Exagamglogene Autotemcel: prescribing information – dosing, contraindications, interactions, side effects

β-thalassemia

Casgevy is indicated for the treatment of transfusion-dependent β-thalassemia (TDT) in patients 12 years of age and older for whom haematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen (HLA)-matched related HSC donor is not available.

Sickle cell disease

Casgevy is indicated for the treatment of severe sickle cell disease (SCD) in patients 12 years of age and older with recurrent vaso-occlusive crises (VOCs) for whom haematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen (HLA)-matched related HSC donor is not available.

Casgevy must be administered in an authorised treatment centre by a physician with experience in HSC transplantation and in the treatment of patients with β-haemoglobinopathies and trained for administration and management of patients treated with the medicinal product.

Before mobilisation, apheresis and myeloablative conditioning are initiated, confirm that haematopoietic stem cell transplantation is appropriate for the patient.

Posology

Casgevy is intended for autologous use (see section 4.4).

Treatment consists of a single dose containing a dispersion for infusion of viable CD34+ cells in one or more vials.

The minimum recommended dose of Casgevy is 3 × 106 CD34+ cells/kg of body weight.

See the accompanying Lot information sheet (LIS) for additional information pertaining to dose.

Mobilisation and apheresis

Patients are required to undergo CD34+ HSPC mobilisation followed by apheresis to isolate the CD34+ cells for medicinal product manufacturing.

Maximise CD34+ cell collection for product manufacturing during each mobilisation and apheresis cycle. Perform two consecutive days of cell collection for product manufacturing per cycle, if clinically tolerated. A total collection target of at least 20 × 106 CD34+ cells/kg is recommended for product manufacture. Collected cells should be sent for product manufacturing even if the total collection target is not achieved. In addition, at least 2 × 106 CD34+ cells/kg are required to be collected for back-up unmodified rescue cells. A third day of cell collection can be used to obtain back-up rescue cells, if needed.

If the minimum dose of Casgevy is not met after initial medicinal product manufacturing, the patient will need to undergo additional cycles of mobilisation and apheresis to obtain more cells for additional product manufacture. Each mobilisation and apheresis cycle must be separated by a minimum of 14 days.

The back-up collection of ≥ 2 × 106 CD34+ cells/kg of unmodified rescue cells must be collected from the patient and be cryopreserved prior to myeloablative conditioning and infusion with Casgevy.

The unmodified cells may be needed for rescue treatment under any one of the following conditions:
compromise of Casgevy after initiation of myeloablative conditioning and before Casgevy infusion;
neutrophil engraftment failure; or loss of engraftment after infusion with Casgevy.

See section 5.1 for a description of the mobilisation regimen used in the clinical study. Refer to the Summary of Product Characteristics for the mobilisation medicinal product(s) prior to treatment with Casgevy.

β-thalassemia
Prior to apheresis procedure it is recommended that patients receive red blood cell (RBC) transfusion(s) with a goal to maintain total haemoglobin (Hb) concentration ≥ 11 g/dL.

Sickle cell disease
Prior to apheresis it is recommended that patients receive RBC exchange or simple transfusion(s) with a goal of maintaining haemoglobin S (HbS) levels < 30% of total Hb while keeping total Hb concentration ≤ 11 g/dL.

Disease modifying therapies (e.g., hydroxyurea/hydroxycarbamide, crizanlizumab, voxelotor) must be discontinued 8 weeks before the planned start of mobilisation and conditioning.

Granulocyte colony stimulating factor (G-CSF) must not be administered for mobilisation in patients with sickle cell disease.

Pre-treatment conditioning

Full myeloablative conditioning must be administered before infusion of Casgevy. Conditioning must not be initiated until the complete set of vials constituting the full dose of Casgevy has been received at the authorised treatment centre, and the availability of the back-up collection of unmodified CD34+ cells is confirmed. See section 5.1 for a description of the conditioning regimen used in the clinical study. Refer to the Summary of Product Characteristics for the myeloablative conditioning medicinal product(s) prior to treatment.

