elivaldogene autotemcel

Action and Spectrum

Actions and Spectrum: 

Mechanism of Action: 

• elivaldogene autotemcel utilizes a lentiviral vector, specifically LentiGlobin BB305, to deliver a functional copy of the beta-globin gene into the patient’s hematopoietic stem cells (HSCs). The lentiviral vector is modified to remove the viral genes and incorporates a functional therapeutic gene cassette. The gene cassette contains a modified version of the beta-globin gene, known as the betaA-T87Q-globin gene. 
• Once administered to the patient, the lentiviral vector enters the patient’s HSCs and inserts the betaA-T87Q-globin gene into the genome of the HSCs. The modified beta-globin gene produces a functional beta-globin protein, a crucial component of hemoglobin. 
• elivaldogene autotemcel aims to increase the production of functional hemoglobin, specifically hemoglobin A (HbA), which is deficient in patients with certain hemoglobinopathies. By increasing the production of HbA, elivaldogene autotemcel aims to reduce or eliminate the need for transfusions and alleviate the symptoms associated with these hemoglobinopathies. 

Spectrum of Activity:  

• elivaldogene autotemcel is primarily targeted for treating transfusion-dependent beta-thalassemia and sickle cell disease.  
• These conditions are characterized by genetic mutations that affect the production of functional beta-globin chains, resulting in abnormal hemoglobin production and subsequent symptoms, such as chronic anemia, organ damage, and reduced quality of life. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

During mobilization and conditioning 

Vomiting (72%) 

Catheter site pain (39%) 

Headache (24%) 

Rash (13%) 

Nausea (79%) 

Decreased appetite (42%) 

Constipation (30%) 

Abdominal pain (21%) 

Febrile neutropenia (73%) 

Abdominal pain (33%) 

Decreased appetite (31%) 

Nausea (27%) 

Diarrhea (21%) 

Mucositis (88%) 

Alopecia (72%) 

Vomiting (31%) 

Pyrexia (27%) 

Constipation (21%) 

1 year after treatment 

Seizure (15%) 

Between the start of treatment and 24 months later 

Lymphopenia (100%) 

Neutropenia (96%) 

Nausea (84%) 

Vomiting (76%) 

Leukopenia (100%) 

Thrombocytopenia (100%) 

Mucositis (92%) 

Anemia (84%) 

Febrile neutropenia (73%) 

1-10% 

Between 1 year and 60 days after the treatment 

Vomiting (6%) 

Pyrexia (9%) 

Between 24 months after treatment and  start of conditioning  

Cough (10%) 

Oropharyngeal pain, Grade 3 or more (4%) 

Transfusion reaction, Grade 3 or more (3%) 

Alopecia, Grade 3 or more (1%) 

Vision blurred (10%) 

Epistaxis, Grade 3 or more (7%) 

Abdominal pain, Grade 3 or more (3%) 

Diarrhea, Grade 3 or more (1%) 

Hypertension, Grade 3 or more (1%) 

Black Box Warning

Black box warning: 

Hematologic Malignancy:  

Hematologic malignancies, including life-threatening myelodysplastic syndrome (MDS) cases, have been reported following treatment with elivaldogene autotemcel.  

The diagnosis of these malignancies occurred between 14 months and 7.5 years after treatment, and it appears that cancer development is related to integrating the lentiviral vector, Lenti-D, into proto-oncogenes. 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

None 

Caution: 

• Safety Monitoring: Close monitoring of patients receiving elivaldogene autotemcel is essential to detect and manage potential adverse events or complications.  
• Immune Response: Gene therapies can trigger immune responses, including inflammation or immune reactions against the viral vector or the modified cells.  
• Long-Term Safety: As elivaldogene autotemcel is a relatively new therapy, long-term safety, and efficacy data may still be limited.  
• Malignancy Risk: As mentioned previously, a black box warning is associated with elivaldogene autotemcel regarding the potential development of hematologic malignancies, including myelodysplastic syndrome (MDS).  
• Patient Selection: Careful patient selection is crucial to ensure that the potential benefits of elivaldogene autotemcel outweigh the risks.  

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

Lactation: Excretion of the drug in human breast milk is unknown 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

elivaldogene autotemcel (formerly known as LentiGlobin gene therapy) is a specialized gene therapy product used to treat certain hemoglobinopathies, such as transfusion-dependent beta-thalassemia and sickle cell disease.  

