Gene therapy developer bluebird bio has faced significant challenges since the company’s founding in 2010. Product development hurdles and access challenges impacted their first European launch and were followed by financial troubles forcing bluebird to lay off 30% of its staff in April of this year. But bluebird may be turning the corner, with recent approvals by the FDA for two of its rare disease therapeutics. Now the company faces the test of whether it can successfully market its effective, but expensive treatments in the United States in the face of reimbursement challenges and looming competition from other gene therapy companies, as well as from effective new medicines.
Bluebird’s focus is in developing treatments for rare, severe, genetic diseases with limited or no treatment options. All of bluebird’s products are ex vivo therapies whereby a functional gene intended to replace a missing or faulty one is added in the laboratory to a patient’s hematopoetic stem cells (HSCs) using a lentiviral vector. The modified cells are then transplanted back into the patient. While bluebird’s therapeutics are designed as one-time administrations, the treatment process is complex, typically taking several months, and must be performed in a center that is experienced in ex vivo gene and cell therapies.
The company’s flagship therapeutic is betibeglogene autotemcel (beti-cel), branded as Zynteglo. Beti-cel is a treatment for adult and pediatric patients with beta thalassemia, who require regular red blood cell (RBC) transfusions every two to five weeks, the result of a faulty beta-globin gene. Such transfusions lead to iron overload, the need for chelation therapy, and the risk of organ damage and other complications. Beti-cel works by adding functional copies of a gene for a modified form of beta-globin into a patient’s HSCs, ultimately allowing the patient’s RBCs to make normal to near-normal levels of hemoglobin. The treatment has been shown to be highly effective, with 90% of those treated in two Phase 3 trials no longer in need of transfusions.
The road to success for beti-cel has been a rocky one, however, first marked by manufacturing delays and commercialization setbacks in Europe, and then by regulatory delays in the United States after the FDA extended the PDUFA date to further scrutinize the data relating to the lentiviral vector used in bluebird’s gene therapies. Beti-cel was approved in Europe in 2019 and was priced at close to 1.58 million Euros (about US $1.8 million) over five years, a price unacceptable to European payers. As a result, bluebird pulled the treatment from the market in 2021.
Now bluebird is focusing its efforts exclusively in the United States. In June 2022, the FDA Advisory Committee that reviewed the license application for beti-cel unanimously recommended the gene therapy’s approval, saying that the efficacy data was outstanding, especially since the ability to become independent from transfusions is likely life-changing for patients with beta thalassemia. The FDA granted marketing approval to beti-cel on August 20 as Zynteglo, the third gene therapy to receive U.S. approval after Novartis’ Zolgensma (Onasemnogene abeparvovec) for spinal muscular atrophy and Spark Therapeutics’ Luxturna (Voretigene neparvovec) for an inherited retinal disease, Leber congenital amaurosis (LCA)
Bluebird has priced beti-cel at $2.8 million with a single upfront payment and further outcomes-based payments. Moreover, the company will reimburse payers up to 80% of the cost if a treated patient fails to achieve and maintain transfusion independence for at least two years following therapy. Analysts estimate there are approximately 1,500 U.S. patients who could qualify for treatment, and they predict peak sales of $64 – $200 million. Bluebird is currently working with payers with respect to reimbursement and is preparing to bring treatment centers online, with the goal of collecting patients’ cells by Q4 2022 and starting the first beti-cel treatments in early 2023.
Despite their regulatory success, bluebird bio may still face further challenges in the form of market competition for beti-cel in the near future. CRISPR Therapeutics and Vertex are in late Phase 3 development of their own hemoglobin-targeted gene therapy, exagamglogene autotemcel (exa-cel). Using a different treatment strategy from beti-cel, exa-cel increases the production of fetal hemoglobin, which is not impacted by the disease-causing mutations, and is being developed as a therapy for both beta thalassemia and severe sickle cell disease (SCD). CRISPR Therapeutics and Vertex plan to submit a Biologics License Application to the FDA before the end of 2022.
Eli-cel (elivaldogene autotemcel) is bluebird’s second gene therapy product, branded as Skysona. In September 2022, the FDA granted an accelerated approval to eli-cel for the treatment of cerebral adrenoleukodystrophy (CALD), a progressive genetic disease that leads to the destruction of myelin and results in a rapid loss of neurological function and typically death within five years of symptom onset in untreated patients.
CALD affects about 1 in 5,000 to 1 in 17,000 newborns, primarily boys, with about 40 new patients diagnosed in the United States each year. Until now, the only treatment for CALD has been stem cell transplant from a genetically matched donor. However, fewer than 30% of patients diagnosed with CALD have such a donor available. For this reason, eli-cel received unanimous recommendation for approval from its FDA Advisory Committee in June, despite that 3 of 67 treated patients developed myelodysplastic syndrome (MDS), a bone marrow neoplasm, within two years. Concern for MDS did, however, cause the FDA to grant an accelerated, rather than full, approval of eli-cel, which means that bluebird must conduct a long-term confirmatory trial, with treated patients monitored for 15 years. Simultaneously with the approval, the FDA lifted the clinical hold that had paused further trials of eli-cel since August 2021.
Bluebird has set the wholesale price of eli-cel at $3 million with no outcomes-based payment program, which the company says could be too challenging to implement both for bluebird and for payers due to the rarity and complexity of CALD. The company expects to launch the product by the end of 2022.
Bluebird’s third advanced gene therapy is lovo-cel (lovotibeglogene autotemcel) for the treatment of severe SCD. Like beti-cel, lovo-cel is designed to add functional copies of a modified beta-globin gene into a patient’s own hematopoietic stem cells, thus enabling the red blood cells to produce normal hemoglobin. Decreasing the proportion of abnormal hemoglobin is expected to reduce the number of sickled RBCs, leading to less anemia and reduction of other complications associated with SCD. There are an estimated 100,000 patients with SCD in the United States, with the condition affecting 1 in 365 among the black population and 1 in 16,300 in the hispanic population.
Results of clinical trials to date have shown lovo-cel to be highly effective, eliminating the most serious complications of SCD for as long as six years post-treatment in some patients. However, the therapy has faced multiple clinical delays that have impacted its development. One trial was temporarily suspended when two treated patients developed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The suspension was dismissed when it was determined that the neoplasias were unrelated to the gene therapy. More recently, a partial clinical hold was placed on patients under age 18 in an ongoing Phase 3 trial of lovo-cel, to investigate a case of persistent, non-transfusion-dependent anemia in one patient. The clinical trial and a long-term follow up study continue to enroll and treat adult patients with SCD, and bluebird is in active discussions with the FDA to lift the clinical hold in patients under age 18. The company has stated that despite the partial clinical hold, it expects to complete a BLA filing for lovo-cel in Q1 of 2023.
Lovo-cel, if approved, could face significant market competition. In addition to the SCD gene therapy under development by CRISPR and Vertex, a number of other treatments have reached the market or are in late stages of development to reduce the frequency of SCD crises and risk of complications. One example is Global Blood Therapeutics’ Oxbryta (voxelator), an oral hemoglobin S polymerization inhibitor that prevents RBCs from sickling. In early August, Pfizer announced plans to acquire Global Blood Therapeutics for $5.4 billion to enhance its presence in rare disease hematology.