β-thalassemia
It is recommended that patients maintain total Hb concentration ≥ 11 g/dL for 60 days prior to myeloablative conditioning.

Sickle cell disease
It is recommended that patients receive RBC exchange or simple transfusion(s) for at least the 8 weeks prior to the initiation of myeloablative conditioning with a goal of maintaining HbS levels < 30% of total Hb while keeping total Hb concentration ≤ 11 g/dL. At initiation of red blood cell exchanges or simple transfusions, discontinue disease modifying therapies (e.g., hydroxyurea/hydroxycarbamide, crizanlizumab, voxelotor).

Iron chelation therapy must be stopped at least 7 days prior to myeloablative conditioning.

Prophylaxis for seizures should also be considered. Refer to the Summary of Product Characteristics for the myeloablative conditioning medicinal product used for information on drug interactions.

Prophylaxis for hepatic veno-occlusive disease (VOD)/hepatic sinusoidal obstruction syndrome should be considered, per institutional guidelines.

Prior to starting the myeloablative conditioning regimen, confirm availability of the complete set of vials constituting the dose of Casgevy, and unmodified rescue cells. See the Lot information sheet (LIS) provided with the product shipment for confirmation of the number of vials and total dose of Casgevy.

Pre-medication

It is recommended that pre-medication with paracetamol and diphenhydramine, or equivalent medicinal products, be administered per institutional guidelines, before the infusion of Casgevy, to reduce the possibility of an infusion reaction.

Special populations

Patients aged 35 years and older

Casgevy has not been studied in patients > 35 years of age. The safety and efficacy of Casgevy in this population has not been established. The benefit of treatment in individual patients should be considered against the risks of HSC transplantation.

Renal impairment

Casgevy has not been studied in patients with renal impairment, defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2. No dose adjustment is required.

Hepatic impairment

Casgevy has not been studied in patients with hepatic impairment. No dose adjustment is required.

Paediatric population

The safety and efficacy of Casgevy in patients < 12 years of age have not been established. No data are available.

Patients seropositive for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)

Casgevy has not been studied in patients with HIV-1, HIV-2, HBV, or HCV. Perform screening for HIV-1, HIV-2, HBV, and HCV and any other infectious agents in accordance with local guidelines before collection of cells for manufacturing. Casgevy must not be used in patients with active HIV-1, HIV-2, HBV or HCV.

Patients with prior HSC transplant

Casgevy has not been studied in patients who have received a prior allogeneic or autologous HSC transplant. Treatment with Casgevy is not recommended in these patients.

Method of administration

Casgevy is for intravenous use only.

After completion of the myeloablative conditioning regimen, a minimum of 48 hours must elapse before Casgevy infusion. Casgevy must be administered between a minimum of 48 hours and a maximum of 7 days after the last dose of myeloablative conditioning.

Before thawing and administration, it must be confirmed that the patient's identity matches the unique patient information on the Casgevy vial(s) and accompanying documentation. The total number of

vials must also be confirmed with patient specific information on the Lot information sheet (LIS) (see section 4.4).

Casgevy is administered as an intravenous bolus via a central venous catheter. Casgevy infusion must be completed as soon as possible and no more than 20 minutes after thawing. In the event that more than one vial is provided, all vials must be administered. The entire volume of each vial must be infused.

For detailed instructions on preparation, administration, measures to take in case of accidental exposure and disposal of Casgevy, see section 6.6.

After Casgevy administration

Standard procedures for patient monitoring and management after HSC transplantation must be followed after Casgevy infusion, including monitoring of complete blood counts and transfusion needs.

Blood products required within the first 3 months after Casgevy infusion must be irradiated.

Restarting iron chelation after Casgevy infusion may be necessary. 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 in lieu of iron chelation, when appropriate (see section 4.5).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Contraindications to mobilisation and myeloablative conditioning medicinal products must be considered.

