Exagamglogene Autotemcel
FDA Drug Information • Also known as: Casgevy
- Brand Names
- Casgevy
- Route
- INTRAVENOUS
- Dosage Form
- INJECTION, SUSPENSION
- Product Type
- CELLULAR THERAPY
Description
11 DESCRIPTION CASGEVY (exagamglogene autotemcel) is a cellular gene therapy consisting of autologous CD34 + HSCs edited by CRISPR/Cas9-technology at the erythroid specific enhancer region of the BCL11A gene to reduce BCL11A expression in erythroid lineage cells, leading to increased fetal hemoglobin (HbF) protein production. CASGEVY is prepared from the patient's own HSCs, which are obtained via apheresis procedure(s). The autologous cells are enriched for CD34 + cells, and then genome edited ex vivo by introducing the CRISPR/Cas9 ribonucleoprotein (RNP) complex by electroporation. The guide RNA included in the RNP complex enables CRISPR/Cas9 to make a precise DNA double-strand break at a critical transcription factor binding site (GATA1) in the erythroid specific enhancer region of the BCL11A gene. As a result of the editing, GATA1 binding is disrupted and BCL11A expression is reduced. This reduction in BCL11A expression conversely results in an increase in gamma-globin expression and downstream fetal hemoglobin formation. The edited CD34 + cells are formulated into a suspension in a sterile cryopreservation medium and cryopreserved. CASGEVY is shipped as a frozen suspension in patient-specific vial(s). The product is thawed prior to infusion and administered as a HSC transplant [see Dosage and Administration (2.2) and How Supplied/Storage and Handling (16) ] . Due to the presence of cells, the thawed product may be clear to slightly cloudy and may contain small inherent proteinaceous particles or visible cell aggregates. The formulation contains 5% dimethyl sulfoxide (DMSO) and dextran 40.
What Is Exagamglogene Autotemcel Used For?
1. INDICATIONS AND USAGE CASGEVY is indicated for the treatment of patients aged 12 years and older with: sickle cell disease (SCD) with recurrent vaso-occlusive crises transfusion-dependent β - thalassemia (TDT) CASGEVY is an autologous genome edited hematopoietic stem cell-based gene therapy indicated for the treatment of patients aged 12 years and older with: sickle cell disease (SCD) with recurrent vaso-occlusive crises (VOCs). ( 1 ) transfusion-dependent β-thalassemia (TDT). ( 1 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION For autologous use only. For intravenous use only. Patients are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34 + cells for CASGEVY manufacturing. ( 2.2 ) Dosing of CASGEVY is based on body weight. The minimum recommended dose is 3 × 10 6 CD34 + cells/kg. ( 2.1 , 2.3 ) Full myeloablative conditioning must be administered between 48 hours and 7 days before infusion of CASGEVY. ( 2.2 ) Prophylaxis for seizures should be considered prior to initiating myeloablative conditioning. ( 2.2 ) Verify that the patient's identity matches the unique patient identification information on the product labels and Lot Information Sheet prior to thaw and infusion. ( 2.2 ) Do not sample, alter, or irradiate CASGEVY. ( 2.2 ) Do not use an in-line blood filter when infusing CASGEVY. ( 2.3 ) Administer each vial of CASGEVY via intravenous infusion within 20 minutes of thaw. ( 2.3 ) 2.1 Dose For autologous use only. For one-time, single dose intravenous use only. The minimum recommended dose of CASGEVY is 3 × 10 6 CD34 + cells/kg. CASGEVY is provided as a single dose for infusion containing a suspension of CD34 + cells in one or more vials. See the Lot Information Sheet provided with the product shipment for additional information pertaining to the number of vials required to achieve the patient-specific dose. Administer all vials. 2.2 Preparation Before CASGEVY Infusion Confirm that hematopoietic stem cell (HSC) transplantation is appropriate for the patient before mobilization, apheresis and myeloablative conditioning are initiated. Screen patients for HIV-1, HIV-2, HBV, HCV, and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. CASGEVY should not be used in patients with active HIV-1, HIV-2, HBV or HCV. Discontinue disease modifying therapies (e.g., hydroxyurea, crizanlizumab, voxelotor) 8 weeks before the planned start of mobilization and conditioning [see Drug Interactions (7.2 , 7.3) ] . Sickle Cell Disease Prior to apheresis it is recommended that patients be transfused with a goal to maintain hemoglobin S (HbS) levels < 30% of total hemoglobin (Hb) while keeping total Hb concentration ≤ 11 g/dL. Transfusion-dependent β-thalassemia Prior to apheresis procedure it is recommended that patients be transfused with a goal to maintain hemoglobin (Hb) ≥ 11 g/dL. Mobilization and Apheresis Patients are required to undergo CD34 + HSC mobilization followed by apheresis to isolate the CD34 + cells needed for CASGEVY manufacturing. Plerixafor and Granulocyte-Colony Stimulating Factor (G-CSF) were used for mobilization in patients with TDT. Single agent plerixafor was used for mobilization in patients with SCD. G-CSF should not be administered for mobilization in patients with SCD. Refer to the prescribing information for the mobilization agent(s) prior to treatment. See Clinical Studies (14) for description of the mobilization regimen...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The most common Grade 3 or 4 non-laboratory adverse reactions (incidence ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and TDT, and decreased appetite in patients with SCD. ( 6 ) The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common Grade 3 or 4 non-laboratory adverse reactions (occurring in ≥ 25%) were mucositis and febrile neutropenia in patients with SCD and patients with TDT, and decreased appetite in patients with SCD. All (100%) of the patients with TDT and SCD experienced Grade 3 or 4 neutropenia and thrombocytopenia. Other common Grade 3 or 4 laboratory abnormalities (≥ 50%) include leukopenia, anemia and lymphopenia. Sickle Cell Disease The safety of CASGEVY in patients with SCD was evaluated in an open-label, single-arm trial (Trial 1) and a long-term follow-up trial (Trial 3), in which 44 adolescent and adult patients with SCD were treated with CASGEVY after undergoing myeloablative conditioning with busulfan. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. The median (min, max) duration of follow-up for 44 patients with SCD after being administered CASGEVY was 19.3 (0.8, 48.1) months. Serious adverse reactions after myeloablative conditioning and CASGEVY infusion were observed in 45% of patients with SCD. The most common serious adverse reactions (≥ 2 patients) were cholelithiasis, pneumonia, abdominal pain, constipation, pyrexia, abdominal pain upper, non-cardiac chest pain, oropharyngeal pain, pain, and sepsis. One (2%) patient died due to a COVID-19 infection and subsequent respiratory failure. The event was not related to CASGEVY. Table 1 presents the Grade 3 or 4 non-laboratory adverse reactions observed after myeloablative conditioning and CASGEVY infusion in at least 10% of patients in Trial 1. Table 2 presents the Grade 3 or 4 laboratory abnormalities that occurred in at least 10% of patients with SCD. Table 1: Grade 3 or 4 non-laboratory adverse reactions in ≥ 10% of patients with SCD who underwent busulfan myeloablative conditioning and received CASGEVY in Trial 1: Day 1 to Month 24 after CASGEVY infusion Table includes adverse events associated with busulfan myeloablative conditioning and treatment with CASGEVY. Adverse event profile generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. System organ class, preferred term Patients with SCD (Trial 1) (N=44) n (%) Blood and lymphatic system disorders Febrile neutropenia 21 (48) Gastrointestinal disorders Mucositis Mucositis includes mucosal inflammation, pharyngeal inflammation, and stomatitis. , Encompasses preferred terms that belong to other system organ class. 38 (86) Abdominal pain Abdominal pain includes abdominal pain and abdominal pain upper. 5 (11) Hepatobiliary disorders Cholelithiasis 5 (11) Metabolism and nutrition disorders Decreased appetite 18 (41) Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain includes back pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, and pain in extremity. , 6 (14) Skin and subcutaneous tissue disorders Pruritus 5 (11) Other clinically important adverse reactions that occurred in less than 10% of patients or were Grade 1 or Grade 2 include the following: Hepatobiliary disorders : Veno-occlusive liver disease (1 [2%] patient). Infusion-related...
Drug Interactions
7 DRUG INTERACTIONS No formal drug interaction studies have been performed. CASGEVY is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters. Granulocyte-Colony Stimulating Factor: Granulocyte-Colony Stimulating Factor (G-CSF) must not be used for CD34 + HSC mobilization of patients with SCD. ( 7.1 ) Hydroxyurea: Discontinue hydroxyurea at least 8 weeks prior to start of mobilization and conditioning. ( 7.2 ) Voxelotor and Crizanlizumab: Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilization and conditioning. ( 7.3 ) Iron Chelators: Discontinue iron chelators at least 7 days prior to initiation of myeloablative conditioning. Avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. ( 7.4 ) 7.1 Use of Granulocyte-Colony Stimulating Factor (G-CSF) Granulocyte-Colony Stimulating Factor (G-CSF) must not be used for CD34 + HSC mobilization of patients with SCD. 7.2 Use of Hydroxyurea Discontinue the use of hydroxyurea at least 8 weeks prior to start of each mobilization cycle and conditioning. There is no experience of the use of hydroxyurea after CASGEVY infusion. 7.3 Use of Voxelotor and Crizanlizumab Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilization and conditioning, as their interaction potential with mobilization and myeloablative conditioning agents is not known. 7.4 Use of Iron Chelators Discontinue the use of iron chelators at least 7 days prior to initiation of myeloablative conditioning, due to potential interaction with the conditioning agent. Some iron chelators are myelosuppressive. If iron chelation is required, avoid the use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after CASGEVY infusion. Phlebotomy can be used instead of iron chelation, when appropriate. 7.5 Live Vaccines The safety of immunization with live viral vaccines during or following CASGEVY treatment has not been studied.
Contraindications
4 CONTRAINDICATIONS None. None. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary There are no clinical data from the use of exagamglogene autotemcel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with exagamglogene autotemcel to assess whether it can cause fetal harm when administered to a pregnant woman. CASGEVY must not be administered during pregnancy because of the risks associated with myeloablative conditioning. Pregnancy after CASGEVY infusion should be discussed with the treating physician. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING CASGEVY is supplied in one or more vials containing a frozen suspension of genome edited autologous CD34 + cells in a cryopreservation medium containing 5% DMSO and dextran 40. CASGEVY is stored in the vapor phase of liquid nitrogen and is shipped from the manufacturing facility to the treatment center storage facility in a cryoshipper. CASGEVY is supplied in vial(s) packaged in carton(s). One carton contains a single lot of CASGEVY consisting of 1 to 9 vials. A single dose of CASGEVY may consist of multiple CASGEVY lots, and therefore may consist of multiple cartons. A Lot Information Sheet listing the total dose of CASGEVY is affixed inside the shipper. NDC 51167-290-09 Match the identity of the patient with the patient identifiers on each carton, vial, and Lot Information Sheet upon receipt. Store the vial(s) in the vapor phase of liquid nitrogen at ≤ -135 °C (≤ -211 °F) until ready for thaw and administration. Thaw CASGEVY prior to administration. Thaw and infuse one vial of CASGEVY at a time [see Dosage and Administration (2.2 , 2.3) ] . Once thawed, CASGEVY must be administered within 20 minutes [see Dosage and Administration (2.2 , 2.3) ] . Do not re-freeze CASGEVY after thawing. Do not irradiate CASGEVY.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.