent patients. In this cohort: Severe vaso-occlusive events were resolved in 30/32 patients (94%) 28/32 patients (88.2%) experienced no vaso-occlusive events at all In the studies, VOEs are defined as episodes of acute pain with no medically determined cause other than a vaso-occlusion, lasting more than two hours and severe enough to require care at a medical facility. This includes acute chest syndrome requiring oxygen treatment and/or blood transfusion, acute hepatic sequestration, acute priapism lasting 2 hours and requiring care at a medical facility and acute splenic sequestration. sVOEs require a 24-hour hospital stay or emergency room visit, or at least two visits to a hospital or emergency room over a 72-hour period, with both visits requiring intravenous treatment; all VOEs of priapism are also considered sVOEs. The most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. As previously reported, three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure. Please see LYFGENIA Important Safety Information below, including a Boxed Warning for Hematologic Malignancy. Patients treated with LYFGENIA in bluebird bio-sponsored clinical studies will be monitored for a total of 15 years through a long-term safety and efficacy follow-up study (LTF-307). About LYFGENIA™ LYFGENIA is a one-time ex-vivo lentiviral vector gene therapy approved for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events (VOEs). LYFGENIA works by adding a functional β-globin gene to patients’ own hematopoietic (blood) stem cells (HSCs). Durable production of adult hemoglobin with anti-sickling properties (HbAT87Q) is possible following successful engraftment. HbAT87Q has a similar oxygen-binding affinity to wild-type HbA, limits sickling of red blood cells and has the potential to reduce and VOEs. The Phase 1/2 HGB-206 study of LYFGENIA is ongoing with enrollment and treatment complete; and the Phase 3 HGB-210 study evaluating LYFGENIA is ongoing. bluebird bio is also conducting a long-term safety and efficacy follow-up study (LTF-307) for patients with sickle cell disease who have been treated with LYFGENIA in bluebird bio-sponsored clinical studies. Indication LYFGENIA is indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events (VOEs). Limitations of Use Following treatment with LYFGENIA, patients with α-thalassemia trait (α3.7/ α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. LYFGENIA has not been studied in patients with more than two α-globin gene deletions. Important Safety Information Boxed WARNING: HEMATOLOGIC MALIGNANCY Hematologic malignancy has occurred in patients treated with LYFGENIA. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through integration site analysis at Months 6, 12, and as warranted. Hematologic Malignancy Hematologic malignancy has occurred in patients treated with LYFGENIA (Study 1, Group A). At the time of initial product approval, two patients treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A) developed acute myeloid leukemia (AML). One patient with α-thalassemia trait (Study 1, Group C) has been diagnosed with myelodysplastic syndrome (MDS). The additional hematopoietic stress associated with mobilization, conditioning, and infusion of LYFGENIA, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population. Patients treated with LYFGENIA may develop hematologic malignancies and should have lifelong monitoring. Monitor for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment with LYFGENIA, 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. Post-Marketing Long Term Follow-Up Study: Patients who intend to receive treatment with LYFGENIA are encouraged to enroll in the study, as available, to assess the long-term safety of LYFGENIA and the risk of malignancies occurring after treatment with LYFGENIA by calling bluebird bio at 1-833-999-6378. The study includes monitoring (at pre-specified intervals) for clonal expansion. Delayed Platelet Engraftment Delayed platelet engraftment has been observed with LYFGENIA. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients (4%) required more than 100 days post treatment with LYFGENIA to achieve platelet engraftment. 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. Neutrophil Engraftment Failure There is a potential risk of neutrophil engraftment failure after treatment with LYFGENIA. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 109 cells/L obtained on different days by Day 43 after infusion of LYFGENIA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with LYFGENIA, provide rescue treatment with the back-up collection of CD34+ cells. Insertional Oncogenesis There is a potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with LYFGENIA. Hypersensitivity Reactions Allergic reactions may occur with the infusion of LYFGENIA. The dimethyl sulfoxide (DMSO) or dextran 40 in LYFGENIA may cause hypersensitivity reactions, including anaphylaxis. Anti-retroviral Use Patients should not take prophylactic HIV anti-retroviral medications for at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells. Hydroxyurea Use Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning. Iron Chelation Drug-drug interactions between iron chelators and the mobilization process and myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of mobilization or conditioning. Do not administer myelosuppressive iron chelators (e.g., deferiprone) for 6 months post-treatment with LYFGENIA. Non-myelosuppressive iron chelation should be restarted no sooner than 3 months after LYFGENIA infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate. Interference with PCR-based Testing Patients who have received LYFGENIA are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, patients who have received LYFGENIA should not be screened for HIV infection using a PCR-based assay. Adverse Reactions The most common adverse reactions ≥ Grade 3 (incidence ≥ 20%) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. Three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A). Pregnancy/Lactation Advise patients of the risks associated with myeloablative conditioning agents, including on pregnancy and fertility. LYFGENIA should not be administered to women who are pregnant, and pregnancy after LYFGENIA infusion should be discussed with the treating physician. LYFGENIA is not recommended for women who are breastfeeding, and breastfeeding after LYFGENIA 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 LYFGENIA 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 LYFGENIA. Advise patients of the options for fertility preservation. Please see full Prescribing Information for LYFGENIA including Boxed WARNING and Medication Guide. About bluebird bio, Inc. bluebird bio is pursuing curative gene therapies to give patients and their families more bluebird days. Founded in 2010, bluebird has been setting the standard for gene therapy for more than a decade—first as a scientific pioneer and now as a commercial leader. bluebird has an unrivaled track record in bringing the promise of gene therapy out of clinical studies and into the real-world setting, having secured FDA approvals for three therapies in under two years. Today, we are proving and scaling the commercial model for gene therapy and delivering innovative solutions for access to patients, providers, and payers. With a dedicated focus on severe genetic diseases, bluebird has the largest and deepest ex-vivo gene therapy data set in the field, with industry-leading 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. bluebird continues to forge new paths as a standalone commercial gene therapy company, 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. LYFGENIA and bluebird bio are trademarks of bluebird bio, Inc. 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 as statements regarding the therapeutic potential of bluebird’s therapies, the potential for its therapies to have a durable impact on patients, including the potentially curative, sustained lifetime impact LYFGENIA may provide, and the commercialization of LYFGENIA, including without limitation, bluebird’s ability to establish commercial infrastructure to support timely, equitable access to LYFGENIA, its ability to successfully partner with payers, including by executing binding agreements with payers, its expectations on timing for activating QTCs, its expectations on the timing and size of its QTC network and the timing of LYFGENIA’s availability at its QTCs, and the availability of services offered by my bluebird support program to support patient treatment. Such forward-looking statements are based on historical performance and current expectations and projections about bluebird’s future 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 bluebird’s control and could cause bluebird’s future 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 for the year ended December 31, 2022, as updated by its subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. These risks and uncertainties include, but are not limited to: delays and challenges in bluebird’s commercialization and manufacturing of its products; the internal and external costs required for bluebird’s ongoing and planned activities, and the resulting impact on expense and use of cash, has been, and may in the future be, higher than expected which has caused bluebird, and may in the future cause bluebird to use cash more quickly than it expects or change or curtail some of its plans or both; substantial doubt exists regarding bluebird’s ability to continue as a going concern; bluebird’s 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 bluebird’s assumptions; the risk that the efficacy and safety results from bluebird’s prior and ongoing clinical trials will not continue or be seen in the commercial context; the risk that bluebird is not able to activate QTCs on the timeframe that it expects; the risk that the QTCs experience delays in their ability to enroll or treat patients; the risk that bluebird experiences delays in establishing operational readiness across its supply chain following approval to support treatment in the commercial context; the risk that there is not sufficient patient demand or payer reimbursement to support continued commercialization of LYFGENIA; the risk of insertional oncogenic or other safety events associated with lentiviral vector, drug product, or myeloablation; and the risk that LYFGENIA will not be successfully 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.