Summary of the safety profile

The safety of Casgevy was evaluated in two open-label, single-arm studies (study 111 and study 121) and one long-term follow-up study (study 131), in which 97 adolescent and adult patients with TDT or SCD were treated with Casgevy.

Treatment with Casgevy was preceded by peripheral blood mobilisation with granulocyte colony-stimulating factor (G-CSF) and plerixafor in patients with TDT and plerixafor only in patients with SCD, followed by apheresis and myeloablative conditioning with busulfan.

The safety profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant after mobilisation and apheresis.

The median (min, max) duration of follow-up after being administered Casgevy was 22.8 (2.1, 51.1) months for patients with TDT (N=54), and 17.5 (1.2, 46.2) months for patients with SCD (N=43).

Serious adverse reactions attributed to Casgevy occurred in 2 (3.7%) patients with TDT:
1 (1.9%) patient with haemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, idiopathic pneumonia syndrome, and headache; 1 (1.9%) patient with delayed engraftment and thrombocytopenia. No patient with SCD had serious adverse reactions attributed to Casgevy.

A life-threatening serious adverse reaction of cerebellar haemorrhage occurred in 1 (1.9%) patient with TDT and was attributed to busulfan myeloablative conditioning.

One (2.3%) patient with SCD died due to a COVID-19 infection and subsequent respiratory failure.
The event was not related to Casgevy.

Tabulated list of adverse reactions

Adverse reactions are listed by MedDRA body system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10) and common (≥ 1/100 to < 1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Tables 1, 2, 3, and 4 are lists of adverse reactions attributed to mobilisation/apheresis with G-CSF and plerixafor, mobilisation/apheresis with plerixafor only, myeloablative conditioning with busulfan, and Casgevy, respectively, experienced by patients with TDT and SCD in clinical studies with Casgevy.

Table 1: Adverse reactions attributed to mobilisation/apheresis in patients with TDT receiving G-CSF and plerixafor (N=59) System organ class (SOC) Very common Common Blood and lymphatic system disorders

Leukocytosis, thrombocytopenia
Metabolism and nutrition disorders

Hypokalaemia
Nervous system disorders
Headache

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain
Gastrointestinal disorders
Nausea
Abdominal pain, vomiting, diarrhoea, oral hypoaesthesia
Musculoskeletal and connective tissue disorders
Musculoskeletal pain *

General disorders and administration site conditions

Pain, pyrexia
* Musculoskeletal pain included back pain, bone pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, pain in extremity.

Table 2: Adverse reactions attributed to mobilisation/apheresis in patients with SCD receiving plerixafor (N=58) System organ class (SOC) Very common Common Blood and lymphatic system disorders

Sickle cell anaemia with crisis
Metabolism and nutrition disorders

Hyperphosphataemia, hypomagnesaemia
Nervous system disorders
Headache

Respiratory, thoracic and mediastinal disorders

Acute chest syndrome
Gastrointestinal disorders
Abdominal pain *, nausea,
Vomiting
Diarrhoea
Musculoskeletal and connective tissue disorders
Musculoskeletal pain †
Arthralgia
General disorders and administration site conditions

Pain, fatigue
* Abdominal pain included abdominal pain upper.
† Musculoskeletal pain included back pain, bone pain, chest pain, neck pain, non-cardiac chest pain, and pain in extremity.

Table 3: Adverse reactions attributed to myeloablative conditioning with busulfan in patients with TDT and SCD (N=97) * System organ class (SOC) Very common Common Infections and infestations

Pneumonia, sepsis, klebsiella sepsis, oral candidiasis, folliculitis
Blood and lymphatic system disorders
Thrombocytopenia, febrile neutropenia, neutropenia, anaemia, lymphopenia †, leukopenia Pancytopenia, reticulocytopenia, splenomegaly Metabolism and nutrition disorders Decreased appetite, hypokalaemia, hyperphosphataemia, hypomagnesaemia, fluid retention, hypophosphataemia Hypoalbuminaemia, hypocalcaemia Nervous system disorders Headache Cerebellar haemorrhage, hydrocephalus, peripheral sensory neuropathy, peripheral neuropathy, neuralgia, dysgeusia Eye disorders

