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First gene therapy for β-thalassemia approved Bluebird Bio’s gene therapy eliminates the need for blood transfusions in patients with β-thalassemia.

luebird Bio has been granted the go-ahead to market its gene therapy Bfor the blood disorder β-thalassemia. Zynteglo gained conditional market approval from the European Commission in June to treat transfusion-dependent β-thalassemia in patients 12 years and older who have no other treatment options. The therapy adds a corrective gene whose product combines with α-globin to produce functional hemoglobin, thereby reversing the ineffective red blood cell production seen in β-thalassemia. This potentially curative treatment sped through the regulatory agency to approval, but the steep price tag—€1.6 million ($1.8 million) for a treatment course—could prove burdensome for payers and national healthcare providers seeking options for this relatively common recessive disorder. For patients, however, a one-off, potentially curative treatment could be life changing. The β-hemoglobinopathies, which include β-thalassemia and sickle cell disease, are caused by mutations in the β-globin gene. These gene mutations, of which there are >200 known in the population, result In people with the inherited disorder β-thalassemia, the oxygen-transport protein hemoglobin in red in either abnormal hemoglobin structure blood cells is defective. Credit: nobeastsofierce Science / Alamy Stock Photo or reduced or absent β-globin chains. The clinical manifestations appear several months after birth when gene expression injection (minimum dose 5.0 × 106 cells and were still independent by the end of the switches from the fetal γ-globin chain to per kilogram), after which they engraft study. “Although these are very successful the adult γ-chain that forms hemoglobin in the bone marrow and differentiate into results, we need to better understand the A (HbA). The β-thalassemias vary in red blood cells that produce a therapeutic long-term sustainability of the response,” severity, but patients with the most severe hemoglobin called HbAT87Q. says Maria Domenica Cappellini, a clinician form, β-thalassemia major, rely on monthly The European Commission based its at the University of Milan and the Maggiore red blood cell transfusions to survive. conditional approval on clinical data from Policlinico Hospital, Milan, Italy. Most Repeated transfusions, however, eventually 32 adults and adolescents with transfusion- clinicians, including Cappellini, expect that result in multi-organ damage due to iron dependent β-thalassemia treated with a patient who has been transfusion-free for overload, which needs daily chelation Zynteglo. In two trials now completed, 12 months will remain this way for many therapy. Allogeneic hematopoietic stem 11 out of 14 patients reached the primary years; to confirm this, Bluebird is following cell transplantation is a curative option for endpoint of transfusion independence. patients from the trial for another 13 years. β-thalassemia major, when a suitable donor From two trials that are ongoing, 4 out Zynteglo is not approved for the most is available. An approach like gene therapy of 5 evaluable patients no longer needed severe type of β-thalassemia. This is because, that obviates the need for a matched donor transfusions. “Becoming transfusion- according to data that were not included represents a milestone for the field. independent and stopping iron chelation is in the approval package, five out of eight Zynteglo is an ex vivo gene therapy that really a life-changing treatment for patients,” patients with the severest form (the β0/β0 requires the harvesting of a patient’s bone says trial physician Marina Cavazzana, genotype) treated with Zynteglo had to marrow stem cells by apheresis (at least a hematologist at the Necker Children’s return to blood transfusions. When this 12 × 106 CD34+ cells per kilogram body Hospital and INSERM, Paris, France. “For information became public, Bluebird’s share weight). CD34+ cells are then transduced example, after the therapy, patients were able price crashed. Since then, the company ex vivo with the gene encoding βA-T87Q-globin to take part in physical activity that would has refined its approach. “The trials really via a BB305 lentiviral vector pseudotyped have been impossible before therapy.” helped the field understand some of the with vesicular stomatitis virus glycoprotein G. It’s still early days, though. The limitations of gene addition therapy,” After patients undergo myeloablative approval trials followed patients for only says Stefano Rivella, a pediatrician at the preconditioning with busulfan, the 2 years, and individuals were considered Children’s Hospital of Philadelphia and transduced CD34+ cells containing the transfusion independent if they did not University of Pennsylvania. For the benefit βA-T87Q-globin gene are given in a single need transfusions for 12 months or more to manifest in β0/β0 patients with the most

