Betibeglogene autotemcel, sold under the brand name Zynteglo, is a medication for the treatment for

beta thalassemia Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to cl ...

. It was developed by Bluebird Bio 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 " ...

designation by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

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

(TDT) 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 differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of ...

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 nutrie ...

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 tissue found within the 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 is composed of hematopoieti ...

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, hemogl ...

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 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 (HBA1, HBA), makes up the most common form of haemoglobin in adult humans, hemo ...

gene leading to reduced or absent synthesis of the beta chains of

hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...

that result in variable outcomes ranging from severe

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, ...

to clinically asymptomatic individuals. LentiGlobin BB305 is a

lentiviral vector Viral vectors are tools commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism (''in vivo'') or in cell culture (''in vitro''). Viruses have evolved specialized molecul ...

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 very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta withi ...

s (HSC)

ex vivo ''Ex vivo'' (Latin: "out of the living") literally means that which takes place outside an organism. In science, ''ex vivo'' refers to experimentation or measurements done in or on tissue from an organism in an external environment with minimal ...

. 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) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red b ...

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. Sympto ...

. 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 pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment o ...

by the European Medicines Agency (EMA) and by the U.S.

(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 particpiants with beta-thalassemia requiring regular transfusions. Effectiveness was established based on achievement of transfusion independence, which is attained when the particpiant maintains a pre-determined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 particpiants 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.

Names

The international nonproprietary name (INN) is betibeglogene autotemcel.

References

{{DEFAULTSORT:Betibeglogene Autotemcel Biotechnology Breakthrough therapy Disorders of globin and globulin proteins Gene delivery Gene therapy Hereditary hemolytic anemias Orphan drugs