Vision blurred, dry eye
Cardiac disorders

Tachycardia
Vascular disorders

Hypotension, hot flush
Respiratory, thoracic and mediastinal disorders
Epistaxis, oropharyngeal pain
Respiratory failure, idiopathic pneumonia syndrome, hypoxia, dyspnoea, cough
Gastrointestinal disorders
Mucositis ‡, nausea, vomiting, abdominal pain §, diarrhoea, constipation, gastritis Colitis, dyspepsia, gingival bleeding, gastrooesophageal reflux disease, haematemesis, oesophagitis, dysphagia, gastrointestinal inflammation, haematochezia, mouth ulceration Hepatobiliary disorders Veno-occlusive liver disease, hyperbilirubinaemia, alanine aminotransferase increased Aspartate aminotransferase increased, hepatomegaly, gamma-glutamyltransferase increased

System organ class (SOC)
Very common
Common
Skin and subcutaneous tissue disorders
Pigmentation disorder #, skin exfoliation, alopecia, petechiae, dry skin, rash ** Pruritus, erythema Musculoskeletal and connective tissue disorders Musculoskeletal pain †† Arthralgia Renal and urinary disorders

Dysuria, haematuria
Reproductive system and breast disorders

Amenorrhoea, intermenstrual bleeding, vulvovaginal pain, dysmenorrhoea, menstruation irregular, premature menopause General disorders and administration site conditions Pyrexia, fatigue Pain Investigations Weight decreased International normalised ratio increased, C-reactive protein increased, weight increased Injury, poisoning procedural complications

Delayed engraftment, subcutaneous haematoma, skin abrasion, skin laceration
* Frequency is based on the highest incidence from study 111 in patients with TDT or from study 121 in patients with SCD.
† Lymphopenia included CD4 lymphocytes decreased and lymphocyte count decreased.
‡ Mucositis included anal inflammation, mucosal inflammation, pharyngeal inflammation, and stomatitis.
§ Abdominal pain included abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and epigastric discomfort.
# Pigmentation disorder included nail pigmentation, skin hyperpigmentation, and skin hypopigmentation.
** Rash included dermatitis, rash erythematous, rash macular, rash maculo-papular, and rash papular.
†† Musculoskeletal pain included back pain, bone pain, chest pain and pain in extremity.

Table 4: Adverse reactions attributed to Casgevy in patients with TDT and SCD (N=97) * System organ class (SOC) Very common Common Blood and Lymphatic system disorders Lymphopenia †, ‡ Thrombocytopenia †, neutropenia †, anaemia †, leukopenia † Immune system disorders

Haemophagocytic lymphohistiocytosis
Metabolism and nutrition disorders

Hypocalcaemia †
Nervous system disorders

Headache †, paraesthesia
Cardiac disorders

Tachycardia †
Respiratory, thoracic and mediastinal disorders

Acute respiratory distress syndrome, idiopathic pneumonia syndrome †, epistaxis † Skin and subcutaneous tissue disorders

Rash †, §, petechiae †
General disorders and administration site conditions

Chills †, pyrexia †
Injury, poisoning and procedural complications

Delayed engraftment †, infusion related reactions #
* Frequency is based on the highest incidence from study 111 in patients with TDT or from study 121 in patients with SCD.
† At least one event was also attributed to busulfan myeloablative conditioning.
‡ Lymphopenia included CD4 lymphocytes decreased and lymphocyte count decreased.
§ Rash included dermatitis.
# Infusion related reactions included chills, sinus tachycardia, and tachycardia.

Description of selected adverse reactions

Platelet engraftment

Platelet engraftment was defined as 3 consecutive measurements of platelet counts ≥ 20 × 109/L in patients with TDT and 3 consecutive measurements of platelet counts ≥ 50 × 109/L in patients with SCD, obtained on 3 different days after Casgevy infusion without administration of platelet transfusions for 7 days. All patients achieved platelet engraftment.