1102 Nature Biotechnology | VOL 37 | OCTOBER 2019 | 1099–1109 | www.nature.com/naturebiotechnology news severe disease, a higher percentage of blood not require good manufacturing practice activin receptor linked to the Fc portion of cells carrying the transgene sequences was (GMP)-compliant facilities. “The need for human IgG1, are under also investigation. required. Bluebird also had to improve the GMP production is really the bottleneck in These ligand traps act on the transforming expression levels and ensure more than one the whole process,” she adds. growth factor-β (TGFβ) superfamily to vector integrated per genome. Zynteglo is also in trials for sickle cell increase late-stage erythropoiesis. Acceleron Bluebird has used this improved vector disease. Like β-thalassemia, sickle cell disease Pharma’s fusion sotatercept improved design and transduction process for the is a monogenic disorder, characterized by hemoglobin levels and reduced transfusion two ongoing trials, which include patients a single mutation in the β-globin gene, the requirements in an open-label dose- with the most severe genotype. To date, the β S mutation, that results in a single amino finding study in β-thalassemia. And in one evaluable patient achieved transfusion acid substitution at codon 6. The amino acid June, the FDA accepted a biologics license independence. Bluebird intends to use substitution prompts the modified β-globin application from Celgene and Acceleron data from these trials to provide the more chains to form polymers, which make the for luspatercept, a ligand-trap drug to comprehensive benefit–risk data that are red blood cells rigid and prone to occluding treat β-thalassemia and myelodysplastic needed to switch the European Union vasculature. Gene-addition therapies in syndrome–associated anemias. conditional approval to standard marketing sickle cell disease aim to dilute out the “The fact that there are both gene authorization, and for a US Food and defective protein that distorts the red blood therapy and pharmacological drugs is Drug Administration (FDA) filing cells into a sickled shape. Hematopoietic really important,” says Rivella. Drugs such anticipated in 2020. stem cell transplantation from a matched as luspatercept could be enough to stop Another β-globin gene therapy in donor is the only curative therapy, but again transfusions in patients who have a less clinical trials is Orchard Therapeutics’ is not an option for the majority of patients. severe type of β-thalassemia, known as OTL-300, which uses the GLOBE lentiviral Early results from Zynteglo in sickle cell thalassemia intermedia, who still have some vector encoding wild-type β-globin that is trials are promising. In the four patients expression of β-globin. administered by intrabone injection. In its with at least 12 months of follow-up, βA-T87Q- Drugs in the pipeline for sickle cell trial of OTL-300, transfusion requirements derived hemoglobin production increased to disease include Global Blood Therapeutics’ were reduced in the three adult participants, ≥50% of total hemoglobin, and symptoms voxelotor, an oral small-molecule therapy and three out of four pediatric participants such as acute chest syndrome and serious that inhibits hemoglobin polymerization, stopped transfusions. Investigators noted vaso-occlusive crisis were eliminated. Another which is in phase 3 trials. Novartis submitted that a younger age and a higher copy way of diluting out defective hemoglobin is a biologics license application to the FDA number were linked with a better outcome. to use fetal γ-hemoglobin—which has anti- for crizanlizumab, a humanized IgG2 Despite the improvements, clinicians expect sickling properties. Aruvant Sciences’ gene monoclonal antibody against CD62 (also more. “Gene therapy must be a cure,” says therapy RVT-1801, which uses an ex vivo known as P-selectin) that reduces cell–cell Cappellini. “Transfusion reduction could be lentiviral vector to deliver a modified fetal interactions, which is hoped to reduce vaso- achieved with other therapeutic approaches γ-hemoglobin gene to a patient’s purified occlusion. Rivipansel from GlycoMimetics for β-thalassemia that are in ongoing trials.” CD34+ cells, reduced vaso-occlusive crises in and Pfizer, a small-molecule pan-selectin The prospect of disease correction is two treated patients with sickle cell disease. inhibitor based on sialyl Lewis X, however, alluring, but gene therapy carries its own Another genome editing approach is to failed phase 3 trials in August. risks. Before administration of gene therapy, reactivate fetal hemoglobin. This can be Pharmacological therapies may benefit patients undergo grueling chemotherapy achieved by suppressing the expression of patients in lower-income countries or lower- with busulfan to wipe out their own mutant the BCL11a gene, which encodes a protein income populations. Even in higher-income cells and ensure that a high proportion involved in the switch from γ- to β-globin countries, gene therapies are a financial of the gene-modified CD34+ cells engraft in erythroid progenitor cells. CRISPR challenge. Bluebird intends to use a pay- in their bone marrow. Myeloablation Therapeutics and Vertex use CRISPR–Cas9 for-performance plan (Nat. Biotechnol. 37, can cause infertility, and the longer term technology to repress BCL11a in their 697, 2019), with initial payment of €315,000 effects are unknown. New vectors can investigational therapy CTX-001 for sickle ($348,000) and four additional annual help reduce some of the risks and side cell disease and β-thalassemia, whereas payments, each of that amount, provided the effects and improve therapeutic safety. “A Sangamo uses gene editing with zinc-finger therapy continues to be effective—for a total stronger vector that expresses higher levels nuclease technology to make the genetic of €1.58 million ($1.8 million) per patient. of hemoglobin per integration site might be changes in ST400, a therapy in development Karl Claxton, Professor of Economics at able cure the disorder without the need for for β-thalassemia. The first patient treated the University of York and former member complete myeloablation,” says Rivella. with ST400, who had a β0/β0 genotype, did of the United Kingdom’s National Institute Manufacturing this type of product not need transfusions during 5 weeks of for Health and Care Excellence (NICE) for roll-out in the clinic remains a major follow-up. Bluebird is using another method Appraisal Committee, believes this is challenge, something that became apparent to silence BCL11a: a lentiviral vector pricing is overly optimistic. “The company the trials leading up to the approval. Once containing short hairpin RNA (shRNA) as are going to offer some pretty substantial patient cells were harvested, they were an RNA interference gene therapy. With discounts and rebates over and above their sent to a central manufacturing facility for this method, Bluebird reduced BCL11A pay-for-performance model for the therapy enrichment and modification with Zynteglo expression by about 90% and eliminated to be deemed cost-effective by government- before being sent back to the clinical trial irreversibly sickled cells in one patient, provided healthcare systems,” he says. ❐ site.“The requirement for centralizing the according to data presented at the American process is a huge obstacle to the wider use Society of Hematology in 2018. Charlotte Harrison of this gene therapy,” says Cavazzana. To Pharmacological approaches to raise Canterbury, UK try to circumvent this issue, she is working hemoglobin levels are also forging ahead. with industrial partners to develop an Fusion proteins known as ACEs, which Published online: 9 September 2019 on-site automated closed system that does contain the extracellular domain of the https://doi.org/10.1038/d41587-019-00026-3

Nature Biotechnology | VOL 37 | OCTOBER 2019 | 1099–1109 | www.nature.com/naturebiotechnology 1103