• Gene Transfer: elivaldogene autotemcel involves the transfer of genetic material into the patient’s hematopoietic stem cells (HSCs) using a modified lentiviral vector. The lentiviral vector delivers a functional copy of the beta-globin gene, which is deficient or mutated in patients with hemoglobinopathies. 
• Transduction and Integration: The lentiviral vector used in elivaldogene autotemcel enters the patient’s HSCs and integrates the therapeutic gene into the genome of these cells. This integration allows for sustained production of the functional beta-globin protein. 
• Restoration of Hemoglobin Production: The functional beta-globin protein produced because of gene transfer contributes to the restoration of hemoglobin production. Normal or functional hemoglobin production is impaired in patients with hemoglobinopathies, such as beta-thalassemia or sickle cell disease. elivaldogene autotemcel aims to address this deficiency by increasing the production of functional hemoglobin. 
• Red Blood Cell Improvement: The increased production of functional hemoglobin improves the quality and function of red blood cells. This can result in reduced reliance on transfusions, decreased anemia, and improved overall health outcomes in patients with transfusion-dependent beta-thalassemia and sickle cell disease. 

Pharmacodynamics: 

The pharmacodynamic effects of elivaldogene autotemcel aim to address the underlying genetic defect and restore functional hemoglobin production, thereby alleviating the symptoms associated with certain hemoglobinopathies. 

Pharmacokinetics: 

Absorption 

Gene therapies are typically administered via specific routes, such as intravenous or direct injection, depending on the target cells or tissues. The absorption process may vary depending on the administration method and the specific characteristics of the therapy. 

Distribution 

After administration, the gene therapy product, in this case, elivaldogene autotemcel, is expected to distribute to the target cells or tissues, primarily hematopoietic stem cells (HSCs). The distribution may be influenced by factors such as blood flow, cellular uptake mechanisms, and the presence of specific receptors or transporters. 

Metabolism 

Traditional drug metabolism does not directly apply to gene therapies like elivaldogene autotemcel. However, it’s worth noting that the lentiviral vector used in the therapy may undergo degradation or clearance within the cells over time. 

Elimination and Excretion 

The excretion of gene therapies may not follow the traditional routes of elimination seen with small-molecule drugs. As the genetically modified cells divide and differentiate, the gene therapy product’s effect is sustained within the patient’s body. Clearance of the therapy may occur naturally through cell turnover and elimination of the modified cells over time. 

Adminstartion

Administration: 

elivaldogene autotemcel (formerly known as LentiGlobin gene therapy) is administered through a specialized procedure involving the infusion of genetically modified cells.  

• Collection of Patient’s Hematopoietic Stem Cells (HSCs): Before administering elivaldogene autotemcel, the patient’s HSCs are collected through apheresis. Blood is drawn from the patient during apheresis, and the HSCs are separated and collected. These HSCs will be genetically modified and expanded to produce the therapeutic product. 
• Genetic Modification of HSCs: The collected HSCs are genetically modified using a modified lentiviral vector in a laboratory setting. The lentiviral vector contains the therapeutic gene cassette, which carries the functional copy of the beta-globin gene. The lentiviral vector is designed to deliver the therapeutic gene into the patient’s HSCs. This process is aimed at restoring the production of functional hemoglobin. 
• Conditioning Treatment: Patients may undergo conditioning before administering the genetically modified HSCs. Conditioning treatment typically involves chemotherapy or other treatments to prepare the patient’s bone marrow for the infusion of the modified cells. Conditioning treatment helps create space in the bone marrow and suppresses the patient’s existing hematopoietic system to make room for the infused cells. 
• Infusion of Genetically Modified Cells: Once the patient’s bone marrow is prepared, the genetically modified HSCs are infused back into the patient’s bloodstream through a vein. The infused cells travel to the bone marrow, engrafting and producing functional hemoglobin. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: elivaldogene autotemcel 

Why do we use elivaldogene autotemcel? 

elivaldogene autotemcel (formerly known as LentiGlobin gene therapy) is used for the treatment of certain hemoglobinopathies, specifically transfusion-dependent beta-thalassemia (TDT) and sickle cell disease (SCD). Here are the uses of elivaldogene autotemcel: 

• Transfusion-Dependent Beta-Thalassemia (TDT): elivaldogene autotemcel is used in patients with TDT who require regular blood transfusions to maintain adequate hemoglobin levels. TDT is a genetic disorder characterized by a deficiency in the production of beta-globin chains, resulting in severe anemia.  
• Sickle Cell Disease (SCD): elivaldogene autotemcel is also utilized in patients with SCD. SCD is a genetic disorder characterized by the presence of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells. These cells can cause blockages in blood vessels, leading to pain, organ damage, and other complications.