In study 111, the median (min, max) time to platelet engraftment in patients with TDT was 44 (20, 200) days (n=53), with one remaining patient achieving platelet engraftment after the time of the interim analysis. The median (min, max) time to platelet engraftment was 45 (20, 199) days in adolescent patients and 40 (24, 200) days in adult patients. Patients without a spleen had an earlier median time to platelet engraftment than patients with an intact spleen. Median (min, max) time to platelet engraftment was 34.5 (20, 78) days in patients without a spleen and 46 (27, 200) days in patients with an intact spleen.

In study 121, the median (min, max) time to platelet engraftment for patients with SCD was 35 (23, 126) days (n=43). The median (min, max) time to platelet engraftment was 44.5 (23, 81) days in adolescent patients and 32 (23, 126) days in adult patients.

There was no association observed between bleeding events and time to platelet engraftment after Casgevy treatment.

Neutrophil engraftment

Neutrophil engraftment was defined as 3 consecutive measurements of absolute neutrophil count (ANC) ≥ 500 cells/µL on 3 different days after Casgevy infusion, without use of the unmodified rescue CD34+ cells. All patients achieved neutrophil engraftment, and no patients received rescue CD34+ cells.

In study 111, the median (min, max) time to neutrophil engraftment in patients with TDT was 29 (12, 56) days (n=54). The median (min, max) time to neutrophil engraftment was 31 (19, 56) days in adolescent patients and 29 (12, 40) days in adult patients.

In study 121, the median (min, max) time to neutrophil engraftment in patients with SCD was 27 (15, 40) days (n=43). The median (min, max) time to neutrophil engraftment was 28 (24, 40) days in adolescent patients and 26 (15, 38) days in adult patients.

There was no association observed between infections and time to neutrophil engraftment.

Paediatric population

The safety of Casgevy was evaluated in 31 adolescent patients aged 12 to less than 18 years with TDT or SCD. The median (min, max) age of adolescent TDT patients was 14 (12, 17) years, and for SCD patients was 15 (12, 17) years. The median (min, max) duration of follow-up was 19.6 (2.1, 26.6) months for adolescent TDT patients and 14.7 (2.5, 18.7) months for adolescent SCD patients. The safety profile was generally consistent among adolescent and adult patients. Engraftment times were similar in adolescent and adult patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Warnings and precautions of mobilisation and myeloablative conditioning medicinal products must be considered.

Traceability

The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after expiry date of the medicinal product.

Autologous use

Casgevy is intended solely for autologous use and must not under any circumstances be administered to other patients. Casgevy must not be administered if the information on the product labels and Lot information sheet (LIS) does not match the patient’s identity.

Transmission of an infectious agent

Although Casgevy is tested for sterility, mycoplasma and endotoxins, a risk of transmission of infectious agents exists. Healthcare professionals administering Casgevy must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.

Hypersensitivity reactions

There is a potential for hypersensitivity reactions with Casgevy, including due to Cas9. Serious hypersensitivity reactions, including anaphylaxis may occur due to dimethyl sulfoxide (DMSO) or dextran 40 in Casgevy. Patients should be observed closely during and after infusion. Vital signs (blood pressure, heart rate, and oxygen saturation) and the occurrence of any symptoms should be monitored prior to the start of the infusion, and approximately every 30 minutes from when the first vial of Casgevy is infused until 2 hours after the last vial of Casgevy is infused.

Potential neutrophil engraftment failure

Neutrophil engraftment failure is a potential risk in haematopoietic stem cell transplant, defined as not achieving neutrophil engraftment after Casgevy infusion and requiring use of unmodified rescue CD34+ cells. Patients must be monitored for absolute neutrophil counts (ANC) and infections must be managed according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, patients must be infused with rescue CD34+ cells (see section 4.8).

