Betibeglogene autotemcel, sold under the brand name Zynteglo, is a

gene therapy Gene therapy is Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA ...

for the treatment for

beta thalassemia Beta-thalassemia (β-thalassemia) is an genetic disorder, inherited hemoglobinopathy, blood disorder, a form of thalassemia resulting in variable outcomes ranging from clinically asymptomatic to severe anemia individuals. It is caused by reduce ...

. It was developed by

Bluebird Bio bluebird bio, Inc., based in Somerville, Massachusetts, is a biotechnology company that develops gene therapies for severe genetic disorders. The company is owned by investment funds managed by The Carlyle Group and SK Capital Partners. One of ...

and was given

breakthrough therapy Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "b ...

designation by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

in February 2015. The most common adverse reactions include reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia (fever), alopecia (hair loss), epistaxis (nosebleed), abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder and pruritus (itch). It was approved for medical use in the European Union in May 2019, Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. and in the United States in August 2022.

Medical uses

Betibeglogene autotemcel is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of people twelve years and older with transfusion-dependent

who do not have a β0/β0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate but a human leukocyte antigen (HLA)-matched related HSC donor is not available. Betibeglogene autotemcel is made individually for each recipient out of

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...

s collected from their blood, and must only be given to the recipient for whom it is made. It is given as an autologous

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

and the dose depends on the recipient's body weight. Before betibeglogene autotemcel is given, the recipient receives conditioning chemotherapy to clear their

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

of cells ( myeloablation). To make betibeglogene autotemcel, the stem cells taken from the recipient's blood are modified by a virus that carries working copies of the

beta globin Hemoglobin subunit beta (beta globin, β-globin, haemoglobin beta, hemoglobin beta) is a globin protein, coded for by the ''HBB'' gene, which along with alpha globin ( HBA), makes up the most common form of haemoglobin in adult humans, hemoglo ...

gene into the cells. When these modified cells are given back to the recipient, they are transported in the bloodstream to the bone marrow where they start to make healthy red blood cells that produce beta globin. The effects of betibeglogene autotemcel are expected to last for the recipient's lifetime.

Mechanism of action

Beta thalassemia is caused by mutations to or deletions of the HBB gene leading to reduced or absent synthesis of the beta chains of

hemoglobin Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...

that result in variable outcomes ranging from severe

anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

to clinically asymptomatic individuals. LentiGlobin BB305 is a

lentiviral vector A viral vector is a modified virus designed to gene delivery, deliver genetic material into cell (biology), cells. This process can be performed inside an organism or in cell culture. Viral vectors have widespread applications in basic research, ...

which inserts a functioning version of the HBB gene into a recipient's blood-producing

hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the ...

s (HSC)

ex vivo refers to biological studies involving tissues, organs, or cells maintained outside their native organism under controlled laboratory conditions. By carefully managing factors such as temperature, oxygenation, nutrient delivery, and perfusi ...

. The resulting engineered HSCs are then reintroduced to the recipient.

History

In early clinical trials several participants with beta thalassemia, who usually require frequent blood transfusions to treat their disease, were able to forgo blood transfusions for extended periods of time. In 2018, results from phase 1-2 trials suggested that of 22 participants receiving Lentiglobin gene therapy, 15 were able to stop or reduce regular blood transfusions. In February 2021, a clinical trial of betibeglogene autotemcel in

sickle cell anemia Sickle cell disease (SCD), also simply called sickle cell, is a group of inherited haemoglobin-related blood disorders. The most common type is known as sickle cell anemia. Sickle cell anemia results in an abnormality in the oxygen-carrying ...

was suspended following an unexpected instance of

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...

. The HGB-206 Phase 1/2 study is expected to conclude in March 2023. It was designated an

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

(EMA) and by the US

(FDA) in 2013. The

has also declared betibeglogene autotemcel a Regenerative Medicine Advanced Therapy. The safety and effectiveness of betibeglogene autotemcel were established in two multicenter clinical studies that included adult and pediatric participants with ''beta''-thalassemia requiring regular transfusions. Effectiveness was established based on achievement of transfusion independence, which is attained when the participant maintains a predetermined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 participants receiving betibeglogene autotemcel, 89% achieved transfusion independence.

Society and culture

Legal status

It was approved for medical use in the European Union in May 2019, and in the United States in August 2022. On 24 March 2022, the European Commission withdrew the marketing authorisation for Zynteglo at the request of bluebird bio (Netherlands) B.V, for commercial reasons.

Economics

Bluebird bio bluebird bio, Inc., based in Somerville, Massachusetts, is a biotechnology company that develops gene therapies for severe genetic disorders. The company is owned by investment funds managed by The Carlyle Group and SK Capital Partners. One of ...

charges $2.8 million in the United States for a treatment of Zynteglo.

Names

The international nonproprietary name (INN) is betibeglogene autotemcel.

References

{{DEFAULTSORT:Betibeglogene Autotemcel Biotechnology Disorders of globin and globulin proteins Gene delivery Approved gene therapies Hereditary hemolytic anemias Orphan drugs