Delayed platelet engraftment

Longer median platelet engraftment times have been observed with Casgevy treatment compared to allogeneic HSC transplantation. There is an increased risk of bleeding until platelet engraftment is achieved.

Patients should be monitored for bleeding according to standard guidelines and medical judgement.
Frequent platelet counts must be conducted until platelet engraftment and platelet recovery are achieved. Blood cell count determination and other appropriate testing must be performed whenever clinical symptoms suggestive of bleeding arise (see section 4.8).

Risk of insufficient mobilisation/apheresis in patients with SCD

Patients with SCD may require more cycles of mobilisation and apheresis compared to patients with TDT and are at higher risk of failure of sufficient mobilisation/apheresis. See section 4.2 for the recommended total CD34+ cell collection target. See section 5.1 for information regarding the average number of cycles of mobilisation and apheresis, and overall discontinuation rates.

Gene-editing related oncogenesis

No cases of myelodysplasia, leukaemia, or lymphoma have been reported in clinical studies with Casgevy. There is a theoretical risk of oncogenesis related to gene editing. Patients should be monitored at least annually (including complete blood count) for 15 years after treatment with Casgevy. If myelodysplasia, leukaemia, or lymphoma are detected, the local representative of the Marketing Authorisation Holder should be contacted to determine appropriate samples for analysis.

The risk of unintended, off-target editing in an individual’s edited CD34+ cells cannot be ruled out. A search spanning the human genome identified off-target editing at a single variant site. The variant was identified in 3.3% (3/91) of patient samples analyzed (edited CD34+ cells). The currently

identified off-target site is located in an intron of a gene not expressed in haematopoietic cells so no adverse effects are expected (see section 5.3).

Immunogenicity

No immune-mediated reactions were observed in clinical studies with Casgevy. It is unknown whether pre-formed antibodies to Cas9 including following recent Streptococcus pyogenes infection could result in immune-mediated reactions and/or clearance of cells with residual Cas9.

Blood, organ, tissue, and cell donation

Patients treated with Casgevy must not donate blood, organs, tissues, and cells for transplantation.

Long-term follow-up

Patients must be monitored annually (including complete blood counts) according to standard guidelines and medical judgement. Patients are expected to be enrolled in a long-term follow-up scheme in order to better understand the long-term safety and efficacy of Casgevy.

Sodium content

This medicinal product contains 5.3 mg to 70 mg sodium in each vial. This is equivalent to 0.3 to 4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

The drug-drug interaction of mobilisation and myeloablative conditioning medicinal products must be considered.

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.

Use of hydroxyurea/hydroxycarbamide must be discontinued at least 8 weeks prior to start of mobilisation and conditioning. There is no experience on the use of hydroxyurea/hydroxycarbamide after Casgevy infusion.

Discontinue the use of voxelotor and crizanlizumab at least 8 weeks prior to start of mobilisation and conditioning, as their interaction potential with mobilisation and myeloablative conditioning medicinal products is not known.

Iron chelators must be discontinued at least 7 days prior to initiation of myeloablative conditioning, due to potential interaction with the conditioning medicinal product. Some iron chelators are myelosuppressive. 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.

Live vaccines

The safety of immunisation with live viral vaccines during or following Casgevy treatment has not been studied. As a precautionary measure, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of the conditioning regimens, during Casgevy treatment, and until haematological recovery following treatment.

Women of childbearing potential/Contraception in males and females

A negative serum pregnancy test must be confirmed prior to the start of each mobilisation cycle and re-confirmed prior to myeloablative conditioning. There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with Casgevy. Women of childbearing potential and men capable of fathering a child must use effective method of contraception from start of mobilisation through at least 6 months after administration of myeloablative conditioning. Please also refer to the Summary of Product Characteristics for the myeloablative conditioning medicinal product.

Pregnancy

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 foetal harm when administered to a pregnant woman. It is not known whether exagamglogene autotemcel has the potential to be transferred to the foetus. Casgevy must not be administered during pregnancy because of the risk associated with myeloablative conditioning.
Pregnancy after Casgevy infusion should be discussed with the treating physician (see guidance on contraception, above).

Breast-feeding

It is unknown whether exagamglogene autotemcel is excreted in human milk or transferred to the breast-feeding child. There are no data available.

Refer to the Summary of Product Characteristics of the mobilisation and myeloablative conditioning medicinal product(s) for guidance on their use during breast-feeding. Because of the potential risks associated with myeloablative conditioning, breast-feeding should be discontinued during conditioning.

The decision to breast-feed after Casgevy treatment should be discussed with the treating physician, taking into account the benefit of breast-feeding for the child versus any potential adverse events from Casgevy or from the underlying maternal condition.

Fertility

There are no data on the effects of exagamglogene autotemcel on human fertility. Effects on male and female fertility have not been evaluated in animal studies. Data are available on the risk of infertility with myeloablative conditioning. It is therefore advised to consider fertility preservation options such as cryopreservation of semen or ova before treatment if possible.

Casgevy has no influence on the ability to drive or use machines.

The effect of mobilisation and myeloablative conditioning medicinal products on the ability to drive or use machines must be considered.

Not applicable.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other haematological agents, other haematological agents, ATC code: B06AX05

Mechanism of action

Casgevy is a cell therapy consisting of autologous CD34+ HSPCs ex vivo edited by CRISPR/Cas9-technology. The highly specific guide RNA enables CRISPR/Cas9 to make a precise DNA double-strand break at the 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 irreversibly disrupted and BCL11A expression reduced. Reduced BCL11A expression results in an increase in γ-globin expression and foetal haemoglobin (HbF) protein production in erythroid cells, addressing the absent globin in transfusion-dependent β-thalassemia (TDT) and the aberrant globin in sickle cell disease (SCD), which are the underlying causes of disease. In patients with TDT, γ-globin production is expected to correct the α-globin to non-α-globin imbalance, thereby reducing ineffective erythropoiesis and haemolysis and increasing total haemoglobin levels. In patients with severe SCD, HbF expression is expected to reduce intracellular HbS concentration, preventing the red blood cells from sickling.

Clinical efficacy and safety

The efficacy of Casgevy was evaluated in adolescent and adult patients with transfusion-dependent β-thalassemia (TDT) or sickle cell disease (SCD) in two open-label, single-arm studies (study 111 and study 121) and one long-term follow-up study (study 131).

Transfusion-dependent β-thalassemia

Study 111 is an ongoing open-label, multicentre, single-arm study to evaluate the safety and efficacy of Casgevy in adult and adolescent patients with transfusion-dependent β-thalassemia. After completion of 24 months of follow-up in study 111, patients were invited to enrol in study 131, an ongoing long-term safety and efficacy study.

Patients were eligible for the study if they had a history of requiring at least 100 mL/kg/year or 10 units/year of RBC transfusions in the 2 years prior to enrolment. Patients were also required to have a Lansky or Karnofsky performance score of ≥ 80%.

Patients were excluded from the study if they had an available HLA-matched related HSC donor.
Patients who had severely elevated iron in the heart (i.e., patients with cardiac T2* less than 10 msec by magnetic resonance imaging [MRI]), or advanced liver disease were excluded from the study. MRI of the liver was performed on all patients. Patients with MRI results demonstrating liver iron content ≥ 15 mg/g underwent liver biopsy for further evaluation. Patients with a liver biopsy demonstrating bridging fibrosis or cirrhosis were excluded.

Of the 59 patients who initiated mobilisation in study 111, 3 patients (5.1%) discontinued prior to Casgevy infusion, all due to withdrawn consent.

The key demographics and baseline characteristics are shown in Table 5 for (1) all patients enrolled in study 111 and (2) all patients infused with Casgevy in study 111.

Casgevy is an autologous cellular therapy medicinal product consisting of CD34+ cells that have been edited ex vivo by CRISPR/Cas9. The nature of Casgevy is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.